Abstract
Objective: To observe the clinical efficacy and safety of the traditional Chinese medicine (TCM) mixture Yingliu combined with methimazole medication for the treatment of Graves disease (GD). Method: In a randomized, paralleled control study, 92 GD patients were randomized into a Yingliu mixture treatment and a control treatment group, both receiving methimazole. Both treatments lasted for 12 weeks and outcome parameter were thyroid function, thyroid autoantibodies, TCM symptome scores and safety indicators. Results: The clinical efficiency of the Yingliu mixture-methimazole combination was 92.5% vs. 82.5% (P < 0.05) of the solely methimazole medication group. After 12 weeks treatments the Yingliu mixture in combination with methimazole improved free triiodothyronine (FT3), free tetraiodothyronine (FT4), thyroid-stimulating hormone (TSH) receptor antibody (TRAb) and thyroglobulin antibody (TGAb) values significantly more than methimazole alone and TCM symptome scores were significant lower after 12 week treatment in the Yingliu mixture- methimazole group (P < 0.05). The thyroid enlargement (21 vs. 10, P < 0.05), fatigue (39 vs. 30, P < 0.01) and dry mouth symptoms (37 vs. 29, P < 0.05) were superior improved in the Yingliu than in the control medication group, respectively. There was no significant difference regarding safety evaluations between both treatment groups (P = 0.499). Conclusion: Yingliu mixture as combined medication with methimazole can significantly improve the outcome of a solely methimazole application for GD treatments.
Keywords: Graves disease, Yingliu mixture, methimazole, TCM
Introduction
With the improvements of diagnostic technologies in recent years, the detection of hyperthyroidism has increased and GD as the most common type accounts for about 85% of hyperthyroidism cases [1]. GD is a kind of autoimmune disorder of unknown etiology, which occurs in any age but is more common in women than in men [2]. Its prominent clinical appearances of hyperthyroidism were accompanied by diffuse goiter, exophthalmos and pretibial myxedema. However, most of the patients have only 1 or 2 of the above visible symptoms, but with noticeable enhanced metabolism and involvement of the nervous and cardiovascular systems. Hyperthyroidism, if not treated actively, will cause damage to multiple systems, such as cardiovascular (hyperthyroidism heart disease), nervous, blood, musculoskeletal, digestive and reproductive systems [3].
At present, Yingliu treatments for GD mainly include anti-thyroid drugs, radioactive iodine and surgery [4], which all have drawbacks, such as long Yingliu treatment period (an average of 18 to 24 months), high recurrence rates (50%) [5], drug-induced liver damage [6], lack of granulocytes, skin rashes and antithyroid drug (ATD)-induced antineutrophil cytoplasmic antibody (ANCA) associated vasculitis [7]. Other effects are hypothyroidism and cancer after radioactive iodine Yingliu treatments [8].
Clinical studies have shown that TCM for the Yingliu treatment of GD has certain beneficial effects like improving symptoms of hyperthyroidism, reducing side effects of western medicine, lowering recurrence rates and shortening the disease course [3].
According to many years of clinical observation in our department, we think TCM influences GD by eliminating phlegm, promoting blood flow and resolving masses as the basic therapeutic principle. The Yingliu mixture is a domestic preparation of our hospital derived from long-term clinical observations and mainly used for goiter Yingliu treatments. In this study, we analyzed the efficiency of Yingliu mixture Yingliu treatment as combination with methimazole medication.
Patients and methods
Patients
The study has been approved by the ethical committee of the Longhua hospital shanghai University of TCM and written informed consent of all participating patients was provided. Ninety-two eligible GD patients who were hospitalized or in outpatient service of the endocrinological department of the Longhua Hospital affiliated to Shanghai University of TCM between April 2011 and March 2013 and met the inclusion criteria were included and randomly divided into Yingliu treatment and control treatment groups.
Diagnostic criteria of GD
TCM diagnosis criteria: Primary symptoms: swelling in the front of the neck, fatigue, and dry mouth and thirsty. Secondary symptoms: patient cannot stand heat and hydrosis, chest tightness, too much phlegm, heart palpitations, upset and irritability, insomnia and much dream, polyphagia and weight loss, dry eye and blurred vision, facial ecchymosis. Tongue picture: dark tongue with petechia or red tongue with teeth marks, thin and greasy fur or less fur or thin, white and dry fur. Pulse condition: slippery, thin or tart pulse. Patients, who met three primary symptoms and two secondary symptoms or above, combined with indicated tongue and pulse conditions, which was verified by two experienced medical doctors, were suspected with GD.
Further diagnoses included (1) symptoms of hyperthyroidism; (2) diffuse enlargement of the thyroid gland (confirmed by ultrasound or palpation); (3) decrease of TSH levels, increase of thyroid hormone levels; (4) exophthalmos; (5) pretibial mucous edema; (6) positive for TRAb or thyroid stimulating hormone receptor antibody (TSAb). Goitre was confirmed by palpation and thyroid enlargement was classified as I degree when not visible but palpable; II degree when visible and palpable, but within the sternocleidomastoid area; III degrees when extended beyond the outer edge of the sternocleidomastoid [9].
Inclusion and exclusion criteria
In inclusion criteria included diagnosed GD, age between 18 to 70 years old and informed consent. Exclusion criteria were GD without goitre, pregnancy or breast feeding; patients with the leukemia, aplastic anemia, leukopenia (white blood cell count lower than 3.0×109/l), granulocytopenia syndrome (neutrophilvalue less than 1.5×109/l) and cardiovascular, liver, kidney or other primary diseases and mental illness. Other exclusion criteria were hyperthyroidism crisis, significantly enlarged thyroid resulting in compression of adjacent organs, all kinds of thyroiditis but without hyperthyroidism; allergic constitution with allergic to a variety of drugs, having taken anti-thyroid drugs in the recent three months, level of alanine amino transferase (ALT) before Yingliu treatment 2 times higher than upper normal limit.
Reasons for preterm trial termination
The clinical trial should be stopped according to the doctor’s judgment of aggravation of illness or other symptoms that can confound the observation of GD. Serious adverse reactions or drug allergy. The drugs lack efficacy or liver damage (ALT more or equal than 2 times the normal limit, white blood cells lower than 2.5×109/l, neutrophils less than 1.×109/l, after the drug use. No adverse drug events occurred, but the Yingliu treatment was discontinued for other reasons (for example, some other disease occurred and the Yingliu treatment had to be interrupted). The patients were the opinion that the drug is ineffective and gave up participating in the trial.
Methods
Experimental drug, dosage and course of Yingliu treatment
Both groups received 5 mg-25 mg/d methimazole (thyrozol) (based on the levels of T3, T4, TSH and the blood index) for 12 weeks. The Yingliu mixture was prepared by the TCM laboratory of the Longhua Hospital (approval number Shanghai Z05170226).The decoction has been prepared with oysters, radix astragali, radix ophiopogonis, smilax, radix scrophulariae, rhizoma anemarrhenae, prunella vulgaris, forsythia, alisma plantago-aquatica, white mustard seed, semen impatientis, thunberg fritillary bulb and 25 ml were administered 3 times a day.
Observation index and methods
The blood serum levels of FT3, FT4, TSH, TRAb, thyroid peroxidase antibodies (TPOAb) and TGAb were analyzed prior as well as 6 and 12 weeks after Yingliu treatment using electrochemiluminescence (E 170 module immunology analyzer, Roche, Germany). Hepatorenal functions were measured with the automatic biochemical analyzer, Roche DB-001 instrument (Roche Co., Shanghai, China). Routine blood and blood cell analysis was performed with a Beckman Coulter LH750 hematology analyzer (Beckman Coulter Inc. Fullerton, CA, USA). Blood routine and liver function was detected before Yingliu treatment, at 2, 6 and 12 weeks after Yingliu treatment start, and the kidney function was examined before and after the Yingliu treatment.
Efficacy evaluations
The TCM symptome score included primary and secondary symptoms (Table 1) and was evaluated before and 6 as well as 12 weeks after start of medication. According to the observation of symptoms, the primary symptom scored 0, 2, 4, 6 points and the secondary symptom scored 0, 1, 2, 3 points.
Table 1.
TCM symptome scoring (see details of goitre classification in the section of diagnostic criteria)
| Primary symptoms | 0 | 2 | 4 | 6 |
|
| ||||
| Goitre | none | I degree | II degree | III degree |
| Fatigue | none | Not stand the labor force | Can insist physical labor | Reluctantly bear daily activities |
| Dry mouth and thirsty | none | Dry mouth but without thirsty | Like to drink | Drink frequently and much |
|
| ||||
| Secondary symptoms | 0 | 1 | 2 | 3 |
|
| ||||
| Unable to stand the heat | none | Feel hot after a little activity | Feel hot even in resting condition | Feel hot and sweatiness in resting condition |
| Hidrosis | none | Easy to sweatiness | Sweatiness after activity | Sweating continually |
| Chest tightness | none | Occasional chest tightness | Frequent chest tightness, which relieve in a short time | Always have chest tightness, which cannot relieve in a short time |
| Much phlegm | none | much phlegm occasionally | Always have much phlegm | Have much phlegm continually |
| Heart palpitations | none | Become marked after physical activity | Have heart palpitations once after physical activity | Have heart palpitations even in resting condition |
| Upset and irritability | none | Emotional instability, impatience | Tempered and irritability, which can be controlled by treatment | Tempered and irritability, which cannot be controlled by treatment |
| Insomnia and much dream | none | Have much dream and several awakening | Have much nightmares and easy to awakening | Hard to fall asleep |
| Polyphagia | none | meal size was increased by less than 1/2 after suffering the disease | Meal size was increased by 1/2 to 1 times | Meal size was increased by more than 1 times |
| Thin | none | Body weight was decreased by less than 20% after suffering the disease | Decreased by 20%-30% | Decreased by more than 30% |
| Dry eye and blurred vision | none | occasionally | Always have dry eye, blurred vision and diplopia | Continually have dry eye, blurred vision and diplopia |
| Facial ecchymosis | none | occasionally | multiple | Darkness and ecchymosis in whole face |
Thyroid palpation
Examinations were performed by specialized medical personnel during the follow-ups. The subjects were in sitting and the physician stood in front. Palpating started upward from the suprasternal notch with the thumb. When checking the thyroid gland lateral lobe, one thumb was used to press on the thyroid cartilage side to move the trachea contralateral. The index and middle fingers of the other hand were used to push forward the lateral lobes of the thyroid in the contralateral sternocleidomastoid trailing edge. Then the thyroid could be palpated with the thumb in the front edge of the sternocleidomastoid when the subjects were asked to swallow.
Evaluation of curative efficacy
The symptome score was calculated using the following formula: Symptome score = (score before treatment-score after treatment)/score before treatment ×100%. Curative efficiency was defined as (1) Cured, when clinical symptoms and signs disappear or nearly disappeared and the symptome scores were reduced by 95% or higher. (2) Marked efficacy was defined as clinical symptoms and signs in traditional Chinese medicine were improved markedly and symptome scores were reduced by 70% or higher. (3) Efficient was defined as clinical symptoms and signs were improved and symptome scores were reduced by 30% or higher, whereas when symptoms were not improved, or even worse and the symptome scores were reduced by less than 30% (4), the outcome was defined as invalid.
Safety evaluation levels
Level 1: secure, without any adverse reaction. Level 2: relative safe; drugs could be given continually without any treatment in case adverse reactions occurred. Level 3: there were security issues and moderate adverse reactions, but drugs could be given continually after treatment. Level 4: test was discontinued because of adverse reactions.
Statistical analysis
SPSS Statistics for Windows (Version 17.0. Chicago: SPSS Inc.) were used for statistical analyses. Measurement data in normal distribution were expressed using mean ± standard deviation and the median (interquartile range) was used for those in abnormal distribution. T-test, nonparametric test, or variance analysis were used for measurement data. Chi-square test was used for count data. Rank sum test was used for ranked data. P < 0.05 was considered to be statistically significant.
Sample size estimation
The number of cases in the Yingliu and control treatment groups was required to be equal in this trial and the sample size was estimated based on the equation:
N = 2×[(α+β)σ/σ]^2 (δ refers to the required differentiation degree, σ was the overall standard deviation, α and β were respectively the corresponding u values of α and β, which could be derived by checking the t boundary value table).
It was presumed that it would be of clinical interest when an average decrease of TRAb became 3.5 mIU/ML higher in the Yingliu treatment than that in control treatment group. Based on relevant literature, standard deviation of TRAb in GD patients was 5.3 mIU/ML, and therefore δ = 3.5 mIU/ML, σ = 5.3 mIU/ML, α = 0.05, β = 0.10, 1-β = 0.90; after checking a t boundary value table (unilateral), t0.05 = 1.645, t0.1 = 1.282, n was calculated as 2×[(1.645+1.282)×5.3/3.5]^2 = 39. At least 39 cases were needed in each group. As the rate of follow-up losses was estimated to be not more than 15%, the sample size was eventually determined to be 92 after the adjustment by 78/(1-0.15).
Results
General information of the patients
92 GD patients were involved in this study, but 12 (13.04%) of them were lost for the final follow up (6 cases in the YM group and 6 cases in the C group). 40 patients in the YM group (8 males and 32 females, aged between 22 and 65 years with a course of disease ranging from 0.5 to 26 months) and 40 patients in control treatment group (11 males and 29 females, aged between 21 and 64 years, with the course of disease ranging from 0.5 to 24 months) finally finished the trial. Most of the patients were females, which was in accordance with the literature [10]. There were 36 cases of primary GD (18 cases in the YM and 18 cases in control treatment group) and 44 cases of recurrent GD (22 cases in YM and 22 cases in control treatment group). There were no significant differences in gender ratio, age and initial thyroid specific blood serum levels as well as pre Yingliu treatment symptome scores between the two groups (P = 0.431, P = 0.977, P = 0.483) (Table 2).
Table 2.
Baseline data of the two groups
| YM (40 cases) | Control treatment (40 cases) | |
|---|---|---|
| Gender | ||
| Male | 8 | 11 |
| Female | 32 | 29 |
| Age (year) | 36.50 (17.00) | 38.00 (24.50) |
| Course of disease (month) | 11.00 (16.25) | 12.50 (18.50) |
| Primary cases (number) | 18 | 18 |
| Recurrent cases (number) | 22 | 22 |
| FT3 (pmol/l) | 18.22 (14.87) | 14.25 (14.88) |
| FT4p (mol/l) | 46.75 (34.95) | 39.34 (27.24) |
| TSHm (IU/L) | 0.004 (0.00) | 0.004 (0.00) |
| TGAb (IU/ML) | 89.90 (370.92) | 89.62 (355.11) |
| TPOAb (IU/ML) | 54.80 (229.20) | 27.80 (250.15) |
| TRAbm (IU/ML) | 12.89 (17.10) | 12.17 (7.43) |
| Symptome score (X̅±sd) | 18.45±2.50 | 18.55±2.05 |
Evaluation of therapeutic efficacy
After 6 weeks of Yingliu treatment, FT3, FT4 in two groups were obviously decreased (P < 0.05) and TSH was increased (P < 0.05), suggesting that the thyroid function effectively improved in both groups, but there were no significant differences of FT3, FT4, TSH concentrations between Yingliu treatment and control treatment group. In addition, TGAb, TPOAb, TRAb thyroid autoantibody levels were significantly lower after Yingliu treatment in both groups (P < 0.05), but without differences between Yingliu and control treatment (Table 3). After 12 weeks, FT3, FT4 and TSH in both groups were all improved effectively (P < 0.001). However, there were significant differences of FT3, FT4 (P = 0.038, P = 0.041) between the Yingliu treatment and control treatment groups, suggesting that a better therapeutic efficacy for FT3 and FT4 improvements could be achieved with the Yingliu treatment. Also TGAb, TPOAb, TRAb levels were significantly lower than before treatments in both groups (P < 0.001), and there were significant differences of TGAb, TRAb (P = 0.026, P = 0.019) between the Yingliu and the control treatment group (Table 3).
Table 3.
Comparison of observed index of pre-treatment and post-treatment at 6 and 12 weeks between two groups (M (QR)
| Yingliu Treatment (40) | Control Treatment (40) | ||
|---|---|---|---|
| FT3 (pmol/l) | pre-treatment | 18.22 (14.87) | 14.25 (14.88) |
| 6 weeks after treatment | 8.92 (8.53)* | 5.60 (6.42)* | |
| Difference after 6 weeks of treatment | 9.3 (6.35) | 8.65 (8.46) | |
| 12 weeks after treatment | 5.44 (3.52)* | 5.61 (5.19)* | |
| Difference after 12 weeks of treatment | 12.78 (11.35)▲ | 8.64 (9.69) | |
| FT4 (pmol/l) | pre-treatment | 46.75 (34.95) | 39.34 (27.24) |
| 6 weeks after treatment | 25.76 (20.10)* | 19.30 (14.00)* | |
| Difference after 6 weeks of treatment | 20.99 (14.85) | 20.04 (13.24) | |
| 12 weeks after treatment | 15.85 (11.64)* | 16.93 (10.50)* | |
| Difference after 12 weeks of treatment | 30.90 (23.31)▲ | 22.41 (16.74) | |
| TSH (mIU/L) | pre-treatment | 0.004 (0.00) | 0.004 (0.00) |
| 6 weeks after treatment | 0.004 (0.003)* | 0.004 (0.080)* | |
| Difference after 6 weeks of treatment | 0.00 (0.003) | 0.00 (0.080) | |
| 12 weeks after treatment | 0.010 (2.26)* | 0.005 (0.59)* | |
| Difference after 12 weeks of treatment | -0.006 (2.26) | -0.001 (0.59) | |
| TGAb (IU/ML) | pre-treatment | 89.90 (370.92) | 89.62 (355.11) |
| 6 weeks after treatment | 77.35 (335.90)* | 83.00 (338.20)* | |
| Difference after 6 weeks of treatment | 12.55 (35.02) | 6.62 (16.91) | |
| 12 weeks after treatment | 65.75 (295.71)* | 71.35 (334.23)* | |
| Difference after 12 weeks of treatment | 24.15 (75.21)▲ | 18.27 (20.88) | |
| TPOAb (IU/ML) | pre-treatment | 54.80 (229.20) | 27.80 (250.15) |
| 6 weeks after treatment | 58.50 (193.30)* | 24.40 (225.60)* | |
| Difference after 6 weeks of treatment | -3.70 (35.9) | 3.40 (24.55) | |
| 12 weeks after treatment | 40.40 (168.83)* | 24.60 (202.58)* | |
| Difference after 12 weeks of treatment | 14.40 (60.37) | 3.20 (47.57) | |
| TRAb (mIU/ML) | pre-treatment | 12.89 (17.10) | 12.17 (27.43) |
| 6 weeks after treatment | 8.46 (12.55)* | 12.68 (24.91)** | |
| Difference after 6 weeks of treatment | 4.43 (4.55) | 0.51 (2.52) | |
| 12 weeks after treatment | 6.17 (9.11)* | 9.04 (19.57)* | |
| Difference after 12 weeks of treatment | 6.72 (7.99)▲ | 3.13 (7.86) |
Compared with pre-treatment,
P < 0.01;
P < 0.05;
compared with control group,
P < 0.05.
Comparison of TCM symptom scores
Repeated measured data were analyzed using variance analysis and the results suggested that there were differences of TCM symptom scores at different time points in both groups which was significant lower in the Yingliu treatment group at week 12 compared to the control treatment group (Table 4).
Table 4.
Comparison of TCM symptome scores at different time points (X̅±s)
| group | Yingliu treatment | Control treatment |
|---|---|---|
| Pre-treatment | 18.45±2.50 | 18.55±2.05 |
| 2 weeks | 16.88±2.28 | 17.10±2.12 |
| 4 weeks | 14.93±2.40 | 15.68±2.07 |
| 6 weeks | 12.58±2.38 | 14.13±2.23 |
| 8 weeks | 10.73±2.41 | 12.35±2.36 |
| 10 weeks | 9.15±2.47 | 11.15±2.92 |
| 12 weeks | 7.78±2.70▲ | 9.85±3.14 |
Note: Compared with control treatment group,
F = 6.417, P < 0.05.
After 12 weeks of treatments, the goitre, fatigue and dry mouth and thirst was significantly better improved in the Yingliu than the control treatment group (21 cases vs. 10 cases (P = 0.012), 39 cases vs. 30 cases (P = 0.003) and 37 cases vs. 29 cases (P = 0.019), respectively) (Table 5). In addition, there were 0 cases of clinical recovery, 14 cases of marked efficacy, 23 cases of effectiveness and 3 cases of invalid outcomes in the Yingliu treatment group with a total effectiveness rate of 92.5%. In the control treatment group were 0 cases of clinical recovery, 6 cases of marked efficacy, 27 cases of effectiveness and 7 cases of invalid outcomes, with a total effectiveness rate of 82.5%. The effectiveness rate was significantly better in the Yingliu than in the control treatment group (P = 0.025, Table 5).
Table 5.
Comparison of primary symptome improvement, clinical efficacy and adverse reaction events between the two groups
| Yingliu Treatment (40) | Control Treatment (40) | ||
|---|---|---|---|
| Goiter | Total efficacy score | 21▲ | 10 |
| Fatigue | Total efficacy score | 39▲▲ | 30 |
| Dry mouth and thirsty | Total efficacy score | 37▲ | 29 |
| Clinical efficacy | Cured | 0 | 0 |
| Marked efficient | 14 | 6 | |
| Efficient | 23 | 27 | |
| Invalid | 3 | 7 | |
| Total effective rate (%) | 92.50▲ | 82.50 | |
| Adverse reaction event | Leukopenia | 5 | 11 |
| ALT elevation | 5 | 1 | |
| Abnormal renal function | 0 | 0 | |
| Rush | 0 | 0 | |
| Safety evaluation | Level 1 | 31 | 28 |
| Level 2 | 2 | 4 | |
| Level 3 | 7 | 8 | |
| Level 4 | 0 | 0 |
Compared with control group,
P < 0.05;
P < 0.01.
Safety evaluation
There were 16 cases of leucopenia (less than 4.0×10^9/l (5 cases in the Yingliu and 11 cases in control treatment group), and 6 cases of ALT level increase (5 cases in Yingliu treatment group and 1 case in control treatment group), but there was no significant difference between the groups (P = 0.094, P = 0.203, Table 5).
According to the safety evaluating criteria, there were 31 level 1cases, 2 level 2 cases, 7 level 3 cases and no level 4 case in the Yingliu treatment group. In the control treatment group 28 level 1 cases, 4 level 2 cases, 8 level 3 cases and no level 4 case occurred. After nonparametric test, no significant differences of safety evaluation was found between two groups (Z = -0.675, P = 0.675, Table 5).
Discussion
The remission rate for GD by antithyroid drugs (ATD) (MMI, PTU commonly used) has been reported to range from 32% to 45.7% [11-13]. The Yingliu mixture is a homemade preparation by our hospital derived from long-term clinical experience and could improve the thyroid enlargement (21 vs. 10, P < 0.05), fatigue (39 vs. 30, P < 0.01) and dry moth symptoms (37 vs. 29, P < 0.05) to better scores than the control medication. The clinical efficiency of the Yingliu mixture-methimazole combination was 92.5% vs. 82.5% (P < 0.05) of solely methimazole medication (Table 5). In addition, after 12 weeks treatments the Yingliu mixture in combination with methimazole improved FT3, FT4, TGAb and TRAb values significantly more than methimazole alone (Table 3) and TCM symptome scores were significant lower after 12 week treatment in the Yingliu mixture-methimazole group (P < 0.05). From the 12 Yingliu mixture ingredients, Radix astragali, Rhizoma anemarrhenae and Prunella vulgaris have been used for Yingliu treatments of hyperthyroidism as single applications already. Radix astragali, which has an effect on non-specific, humoral and cellular immunity, was applied in combination with prednisone to hyperthyroidism patient with leukopenia. In the Yingliu treatment group CD4 cells were obviously decreased and CD8 cells increased. The improved CD4/CD8 ratio promoted the recovery of thyroid functions and shortened the course of the treatment [14]. Rhizoma anemarrhenae, which eliminates internal excessive heat and has antipyretic effects, reduced the oxygen consumption caused by thyroxine via inhibiting the Na+-K+-ATPase activities of hyperthyroidism rats [15]. Prunella vulgaris has effects of clearing body heat and resolving hard masses. A previous study revealed that in hyperthyroidism patients treated with prunella liquid plus methidathion the thyroid size was obviously more reduced than in the control treatment group treated with methidathion alone [16]. Radix ophiopogonis can remove dysphoric heat. A study showed that it promotes immunity and has antithrombotic effects. The chemical components of the herb evidently increased the thymus and spleen weights as well as activated the phagocytosis of the reticuloendothelial system in mice [17]. Smilax is dispelling cold and improving body dampness, detoxifying and removing tumescences via blood-activating and stasis-dissolving properties [18]. Radix scrophulariae is decreasing excessive internal heat, detoxifying and removing urine and blood circulation stagnations and was also shown to have antipyretic and immunity enhancement effects [19,20]. Forsythia can reduce internal excessive heat and has anti-inflammatory and anti-endotoxin effects [21]. Thunberg fritillary bulb is clearing body heat and dispersing blood stasis due to anti-inflammatory, blood-activating and stasis-dissolving properties [22]. Alisma plantago-aquatica is a mild diureticum and used to treat difficulty in micturition, edema, diarrhea, as well as clearing heat. The effect of white mustard seed, which is also a radical quencher [23], is softening hard masses. Semen impatient is improving blood stasis as well as softening and resolving hard masses. A pharmacological study showed that semen impatientis decoction reduced whole blood viscosity, plasma viscosity, erythrocyte sedimentation rate, fibrinogen and hematocrit [24]. Oysters are included into TCM preparations for softening and resolving hard masses and used for treating subcutaneous nodules, tuberculous lymph nodes and abdominal mass. They also have been shown to enhance immunity [25]. Taken together, Yinliu herbs have mainly beneficial effects on excessive body heat, followed by softening and resolving hard masses, improving immunity and stasis dissolving. There were 16 cases of leucopenia (5 cases in the Yingliu treatment group and 11 cases in the control treatment group) and increase of ALT in 6 cases (5 cases in the Yingliu treatment group and 1 case in the control treatment group). Although the leukopenia case number of in the Yingliu treatment group was less than in the control treatment group the difference was not significant, suggesting that the Yingliu mixture did not reduce the adverse effects of methimazole. This is not consistent with a previous report that the YiQi and YangYin method could effectively improve GD related leukopenia and further research is needed to confirm it.
There were some drawbacks in this study. The sample size was relative small and changes of TSH levels may not have been manifested due to the limited observation time.
In conclusion, Yingliu mixture as combination with methimazole could improve effectively the thyroid gland function, decrease the level of thyroid gland autoantibodies and improve the symptoms and signs of GD compared to a solely methimazole medication.
Acknowledgements
This project was supported by the revaluation of the clinical outcome of Yingliu mixture on Graves disease (12401902103).
Disclosure of conflict of interest
None.
References
- 1.Galofre JC, Davies TF. Autoimmune thyroid disease in pregnancy: a review. J Womens Health (Larchmt) 2009;18:1847–1856. doi: 10.1089/jwh.2008.1234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Vanderpump MPJ, Tunbridge WMG. The epidemiology of autoimmune thyroid disease. Humana Press. 1999;15:141–162. [Google Scholar]
- 3.Gao XW, Li JL. Thyroid disease. People’s Medical Publishing House. 2000:93–95. [Google Scholar]
- 4.Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell’Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E, Pinchera A. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med. 1998;338:73–78. doi: 10.1056/NEJM199801083380201. [DOI] [PubMed] [Google Scholar]
- 5.Benker G, Reinwein D, Kahaly G, Tegler L, Alexander WD, Fassbinder J, Hirche H. Is there a methimazole dose effect on remission rate in Graves’ disease? Results from a long-term prospective study. The European Multicentre Trial Group of the Treatment of Hyperthyroidism with Antithyroid Drugs. Clin Endocrinol (Oxf) 1998;49:451–457. doi: 10.1046/j.1365-2265.1998.00554.x. [DOI] [PubMed] [Google Scholar]
- 6.Fu SX. The current treatment of hyperthyroidism hepatic dysfunction. Hebei medical joural. 2009;31:2. [Google Scholar]
- 7.Bonaci-Nikolic B, Nikolic MM, Andrejevic S, Zoric S, Bukilica M. Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides. Arthritis Res Ther. 2005;7:R1072–1081. doi: 10.1186/ar1789. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, Mandel SJ, Stagnaro-Green A. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2007;92:S1–47. doi: 10.1210/jc.2007-0141. [DOI] [PubMed] [Google Scholar]
- 9.WHO/UNICEF/ICCIDD Joint Consultation. Indicators for assessing iodine deficiency disorders and their control through salt iodization. WHO/NUT/94.6. Geneva: WHO. 1994 [Google Scholar]
- 10.Wong GW, Cheng PS. Increasing incidence of childhood Graves’ disease in Hong Kong: a follow-up study. Clin Endocrinol (Oxf) 2001;54:547–550. doi: 10.1046/j.1365-2265.2001.01252.x. [DOI] [PubMed] [Google Scholar]
- 11.Ishtiaq O, Waseem S, Haque MN, Islam N, Jabbar A. Remission of Grave’s disease after oral anti-thyroid drug treatment. J Coll Physicians Surg Pak. 2009;19:690–693. [PubMed] [Google Scholar]
- 12.Lumholtz IB, Poulsen DL, Siersbaek-Nielsen K, Friis T, Rogowski P, Kirkegaard C, Hansen JM. Outcome of long-term antithyroid treatment of graves’ disease in relation to iodine intake. Acta Endocrinol (Copenh) 1977;84:538–541. doi: 10.1530/acta.0.0840538. [DOI] [PubMed] [Google Scholar]
- 13.Peixoto MC, Coeli CM, Vaisman M. [Evaluation of the medical treatment of Graves’ disease (GD)] . Arq Bras Endocrinol Metabol. 2005;49:410–419. doi: 10.1590/s0004-27302005000300013. [DOI] [PubMed] [Google Scholar]
- 14.Wang D, Fang XM, Liu Y. The changes of T cell subsets after the treatment of astragalus injection in hyperthyroidism (Graves disease) West China Medical Journal. 2001;16:465–466. [Google Scholar]
- 15.Kun LT, Gao H, Jiang YL. Influences of Anemarrhenae Rhizoma and One Processed with Salt-Water on Na +-K +-ATP Enzyme in Erythrocyte Membrane in Rats with Hyperthyroidism and Yin Deficiency. Chinese Journal of Experimental Traditional Medical Formulae. 2011;17:184–186. [Google Scholar]
- 16.Yang K, Guo KQ, Wu HY. Clinical effect of prunrllae oral solution in treating hyperthyrea. China Journal of Chinese Materia Medica. 2007;32:1706–1708. [PubMed] [Google Scholar]
- 17.Tang J, Huang Q, Xu ZY. Study on the immune activity of polysaccharides in Ophiopogon japonicus. Journal of Basic Medicine in Traditional Chinese Medicine in China. 1998;4:44–46. [Google Scholar]
- 18.Lv YN, Cheng DS, Xu CH. Study on the pharmacological effects of Smilax China L on promoting blood circulation. Chin J Hosp Pharm. 2002;22:538–540. [Google Scholar]
- 19.Zhang JC, Zhu JM. Advance of research on chemical constituents and pharmacological activities of Scrophularia Ningpoensis. Handong Pharmaceutical Industry. 2003;22:25–27. [Google Scholar]
- 20.Garg HS, Bhandari SPS. Antihepatotoxic and Immunositumlant Porperties of Iirdoid Glycosides of Scorphulaira Koelzii. Phytother Res. 1994;8:224. [Google Scholar]
- 21.Hu JY, Lei L, Yu Y. The study on antiinflammatory and antipyretic effect of Forsythia suspensa. Pharmacology and Clinics of Chinese Materia Medica. 2007;23:51–52. [Google Scholar]
- 22.Zhang MF, Shen YQ, Zhu ZP. Study of the property in Chinese herbs with spicy warm/thermal (Sinwin) in spleen and stomach (III): anti-inflammatory effect. Pharmacol Clin Chin Mater Med. 1998;14:12–16. [Google Scholar]
- 23.Li WY, Li Q. Protective effects of Sinapine on DNA damage caused with radiation and reactive oxygen species. Plant Physiology. 1997;23:319–323. [Google Scholar]
- 24.Zhao Q. Effects of Semen Impatientis decoction on blood rheology in rabbits with the syndrome of experimental blood stasis. Shanxi College of Traditional Chinese Medicine. 2006;29:47–48. [Google Scholar]
- 25.Li M, Du GW, Liu S. Experimental study of antivirus effect of glycosaminoglycan from oyster against herpes simplex virus type 1. Chin J Mar Drugs. 2008;2:50. [Google Scholar]