This randomized, double-dummy, double-blind study was to observe the therapeutic effects of compound Danshen dripping pill (CDDP) in treating early diabetic retinopathy (DR). All the 57 type 2 diabetes cases in nonproliferative diabetic retinopathy (NPDR) stage were divided into two groups randomly: 28 cases treated with CDDP as the treated group and 29 cases treated with calcium dobesilate as the control group. The best corrected visual acuity (BCVA) in the treated group was significantly improved after treatment when compared to that before treatment (
Diabetic retinopathy (DR) is a common microvascular complication of diabetes. DR is characterized by microaneurysm, exudation, neovascularization, vitreous hemorrhage, and so on in the retinal microvasculature, which can cause different degrees of vision loss or irreversible blindness. Approximately, more than 30% of these patients have DR [
Traditional Chinese medicine (TCM) considered that DR is developed because of blood stasis, which causes hemorrhage and angiogenesis [
Several Chinese herbs can remove blood stasis including Danshen,
From June 2010 to April 2013, 60 patients diagnosed with NPDR because of type 2 diabetes were recruited in the Department of Ophthalmology, China-Japan Friendship Hospital. The Institutional Review Boards and Ethics Committees of the China-Japan Friendship Hospital in accordance with the provisions of the Declaration of Helsinki approved the study protocol. All patients signed the consent form. The inclusion criteria were as follows: (1) HbA1C blood was below 8% in the past 3 months and (2) the fundus condition had no significant aggravating period. The exclusion criteria were as follows: (1) patients with other retinopathy diseases, glaucoma, or influencing fundus examination diseases; (2) patients with uveitis, retinal detachment, or optic nerve diseases; (3) patients with severe heart, liver, or hematopoietic system diseases; (4) patients with renal failure caused by diabetic nephropathy; (5) pregnant or lactating patients or those with psychosis; and (6) patients participating in other clinical trials or taking other drugs that affect the results of this study.
CDDP was prepared by Tasly Pharmaceutical Group Co., Ltd. (Tianjin, China), which includes Danshen (
The primary outcome was the best corrected visual acuity (BCVA). Visual acuities were converted to logarithm of the minimum angle of resolution (Log MAR) values for analysis. The criteria of visual acuity were as follows: improvement ≥ 4 lines indicated excellent effective rate; improvement of 2 to 3 lines indicated effective rate; improvement of 1 line or no changes indicated stable rate; and decline ≥ 2 lines indicated ineffective rate.
The secondary outcomes included mean defect (MD) of visual field, hemorrhage area of fundus, the microaneurysm number, fluorescent leakage area, and capillary nonperfusion area. MD of the visual fields of all eyes was tested using the Octopus 101 perimeter (InterZeag Inc., Switzerland) under the aid of an examiner. Each patient should complete the perimetry at least twice to judge the repeatability of the result. We required false positive or negative rates < 30% or reliable factor < 15%. The MD of the visual field was evaluated over the normal range, which was ≥ 10%, indicating excellent effective rate; ≥0 and <10% indicated effective rate; and <0 indicated ineffective rate.
After mydriasis, the patients were given 3 mL of 20% sodium fluorescein through elbow vein injection for the fundus fluorescein angiography (FFA; Topcon TRC-50DX, Topcon Corp., Tokyo, Japan) image monitoring for 20 min. The microaneurysm number, hemorrhage area of fundus, fluorescent leakage area, and capillary nonperfusion area were evaluated in the four quadrants of the fundus with FFA. The criteria of the microaneurysm number were as follows: reduction of ≥10% indicated excellent effective rate; reduction of ≥0 and <10% indicated effective rate; and increased value indicated ineffective rate. The extent of the area was estimated using optic disc area as the basic unit. The criteria of decreasing rate of the area were as follows: ≥ 10% had excellent effective rate; ≥0 and <10% had effective rate; and increased value had ineffective rate.
Before and after treatment, the blood routine, liver and kidney function, fasting blood sugar, and urine sugar tests were performed for safety evaluation. During the study, any adverse events related to CDDP were recorded, including clinical signs and symptoms.
All data of the results were presented as the means ± standard deviations and analyzed with SPSS 17.0 (SPSS Inc., Chicago, IL, USA). The basic characteristics were determined by descriptive analysis. Paired
After eliminating 3 cases for angle-closure glaucoma and cataract, a total of 57 eligible cases (114 eyes) were enrolled into this study. The statistical analysis was conducted by dividing the samples into two groups by random allocation. As shown in Table
Basic characteristics of study subjects.
Characteristic | The treated group | The control group |
---|---|---|
Age (years) | 59.54 ± 7.46 (range: 43–67) | 57.86 ± 10.03 (range: 45–64) |
Gender, number (%) | ||
Male | 18 (64.3%) | 19 (65.5%) |
Female | 10 (35.7%) | 10 (34.5%) |
Mean duration (years) | 14.52 ± 3.29 (range: 7–21) | 15.74 ± 3.63 (range: 9–21) |
Diagnosis, eye/number | ||
Mild NPDR | 18 | 19 |
Moderate NPDR | 22 | 25 |
Severe NPDR | 16 | 14 |
The BCVA changes of both groups before and after the treatment are listed in Table
BCVA (
Group |
|
Before treatment | After treatment | BCVA evaluation after treatment | |||
---|---|---|---|---|---|---|---|
Improvement ≥ 4 lines | 2 to 3 lines | 1 line or no changes | Decline ≥ 2 lines | ||||
Treated group | 56 | 0.25 ± 0.19 | 0.14 ± 0.17 | 8 (14.29%) | 32 (57.14%) | 14 (25.00%) | 2 (3.57%) |
Control group | 58 | 0.32 ± 0.21 | 0.17 ± 0.18 | 6 (10.34%) | 30 (51.72%) | 20 (34.48%) | 2 (3.45%) |
Visual field means the space scope felt by the patient with single eye looking in the due front direction. The defect of visual field showed the lesions in the relevant fundus parts. Colors are used to indicate the degree: yellow means normal, and green, red, and black indicated that the lesions were worsened (Figure
MD (dB) comparison of the two groups before and after treatment.
Group |
|
Before treatment | After treatment | MD evaluation after treatment | ||
---|---|---|---|---|---|---|
≥10% | ≥0 and <10% | <0 | ||||
Treated group | 56 | 4.61 ± 3.54 | 3.76 ± 3.94 | 9 (16.07%) | 26 (46.43%) | 21 (37.5%) |
Control group | 58 | 5.08 ± 4.58 | 3.68 ± 2.65 | 5 (8.62%) | 34 (58.62%) | 19 (32.76%) |
Representative images of a case before and after CDDP treatment. (a) Visual field before treatment. (b) Visual field after treatment.
Microaneurysm number can reflect long-term progression in DR [
Microaneurysm number comparison of the two groups before and after treatment.
Group |
|
Before treatment | After treatment | Microaneurysm number evaluation after treatment | ||
---|---|---|---|---|---|---|
≥10% | ≥0 and <10% | <0 | ||||
Treated group | 56 | 23.16 ± 18.16 | 21.14 ± 18.57 | 15 (26.93%) | 27 (48.07%) | 14 (25.0%) |
Control group | 58 | 23.79 ± 17.30 | 21.88 ± 15.49 | 14 (24.14%) | 31 (53.45%) | 13 (22.41%) |
Representative images of a case before and after CDDP treatment. (a) Color fundus photograph and FFA photograph before treatment. (b) Color fundus photograph and FFA photograph after treatment.
Changes in hemorrhage area of fundus are shown in Table
Hemorrhage area (PD) comparison of the two groups before and after treatment.
Group |
|
Before treatment | After treatment | Hemorrhage area evaluation after treatment | ||
---|---|---|---|---|---|---|
≥10% | ≥0 and <10% | <0 | ||||
Treated group | 56 | 0.30 ± 0.54 | 0.14 ± 0.52 | 20 (35.71%) | 25 (44.64%) | 11 (19.64%) |
Control group | 58 | 0.29 ± 0.48 | 0.15 ± 0.46 | 18 (31.03%) | 25 (43.10%) | 15 (25.86%) |
After treatment, fluorescent leakage area had notable narrowing in each group (
Fluorescent leakage area (PD) comparison of the two groups before and after treatment.
Group |
|
Before treatment | After treatment | Fluorescent leakage area evaluation after treatment | ||
---|---|---|---|---|---|---|
≥10% | ≥0 and <10% | <0 | ||||
Treated group | 56 | 0.16 ± 0.16 | 0.13 ± 0.20 | 16 (28.57%) | 23 (41.07%) | 17 (30.36%) |
Control group | 58 | 0.17 ± 0.17 | 0.12 ± 0.20 | 17 (29.31%) | 24 (41.38%) | 17 (29.31%) |
Table
Capillary nonperfusion area (PD) comparison of the two groups before and after treatment.
Group |
|
Before treatment | After treatment | Capillary nonperfusion area evaluation after treatment | ||
---|---|---|---|---|---|---|
≥10% | ≥0 and <10% | <0 | ||||
Treated group | 56 | 0.21 ± 0.22 | 0.15 ± 0.15 | 12 (21.43%) | 26 (46.43%) | 18 (32.14%) |
Control group | 58 | 0.22 ± 0.23 | 0.14 ± 0.17 | 15 (25.86%) | 25 (43.10%) | 18 (31.03%) |
After the treatment, we analyzed each abnormal result in the blood routine, liver and kidney function, fasting blood sugar, and urine sugar tests. However, these tests had nothing to do with CDDP. Each laboratory examination had no significant differences between the two groups or before and after treatment of each group (
Comparison of the results of the laboratory examinations: comparison of the two groups before and after the treatment.
Treated group | Control group | |||
---|---|---|---|---|
Before treatment | After treatment | Before treatment | After treatment | |
Red blood cell (×1012/L) | 4.55 ± 0.48 | 4.64 ± 0.44 | 4.52 ± 0.47 | 4.50 ± 0.45 |
White blood cell (×109/L) | 6.81 ± 1.96 | 6.56 ± 2.03 | 7.02 ± 2.33 | 6.33 ± 1.44 |
Neutrophils (%) | 57.21 ± 10.26 | 56.49 ± 9.91 | 59.23 ± 9.85 | 59.37 ± 8.66 |
Lymphocyte (%) | 30.39 ± 7.17 | 32.62 ± 9.31 | 30.22 ± 8.19 | 29.24 ± 6.69 |
Hemoglobin (g/L) | 142.54 ± 13.48 | 146.50 ± 11.70 | 139.90 ± 16.37 | 137.71 ± 13.70 |
Platelet (×109/L) | 230.07 ± 73.65 | 222.77 ± 64.40 | 232.90 ± 61.51 | 228.74 ± 68.22 |
Alanine aminotransferase (U/L) | 23.30 ± 15.40 | 20.50 ± 8.74 | 21.54 ± 8.85 | 25.36 ± 14.04 |
Aspartate aminotransferase (U/L) | 22.89 ± 9.62 | 21.04 ± 6.35 | 21.93 ± 7.25 | 25.07 ± 11.84 |
Blood urea nitrogen (mmol/L) | 5.89 ± 1.70 | 5.95 ± 1.54 | 6.04 ± 1.81 | 6.11 ± 1.59 |
Blood creatinine ( |
83.04 ± 12.26 | 82.19 ± 12.04 | 87.45 ± 16.65 | 88.03 ± 14.72 |
Fasting blood sugar (mmol/L) | 6.74 ± 2.85 | 6.32 ± 2.76 | 6.48 ± 3.94 | 6.01 ± 2.64 |
Urine sugar (mmol/L) | 7.93 ± 17.06 | 7.72 ± 15.46 | 8.61 ± 16.48 | 5.99 ± 13.05 |
DR occurrence reflects the diabetic metabolic disorder and the effect of endocrine and hematological systems on retina. Although the microvascular complications in the retina caused by diabetes have been widely studied, the mechanisms and factors are not yet fully understood. The pathology of PDR is more severe than that of NPDR [
In case of high blood viscosity, the erythrocytes display low deformability and high aggregation, which can both decrease the blood flow; therefore, microthrombus is prone to occur, which might block the capillary vessels and lead to hypoxia-ischemia in retina tissue [
CDDP mainly consists of
However, after 3 months of CDDP and dobesilate treatments, no significant statistical differences were observed between the two groups in the present study. Compared with before treatment, the treated group with CDDP showed obvious improvement in BCVA with a total effective rate of 71.43%, as well as the scope of visual field defect with the total effective rate of 62.50%. Thus, CDDP could effectively improve the hypoxia-ischemic condition of retina tissue. Because the retina tissue is sensitive to hypoxia-ischemia, a certain defect in the visual field was observed. From the pathological changes in retinal tissue, we also found that microaneurysm and hemorrhage were absorbed obviously after CDDP treatment and capillary nonperfusion area also narrowed, thereby demonstrating the microcirculation improvement further.
Clinically, some cases use CDDP to treat ophthalmic diseases caused by blood stasis or obstructed blood circulations, such as central retinal artery occlusion, retinal vein obstruction, central serous chorioretinopathy, central exudative chorioretinitis, and optic atrophy [
In conclusion, by observing the clinical related evaluation indexes, this study proved that CDDP has obvious clinical curative effect on early DR, including the control of microaneurysm and hemorrhage and improved visual acuity and visual field. This effect is similar to that of calcium dobesilate. In future DR treatments, CDDP may function as the auxiliary drug. Because of the limitation of capital and sample size, supporting evidence on the mechanism of curative effect in the body was lacking. To achieve the application and popularization of CDDP in the future clinical treatment of early DR, we will improve the design of experiment and perform an in-depth experimental study.
All authors declare that they have no conflict of interests.
This work was supported by the Department of Ophthalmology, China-Japan Friendship Hospital.