Research progress of compound Baiyu powder in treatment of chronic refractory wounds

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(1.Urinary Surgery; 2.Nursing Department; 3.Laboratory Medicine; 4.Laboratory of Cell and Molecular Biology; 5.Orthopedics Department, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu, 210028)

ABSTRACT: Chronic refractory wounds are common and frequently-seen diseases in surgery.Due to their long course of disease and complex pathogeneses, chronic refractory wounds arouse high attention in clinic.With the preliminary results of clinical research of their pathogeneses and new treatments achieved, traditional Chinese medicine (TCM), with its unique concept, breaks the limitation commonly existing in the methods of western medicine, especially obtaining certain achievements in chronic refractory wounds.This paper reviewed the therapeutic effects of compound Baiyu powder in the treatment of chronic refractory wounds to prove to be effective, convenient to use and save medical costs.

KEY WORDS: compound Baiyu powder; chronic refractory wounds; oral ulcer; abscess; diabetic foot; empirical formula; bacterial biofilm; pathogeneses

Chronic refractory wounds are localized skin and tissue injuries caused by trauma and diseases[1].They are clinically difficult problems commonly in surgical diseases, and their morbidity takes up 1%-3% of the general population.According to the statistics[2], chronic refractory wounds cost 500 to 850 millions of dollars on medical expenses annually in the United States alone, and an average of more than 10 000 dollars for each patient.Compound Baiyu powder is an empirical formula from Professor LIU Zaipeng, a prestigious physician of traditional Chinese medicine (TCM), for the treatment of chronic refractory wounds[3].The members of the project team of our hospital used it in clinic, and found that it was effective in the treatment of chronic refractory wounds.Therefore, this paper made a review of the relevant research literatures in the recent years.

Pathogeneses of chronic refractory wounds Viewpoints of modern medicine research

Chronic refractory wounds are complex in pathogeneses and difficult to heal.The main reasons are persistent inflammatory response, infection, formation of bacterial biofilm, and poor blood supply for wounds[4].Modern medicine research holds that wound healing is an autologous regeneration process and a repair process generated to maintain body's stability.Generally, wound healing includes three phases (embracing three phases of biological process).The first phase is inflammation, the second phase is tissue formation, and the third phase is tissue remodeling.The tissue of the body suffers wounds, it first manifests by inflammatory response, and granulation tissue regenerate afterwards.Epidermal basal hyperplasia around the edge of the wound occurs, migrates towards the center of the wound to form epithelium, and cover the surface of granulation tissue.After the new skin barrier is established, granulation tissue is self-repairing again, and finally, normal fibrous tissue forms.During the whole process of wound healing, growth factor, cytokines and inflammatory medium play a certain role.

Viewpoints of TCM research

Chronic refractory wounds belong to the categories of “obstinate pythogenic sore of skin”, “ecthyma”, “gangrene of finger or toe” and “decubitus ulcer” in TCM.It is widely believed that their pathogeneses are mainly associated with weak healthy qi, blood stasis and accumulated toxin although there are many theories like weak healthy qi, dampness-heat, heat toxin, and blood stasis, ect..Hence, a TCM doctor writes out a prescription for patients at different stages of diseases usually based on pathogenic factors such as “deficiency”, “stasis” and “evil (toxin)”.For example, drugs of removing pus to activate blood stasis, tonifying deficiency, promoting tissue regeneration, clearing away heat and toxin, and removing dampness to dredge collaterals are used in external therapy to promote wound repair[5].

Treatment principle of chronic refractory wounds

Chronic refractory wounds are caused by multiple factors.To improve therapeutic effect, comprehensive therapies are generally adopted.And no matter what the cause, treatment follows TIME (tissue, infection, moisture and edge) principle[6].“T (Tissue)” means removal of inactive and necrotic tissue.Inactive wound tissue provides a place for bacterial growth which leads to inflammatory response and retards the epithelization, so the first thing is debridement for chronic wounds.“I (Infection)” means control of inflammation and infections in and around the edge of the wound.Uncontrollably spontaneously formed inflammatory response is considered as the primary cause that chronic wound is hard to heal.To be specific, chronic inflammatory response leads to accumulation of neutrophile granulocyte and macrophagocyte, which makes inflammatory factors released and accumulated, finally slowing the healing speed of wound[7].“M (Moisture)” means keeping wound moisture balanced.The environment with relative moisture is conductive to the epithelization of wound, but excessive fluid in the wound results in the infiltration at the edge of wound, and makes the wound hard to be healed.“E (Edge)” means removal of non-transitional tissue at the edge of wound.In recent years, due to the features of long course, high medical expenses and complex pathogeneses, chronic refractory wounds arouse high attention in clinic.The preliminary achievements of clinical research on their pathogeneses and new treatments are gained such as vacuum aspiration, stem cell transplantation, growth factor, physical therapy, hyperbaric oxygen therapy, larval debridement, and TCM therapy.Especially TCM, with its unique concept, breaks the limitation commonly existing in the methods of western medicine, particularly obtaining certain achievements in the treatment of chronic refractory wounds.

Research of compound Baiyu powder for treating chronic refractory wounds Main ingredients of compound Baiyu powder

The main ingredients of compound Baiyu powder are Baizhi (radixangelicaedahuricae), calcined Shigao (gypsumfibrosum), and Baiji (bletillastriata).Baizhi, a monarch drug in the prescription, warm in property and pungent and slightly bitter in flavor, possesses the function of activating blood circulation and generating muscle.Baiji and calcined Shigao are assistant drugs in the prescription, of which Baiji, slightly cold in property and bitter and astringent in flavor, assists to stop bleeding, and to dispel edema to generate muscle, and calcined Shigao, cold in property and sweet, pungent and astringent in flavor, is to remove dampness to generate muscle, and to astringe the wound to stop bleeding.Those two drugs assist Baizhi to generate muscle to heal the wound.Additionally, borneol, an assistant drug in the prescription, cool in property and bitter in flavor, is to clear away heat, detoxify, and contract the wound.Together, this prescription has the effect of dispelling edema, stopping bleeding, and generating muscle to heal the wound.In this paper, the formula of compound Baiyu powder in the treatment of chronic refractory wounds is thought to be based on the theoretical bases of TCM pathogenesis and syndrome differentiation and treatment[8-10].

Clinical researches

Treatmentoforalulcer: Compound Baiyu powder can up-regulate the expression of epithelial growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), increase the density of micro-vessels, and reduce the inflammatory response of oral musositis[11].This project team conducted the prospective clinical study of compound Baiyu powder in the treatment of patients with oral ulcer in earlier stage[12].Totally 120 patients were divided into observation group (n=60) and control group (n=60) according to random number table.Patients in control group were given symptomatic treatment, while those in observation group were supplemented by compound Baiyu powder and the corresponding nursing interventions.The research results showed the total effective rate was 100.00% (8 cured cases+14 particularly effective cases+38 effective cases) in observation group was obviously higher than that in control group.

Inhibitionofbodysurfaceabscess: The frequency of dressing change and healing time of the 15 patients with abscess incision and drainage treated with compound Baiyu powder plus vaseline gauze were compared with those of the other 15 cases treated with vaseline gauze routinely, and the results showed that the former had an obviously shorter course, less frequent dressing changes, and shorter healing time than the latter[13].

Ulcerativegranulationtissue: Compound Baiyu powder can promote the growth of fibroblast on the wound and facilitate wound healing[3].The project team observed the clinical effects of compound Baiyu powder in the treatment of patients with chronic refractory wounds.All patients were given treatment for primary disease and wound management like cleaning up the wound, assessment of the wound, and debridement.Based on that, patients in control group were used oily gauze + gauze for dressing change daily or every other day, while those in treatment group were used compound Baiyu powder +oily gauze + gauze or cotton cushion for dressing change every 2-3 days.The pressure ulcer scale for healing (PUSH) scores <14, and improvement conditions of exudate smell, bacterial culture negative transformation, infection control, and pain scores <5 in treatment group were better than those in control group (P<0.05).Thirty-five days after treatment, the response rate of treatment group was higher than that of control group.Moreover, the healing time, frequency of dressing changes, total treatment expenses and patients' satisfaction degree of treatment group were superior to those of control group (P<0.05).Together, those proved that compound Baiyu powder had better therapeutic effects and indications in the treatment of chronic refractory wounds.

Diabeticfoot: Compound Baiyu powder was effective in the treatment of refractory diabetic wound[14].The project team selected 47 patients with diabetic foot according to the diagnostic standards, and divided them into treatment group (n=24) and control group (n=23).Patients in treatment group were given compound Baiyu powder for external application based on treatment in control group.The results showed that the clinical effects of treatment group was better than that of control group (P<0.05); the wound healing rate in treatment group was higher than that in control group on the 7thday and on the 21stday (P<0.05); the healing time in treatment group was lower than that in control group (P<0.05).

Crackednippleinlactationperiod: Compound Baiyu powder was effective in the treatment of cracked nipple, with good analgesic effects[15].The project team enrolled 60 puerperae with cracked nipple, of which, 30 patients in observation group were used compound Baiyu powder based on conventional treatment in control group, and the results showed that the therapeutic effect of observation group was 96.70%, higher than 86.67% of control group.

Basic researches

Inhibitingthegrowthofstaphylococcusaureusandpseudomonasaeruginosa: In vitro study verified that compound Baiyu powder could inhibit the growth of staphylococcus aureus (SA) and pseudomonas aeruginosa (PA)[16].Under the in vitro condition, compound Baiyu powder solution could inhibit the proliferation of SA (ATCC29213) and PAO1, and lower the optical density (OD) value of those two bacterial genuses.The project team used double broth dilution method to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of compound Baiyu powder acting on standard strains ATCC29213 and 33 stains of clinically isolated SA, and used crystal violet staining to determine minimal inhibiting concentration (sMIC) of compound Baiyu powder against biofilm.The results showed that the MIC of compound Baiyu powder against standard strains ATCC29213 and strong biofilm strain SA17 was 25 mg/mL and 50 mg/mL respectively, and the MBC of those was 50 mg/mL and 100 mg/mL respectively.Standard strain ATCC29213 was biofilm positive bacterium, and among 33 strains of isolated SA, 25 ones were biofilm positive bacteria and the positive rate was 75.60%.The sMIC50 and sMIC80 of compound Baiyu powder against standard strain ATCC29213 were 1.6 mg/mL and 6.3 mg/mL respectively, and those of compound Baiyu powder against strong biofilm strain SA17 were 3.2 mg/mL and 6.3 mg/mL respectively.This proved that compound Baiyu powder could inhibit the biofilm formation of SA and possessed bacteriostatic and bactericidal effect.

Eradicatingbacterialbiofilm: Traditional concept holds that tissue repair, which is a dominant factor of wound healing, contains extracellular matrix in the local wound, repairing cells and expressions of growth factors.The research showed that difficultly-inhibited residual bacteria play an important role in the process of wound healing in that the main factors of the their formation were bacterial biofilm and quorum sensing system[17].At present, local treatment is mainly adopted for bacterial biofilm of wound for systemic medication is difficult to invade the bacterial biofilm.As for chronic refractory wounds, the comprehensive treatment, besides inhibiting quorum sensing singling, is used to repair the wound and to strengthen the local immune responses which play a certain role in reducing biofilm formation[18].A single drug is difficult to achieve the above multiple effects, hence, compound Baiyu powder for external application provides a new thought for the treatment of chronic refractory wounds caused by bacterial biofilm.Its effects are associated with the inhibition of quorum sensing of bacterial biofilm and eradication of bacterial biofilm.For example, it can eradicate bacterial biofilm on wound in the treatment of skin ulcer.For two quorum sensing systems of SA and PA with bilfilm formation, we establishedinvitromodel of bacterial biofilm andinvivomodel of rats with skin ulcer to prove that compound Baiyu powder had the inhibiting effect on bacterial bilfilm formation.

Conclusion

Compound Baiyu powder has a certain effect on chronic refractory wounds, especially effective in the treatment of oral ulcer and diabetic foot in clinical practice.It can inhibit body surface abscess, promote the growth of fibroblasts on the wound, and cure cracked nipple in lactation period.In basis research, it can inhibit the proliferation of SA and PA and eradicate the bacterial biofilm on the wound.Based on the previous studies, the project team will continue to explore the relative mechanisms and clinical practice of compound Baiyu powder in the treatment of chronic refractory wounds in the future studies.