Effect of Shuxuening Injection Combined with Alprostadil on Healing of Diabetic Foot Ulcers and Hemodynamic Indexes of Dorsal Artery of Foot

Cao Jie (曹 潔), Wei Qi (魏 琦), Xie Dan (謝 丹)

Wuhan Red Cross Hospital, Wuhan, 430000, China

ABSTRACT OBJECTIVE: To observe the effect of Shuxuening Injection combined with alprostadil on healing of diabetic foot ulcers and hemodynamic indexes of dorsal artery of foot. METHODS: A total of 84 cases of diabetic foot patients treated in Wuhan Red Cross Hospital (from February 2016 to April 2017) were divided into treatment group (42 cases) and control group (42 cases) by the random digital table. The control group was given basic clinical treatment while the treatment group was given Shuxuening Injection combined with alprostadil on the basis of the treatment in control group. After 2 weeks of treatment, the improvement of TCM symptom scores (pain, numbness, swelling, claudication), conditions of foot ulcer healing(ulcer area, wound oxygen pressure, wound pH), the hemodynamics of the dorsum pedis artery (the blood flow velocity of the dorsum pedis artery, the blood vessel diameter, resistance index (RI), pulsation index (PI)) of both groups were compared,and the clinical efficacy of 2 groups were statistically analyzed. RESULTS: The scores of pain, numbness, swelling and claudication were significantly reduced in 2 groups after the treatment (P ＜ 0.05), and the improvement of the above symptom scores in the treatment group were all significantly better than that in the control group (P ＜ 0.05). The area of ulcer and the pH of the wounds in the 2 groups were significantly decreased after the treatment (P ＜ 0.05), and the oxygen partial pressure in the wound was significantly increased (P ＜ 0.05), and the improvements of the wound healing outcomes in the treatment group were significantly better than that in the control group (P ＜ 0.05). The blood flow velocity of the foot, the blood vessel diameter, the level of RI and PI after treatment in both groups were significantly increased after the treatment (P ＜ 0.05), and the improvement of the hemodynamic index of the foot back after treatment in the treatment group was significantly better than that in the control group (P ＜ 0.05). The total effective rate of the treatment group was significantly higher than that of the control group (P ＜ 0.05). CONCLUSION: The application of Shuxuening Injection combined with alprostadil can quickly improve the clinical symptoms of the patients, correct the abnormal hemodynamics of the dorsum pedis artery and promote the healing of foot ulcers, and the combination of the two medicines has a synergistic effect.

KEYWORDS: Diabetic foot; Ulceration; Shuxuening Injection; Alprostadil; Dorsal artery hemodynamics

Diabetic foot is one of the common chronic complications of diabetes mellitus. It refers to the foot disease of the patients with diabetic ulcer, infection or deep tissue damage due to the neuropathy and/or lesions of peripheral vessels of lower limb[1]. The pathogenesis of this disease covers infection, nerves and blood vessels,in which the insufficiency of blood supply to lower limbs caused by peripheral vascular lesions (including large vessels and microvascular) is one of the important factors that induce diabetic foot, and hemorheological abnormality is an important inducement to accelerate the occurrence and development of vascular diseases[2,3].

At the early stage of diabetic foot, the clinical symptoms of patients are mild, and treatment mainly is based on controlling blood glucose, reducing blood pressure, anti-infection and improving the microcirculation. As it develops into ulcer stage,surgical treatment is required while the effect usually is not good. The ulcers are difficult to be cure and can possibly complicate with limb gangrene at the end.High amputation is usually needed in preventing disease deterioration[4], which brings great pain to patients,reduces their quality of life seriously, and creates great economic pressure to their families[5]. Therefore, early prevention and treatment of diabetic foot has great clinical significance in delaying the development of diabetic foot and reducing the disability rate of patients.In recent years, the researches of Traditional Chinese Medicine (TCM) on diabetic foot have made a lot of meaningful achievements. The treatment of TCM has the advantages of simple operation, low cost, little trauma and less adverse reactions, and has been widely accepted by patients in clinical practice. Besides, a large number of clinical studies have confirmed that the treatment of traditional Chinese medicine on the basis of conventional Western medicine treatment can quickly promote the healing of the wounds, reduce the amputation rate of diabetic foot gangrene and improve therapeutic effect[6,7].

The authors observed the effect of Shuxuening Injection combined with alprostadil on the healing of diabetic foot ulcer and the hemodynamic indexes of dorsal plantar arteries from February 2016 to April 2017.

CLINICAL MATERIALS

General materials

A total of 84 patients of diabetic foot admitted to the Wuhan Red Cross Hospital (from February 2016 to April 2017) have been selected. Western medicine diagnosis was made with reference to the Diagnosis and Treatment of Diabetic Foot and Related Complications[8], including:a clear history of diabetes, feet neuropathy with atrophy of the epidermis, weakening of the dorsal artery of the foot with appearance of peripheral vascular lesions such as dark red or purple skin, ulceration of the skin on the foot and ulcers can form gangrene when it goes into the joints, bones and muscles. The diagnosis of TCM was made according to the prescription for dampness and heat syndrome in the Guidelines for Clinical Research of New Medicines in Traditional Chinese Medicine[9], including:swollen body, stretched and bright skin, fullness in chest,thirst and heat with vexation, dry stool, concentrated urine. The tongue and pulse present as red tongue texture,yellow and greasy tongue coating, deep and rapid pulse.Inclusion criteria: aged between 18 to 70; Wagner grade was 1 to 2; blood glucose is stable under the control;the level of glycosylated hemoglobin7.5%. This study was approved by the ethics committee of the hospital,and informed consents were signed by all the patients.Patients with vascular diseases such as varix of lower limb and thrombus of lower limbs, foot ulcer caused by non-diabetic foot such as the injury and infection of the toe, combining dysfunction of blood coagulation,the dysfunction of liver and kidney and severe systemic inflammatory response were not included in this study.

The patients were randomly divided into 2 groups:42 patients in the treatment group including 25 males and 17 females; aged 35-70 (57.5±3.5) years old, the duration of diabetes was 1-15 (6.5±1.5) years. Another 42 patients were in the control group, including 26 males and 16 females, aged 38-67 (56.7±3.6) years old, the duration of diabetes was 1-16 (6.8±1.3) years. There was no statistical significance in gender, age, and duration of diabetes between the 2 groups (P ＞ 0.05).

Treatment methods

Routine clinical treatment was used in the control group, including: ① glycemic control: reasonable diet, especially the intake of protein; subcutaneous injection of insulin to ensure the fasting blood glucose＜7.0 mmol/L, and ＜11.1 mmol/L 2h after the meal.② anti-infection treatment: to select the appropriate antibiotic treatment according to the results of susceptibility test. ③ debridement: saline and hydrogen peroxide were used to thorough debridement of the foot ulcer. To maintain the wound dry, clean, and change the medicines every day.The alprostadil injection (made by Harbin Pharmaceutical Group Bioengineering Co., Ltd., SFDA: H20084565,specifications: 2ml: 10ug) was used in treatment group on the basis of the treatment in control group. Add 10ug of alprostadil to 250ml of 0.9% saline, for intravenous drip for 1 time a day. Shuxuening Injection (made by Divinity Shineway Group Co., Ltd., SFDA: Z13020795,specifications: 5ml) was used in both 2 groups, add 20ml Shuxuening Injection to 250ml 0.9% saline, intravenous drip for 1 time a day. The curative effects in 2 groups were evaluated after the treatment for continuous 2 weeks.

Observation index

① Clinical efficacy: refer to the efficacy standard in Internal Medicine[10]. Markedly effective: the clinical symptoms or signs disappeared or significantly improved,wound healing more than 90%. Effective: the clinical symptoms or signs have been improved to some extent, and wound healing rate is 60%-90%. Ineffective: the clinical symptoms and signs have not been improved at all, and even worsened, the wound healing rate is less than 10%.Total effective = markedly effective + effective. ② TCM symptom scores: to evaluate the improvement of TCM symptoms in 2 groups before and after treatment according to the Guidelines for Clinical Research of New Medicines in Traditional Chinese Medicine[9], including pain, numbness,swelling, claudication, and score 0 to 3 points according to the severity of symptoms. The higher the score is, the more severe the symptoms are. ③ Healing outcomes of foot ulcer: the skin ulcer area was observed and compared of the 2 groups before and after treatment. The percutaneous oxygen partial pressure and the pH value of the wound were measured by percutaneous oxygen partial pressure meter in 3 cm around the ulcer surface before and after treatment. ④ The hemodynamics of the dorsal artery: patients' flow velocity of dorsalis pedics artery, blood vessel diameter, resistance index(RI) and pulsatility index (PI) etc. have been detected by color Doppler ultrasound before and after the treatment.

Statistical analysis

SSPS 22.0 statistic software was used in statistical analysiswas used in data measurement with T test in comparison. Cases (%) were used in data counting with the χ2test in comparison. P ＜ 0.05 indicates statistically significance.

RESULTS

Comparison on the clinical effects in 2 groups

The total effective rate of treatment group was significantly higher than that of the control group after the treatment, and the difference was statistically significant(P ＜ 0.05). See Table 1.

Comparison on clinical symptoms in 2 groups before and after the treatment

The scores of pain, numbness, swelling, claudicationin 2 groups have no statistically significant difference before the treatment. (P ＞ 0.05), while were significantly decreased after the treatment(both P ＜ 0.05), and the improvement of the symptom scores in treatment group was significantly higher than that in the control group (both P ＜ 0.05). See Table 2.

Table 1. Comparison on the clinical effects in 2 groups [n (%)]

Comparison on the healing outcomes of foot wound in 2 groups before and after the treatment

The comparison on ulcer area, the wound oxygen partial pressure and the wound pH in 2 groups have no significant difference before the treatment (P ＞ 0.05), while vitally decreased after the treatment (all in P ＜ 0.05). The oxygen partial pressure of the wound were significantly increased(P ＜ 0.05), and the improvement of wound healing in the treatment group was significantly higher than that in the control group after the treatment (all P ＜ 0.05). See Table 3.

Comparison on hemodynamic index of the foot back in 2 groups before and after the treatment

The comparison on blood flow velocity, blood vesseldiameter, RI and PI level of the two groups before treatment has no statistically significant difference (P ＞ 0.05), while were significantly increased after the treatment (all in P ＜ 0.05), and the improvement of acrotarsium hemodynamics in the treatment group was significantly higher than that in the control group (all in P ＜ 0.05). See Table 4.

Table 2. Comparison on clinical symptoms in 2 groups before and after the treatment , scores)

Table 2. Comparison on clinical symptoms in 2 groups before and after the treatment , scores)

Note: ① Compared with scores before the treatment, P ＜ 0.05. ② Compared with control group, P ＜ 0.05

Table 3. Comparison on the healing outcomes of foot wound in 2 groups before and after the treatment

Table 3. Comparison on the healing outcomes of foot wound in 2 groups before and after the treatment

Note: ① Compared with before the treatment, P ＜ 0.05. ② Compared with control group, P ＜ 0.05

Table 4. Comparison on hemodynamic index of the foot back in 2 groups before and after the treatment

Table 4. Comparison on hemodynamic index of the foot back in 2 groups before and after the treatment

Note: ① Compared with before the treatment, P ＜ 0.05. ② Compared with control group, P ＜ 0.05

DISCUSSION

Diabetic foot is a common clinical complication of diabetes mellitus, including diabetic neuropathy, neurogenic arthritis, peripheral vascular lesions, ulcers and diabetic foot osteomyelitis, etc.[11]. The latest statistics shows that the incidence of diabetic foot in diabetic patients is about 1%-4%, and increases with a speed of 2% annual[12]. In addition, according to epidemiological statistics, the annual amputation rate due to diabetic foot is as high as 30% in China, which has become the main factor that threatens the survival and the quality of life of diabetics patients[13]. The pathological studies indicate that[14]the onset of diabetic foot is mainly related to peripheral vascular disease,neuritis lesions, plantar pressure and foot infection etc.,and the pathogenesis of which is the disorders of glucose metabolism, fat metabolism, electrolyte etc. of diabetes mellitus patients, resulting in plant neurological dysfunction,peripheral artery ischemia, occlusion, if the foot skin suffers from physical and chemical infection under such a condition,it will eventually develop into diabetic foot. Moreover, the clinical studies found that the abnormal hemorheology is closely related to the onset of diabetic foot, and abnormal hemorheology will lead to changes of blood flow in blood vessel so as to accelerate the occurrence and development of vascular disease, and peripheral vascular lesions are the main factors inducing the occurrence of diabetic foot[15].

In recent years, although Western medicine has made great progress in the treatment of diabetic foot, techniques such as stem cell transplantation have not been mature yet,and the clinical efficacy needs to be confirmed by long-term practice and researches[16]. Alprostadil is a kind of PGE1 and can be used in widely vasodilatation. Its main carrier is lipid microsphere. The main features of the basic structure are high activity, fast decomposition and metabolism[17]. Firstly,PGE1 is not easy to be inactivated under the protection of lipid microspheres, which is helpful in promoting medicines target at damaged blood vessels, thus inhibiting the blood vessels' expansion, platelet aggregation and reducing blood viscosity[18]. Secondly, alprostadil is a kind of medicine which can extensively dilate vascular, selectively expand the blood vessels at the site of blockage and add the collateral circulations. Thirdly, it can significantly enhance the deformability and oxygen-carrying capacity of erythrocyte,so as to improve the ischemia and hypoxia status of lower limb. In addition, alprostadil has a definite effect in treating the lower limb arteria vasculopathy of patients with diabetes mellitus, and can significantly improve the patients' limbs pain and numbness and other peripheral neuropathy symptoms. Therefore, it is widely used in the clinical treatment of diabetic complications.

The diabetic foot belongs to the category of gangrene in traditional Chinese medicine. It is conceived as closely related to the formation of blood stasis, and the key pathogenesis is static blood blocking collaterals. Patients who suffer from the consumptive thirst for a long time will be with the performance as deficiency of both qi and blood, powerless movement of blood and static blood blocking collaterals,and making the limbs lack the nourishment of blood, yin impairment affecting yang and then both yin and yang being impaired, and finally the disease developing into diabetes mellitus[19]. Diabetes mellitus belongs to the symptom of deficiency of the root while excess of manifestation. The deficiency of the root refers to the deficiency of both qi and yin, while excess of manifestation refers to pathological obstruction like blood stasis, phlegm-dampness and heat in the body vessels, and the final formation of vessel impediment, yin gangrene, blood impediment, etc. Treatment should mainly be based on invigorating blood and dissolving stasis, as well as warming and promoting the channels.

Shuxuening Injection is a kind of pure Chinese herbal preparation made from Ginkgo Biloba extract, which has the function of invigorating blood and dissolving stasis, as well as warming and promoting the channels. The main components of the medicine are Ginkgo flavone glycosides and Ginkgo lactone with various biological effects. The ginkgo flavonoids can activate the enzymatic activity of superoxide dismutase, inhibit the activity of lipid hydroperoxide, enhance the deformability of erythrocyte,reduce blood viscosity and improve the function of hemorheology, Ginkgo Lactone is regarded as the most promising natural antagonist of platelet activating factor in clinical practice, which can specifically antagonize platelet aggregation caused by PAF, thus effectively inhibiting the formation of thrombus[20]. Therefore, Shuxuening Injection has synergistic pharmacological effect with alprostadil, and these 2 medicines can alleviate patients' clinical symptoms by improving the blood supply of occluded blood vessels and hypoxia-ischemic symptoms of peripheral tissue.

The result of this study shows that the total effective rate of the observation group was significantly higher than that of the control group. The improvement of syndrome score of Chinese medicine (pain, numbness, swelling,claudication), the healing outcomes of foot ulcer (ulcer area, oxygen partial pressure of wound, pH of wound),hemodynamics of dorsal artery (blood flow velocity of dorsal foot artery, blood vessel diameter, RI, PI) etc.were significantly higher than that in the control group.The result indicates that the combination of Shuxuening Injection and alprostadil can quickly improve the clinical symptoms, correct the hemodynamic abnormality of dorsal foot artery and promote the healing of foot ulcer.These 2 medicines have synergistic effect.