Retrospective Analysis and Summary on Efficacy of Jianpi Shengxue Tablet in the

Jinqing LI, Longjiao CONG, Muchen LI, Chongluan SHI, Wenlan LIU, Wenjuan WANG, Naidong HU*

1.Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 101100, China; 2.Chaoyang Hospital, Capital Medical University, Beijing 100020, China; 3.School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China

Abstract [Objectives]The research aimed to make a retrospective analysis and summary on the efficacy of Jianpi Shengxue Tablet in the treatment of iron deficiency anemia.[Methods]A total of 200 patients with iron deficiency anemia who were treated at outpatient in Tongzhou District of Dongzhimen Hospital of Beijing University of Chinese Medicine from January 1, 2017 to October 30, 2020 were selected as the research objects.All these patients were given treatment with Jianpi Shengxue Tablet for the first time.Results of blood routine examination, serum iron concentration, total iron binding capacity and ferritin were compared before and after treatment at different dates.Subjective symptoms and adverse reactions were also described.Jianpi Shengxue Tablet was given orally after meals, 3 tablets each time, 3 times a day.[Results]Hemoglobin level was(83.58±15.81)g/L(M±SD, n=200)before treatment, and(103.40±12.60)g/L(n=74)after 2 week’s treatment, with a 24.3% increase(P=0.004 7).Hemoglobin concentration was(111.9±19.4)g/L(n=47)at the 4th week after treatment, which was near normality;(126.0±9.49)g/L(n=30)at the 6th week with complete normality and(130.7±7.95)g/L(n=23)at the 8th week.MCV, MCH and MCHC increased gradually after treatment.Serum total iron biding capacity decreased, while serum iron and ferritin increased gradually, and the three indexes were significantly different at the 4th week after treatment as compared with those before treatment(P﹤0.01).Subjective symptoms were improved in the 1st week from starting treatment among all the cases.The adverse events were mainly gastrointestinal irritation, occurring in 7/200 cases(3.5%).[Conclusions]Jianpi Shengxue Tablet is quite effective and safe in the treatment of iron deficiency anemia, with rapid comprehensive improvement of anemia-related symptoms and increase of hemoglobin and red blood cell parameters.

Key words Iron deficiency anemia, Jianpi Shengxue Tablet, Therapy, Traditional Chinese medicine and drugs

1 Introduction

Iron deficiency anemia is the most common type of anemia, which is induced by insufficient hemoglobin synthesis caused by iron deficiency, and common causes are menorrhagia, chronic gastrointestinal bleeding, too little meat intake and long-term drinking a lot of strong tea[1].A few patients can be caused by the loss of iron from the urinary tract due to chronic intravascular hemolysis, such as paroxysmal nocturnal hemoglobinuria[2].The blood routine of typical iron deficiency anemia is microcytic hypochromic anemia, accompanied by abnormal iron metabolism indexes.The treatment is mainly oral iron, and the commonly used oral dosage form is ferrous succinate[3], ferrous sulfate and polysaccharide iron complex[4].Intravenous iron supplementation should be considered only when iron cannot be taken orally, or oral iron has obvious gastrointestinal symptoms, or iron deficiency needs to be corrected quickly.Ferrous succinate and other oral iron agents have obvious adverse stimulating effect on the stomach, and 40% of patients have obvious adverse reactions[5], which cause that some patients are unable to continue treatment.Intravenous iron often has adverse reactions such as chest tightness, dyspnea and decreased blood pressure.Therefore, clinically, we are eager for preparations with better safety, fewer adverse reactions and faster effect to treat this disease.Jianpi Shengxue Tablet is a compound preparation containing traditional Chinese medicine for strengthening spleen, tonifying Qi, nourishing yin and calming nerves, as well as ferrous sulfate.When applying Jianpi Shengxue Tablet to cure iron deficiency anemia, it is observed the advantages of rapid improvement of anaemia, less adverse reactions and high patient compliance.Retrospective analysis on efficacy and side effects of 200 patients was conducted.

2 Data and methods

2.1 General information200 patients with iron deficiency anemia diagnosed at outpatient in Department of Hematology and Oncology, Tongzhou District, Dongzhimen Hospital from January 1, 2017 to October 30, 2020 were taken as research objects.Among them, there were five men and 195 women, and the age ranged from 19 to 88 years old, and mean age was(40.9±11.8)years old.The course of disease was between 0.5 and 7.0 years, and average course of disease was(2.7±1.4)years.Collection methods: patient data from the doctor’s outpatient workstation was collected.According to the setting time, the patients were arranged in reverse Pinyin order, and a total of 200 cases were collected.To observe therapeutic effect of anemia and changes of erythrocyte parameters, they were divided into pre-treatment group, 2 weeks’ treatment group, 4 weeks’ treatment group, 6 weeks’ treatment group and 8 weeks’ treatment group.To observe changes of iron metabolism indexes before and after treatment, they were divided in to pre-treatment group, 4 weeks’ treatment group, 6 weeks’ treatment group and 8 weeks’ treatment group.Because there was little change in iron metabolism indexes after 2 weeks’ treatment, and the patient’s compliance was small when blood was drawn again for checking iron metabolism indexes after 2 weeks’ treatment, so the iron metabolism indexes after 2 weeks’ treatment were not observed.

2.2 Diagnostic criteria(i)Microcytic hypochromic anemia: male hemoglobin<120 g/L, female hemoglobin<110 g/L, mean corpuscular volume(MCV)<80 fl, mean corpuscular hemoglobin(MCH)<27 pg, mean corpuscular hemoglobin concentration(MCHC)<320 g/L;(ii)clear etiology and clinical manifestations: more menstruation, less meat intake, too much drinking of strong tea and coffee for a long time;(iii)serum iron<8.95 μmol/L, total iron binding capacity(TIBC)>64.44 μmol/L;(iv)serum ferritin<12 μg/L; iron deficiency anemia can be diagnosed if any two of items 1 and 2 and 4 are met.

2.3 Inclusion criteria(i)Corresponding with diagnosis of iron deficiency anemia;(ii)Jianpi Shengxue Tablet was used continuously for more than 4 weeks;(iii)blood routine examination was conducted at least once within 4 weeks;(iv)first outpatient treatment in Department of Hematology and Oncology, Tongzhou District, Dongzhimen Hospital from January.

2.4 Exclusion criteriaPatients complicated with renal insufficiency, malignant tumor, rheumatic immune disease and liver disease were excluded.

2.5 Shedding and exclusion criteria(i)Adverse reactions during treatment and intolerable;(ii)those who did not complete the treatment and lost the halfway visit;(iii)self quitter.

2.6 Therapeutic methodBlood routine must be checked before treatment, and four anemia items must be checked before treatment in most patients(containing total iron binding capacity, serum iron, serum ferritin, folic acid and vitamins B12).In treatment process, patients were required to recheck blood routine once every 2 weeks and recheck 4 anemia items and ferritin after 1 month’s treatment, but not all patients could be fully implemented.Therefore, the number of patients rechecking blood routine and iron metabolism indexes at different times during the treatment was not exactly the same.Therapeutic method: Jianpi Shengxue Tablet(Wuhan Jianmin Pharmaceutical Co., Ltd., Guoyao Zhunzi Z10940043), 3 tablets/times, 3 times/d, which was taken orally in 0.5 h after meal.If the patient had gastrointestinal symptoms such as stomach discomfort, nausea and abdominal distension, the oral dose was reduced to 2 tablets/time, 3 times/d, oral administration after 0.5 h.The recommended course of treatment was 4 months.In the statistical data, all patients took medicine for at least 2 weeks, and they should avoid tea and coffee during medication.If the patient had obvious hair loss, insomnia and constipation, Shengxuebao Oral Liquid could be added(Tsinghua Jianren Xi’an Xingfu Pharmaceutical Co., Ltd., Guoyao Zhunzi Z20050770), 15 mL/times, 3 times/d.When sleep and constipation were improved, Shengxuebao Oral Liquid could be stopped, and it was generally used for 2-4 weeks.

2.7 Observation indexesHemoglobin, MCV, MCH, MCHC, serum iron, total iron binding capacity, and ferritin.

2.8 Efficacy criteriaAfter treatment, it was judged as effective when the hemoglobin level increased by more than 15 g/L.Dizziness, fatigue, anorexia, pale complexion, palpitation, shortness of breath and other conscious symptoms were improved.

2.9 Statistical methodsExcel was used to calculate days difference between the start of treatment and each review, and then it was divided by 7 to converted to the number of weeks between treatment and review.Statistical software GraphPad Prism 5 was used for descriptive analysis, unpaired two tailedt-test, mapping, andP<0.05 showed that the difference had statistical significance.

3 Results

3.1 Dynamic changes of hemoglobin200 patients were tested for blood routine before treatment, but only some patients were rechecked at different times after the beginning of treatment.The results displayed that hemoglobin concentration was(83.58±15.81)g/L(M±SD,n=200)before therapy;(103.40±12.60)g/L(n=74)after 2 weeks’ treatment, which rose by 24.3%;(111.9±19.4)g/L(n=47)after 4 weeks’ treatment, which was close to normal.After 6 weeks’ treatment, hemoglobin was(126.0±9.49)g/L(n=30), which was completely normal.After 8 weeks’ treatment, hemoglobin concentration was(130.7±7.95)g/L(n=23).The results were shown in Fig.1.

Note: There were 200 cases before treatment, and 74 cases were reexamined after 2 weeks’ treatment.47 cases were reexamined after 4 weeks’ treatment, and 30 cases were reexamined after 6 weeks’ treatment, while 23 cases were reexamined after 8 weeks’ treatment.

3.2 Dynamic changes of erythrocyte parametersAfter therapy, MCV, MCH and MCHC in erythrocyte parameters were obviously improved than those before therapy.Among them, it showed a rapid improvement trend by 2-4 weeks’ treatment, and the patients completely returned to normal in about 6 weeks, and the difference had statistical significance.The results were shown in Fig.2.

Note: Panel A was change of MCV before and after therapy; Panel B was change of MCH before and after therapy; Panel C was change of MCHC before and after therapy.There were 200 patients before therapy, and 74 cases were reexamined after 2 weeks’ treatment.47 cases were reexamined after 4 weeks’ treatment, and 30 cases were reexamined after 6 weeks’ treatment, while 23 cases were reexamined after 8weeks’ treatment.

3.3 Dynamic changes of iron metabolism indexesAfter therapy, the total iron binding capacity decreased gradually, and serum iron and ferritin increased gradually.The improvement in the 4thweek after therapy was the most obvious, and then it has improved slowly.The results were shown in Fig.3.

Note: Panel A, total iron binding capacity gradually declined.Panel B, serum iron rose.Panel C, ferritin also rose.The three iron metabolism indexes were improved obviously after 4 weeks’ therapy(P﹤0.01).For total iron binding capacity examination, there were 110 patients conducted before therapy, and 8 cases were reexamined after 4 weeks’ treatment.9 cases were reexamined after 6 weeks’ treatment, while 5 cases were reexamined after 8 weeks’ treatment.For serum iron, there were 110 patients conducted before therapy, and 8 cases were reexamined after 4 weeks’ treatment.9 cases were reexamined after 6 weeks’ treatment, while 5 cases were reexamined after 8 weeks’ treatment.For ferritin, there were 97 patients conducted before therapy, and 8 cases were reexamined after 4 weeks’ treatment.8 cases were reexamined after 6 weeks’ treatment, while 5 cases were reexamined after 8 weeks’ treatment.

3.4 Symptom improvement and adverse reactionsAll cases achieved significant symptom improvement within 1 week of treatment, including increased physical strength, excited appetite, relief of palpitation, reduction of shortness of breath, improvement of sleep and disappearance of abdominal distension.In 4 weeks, both symptoms and laboratory indexes were improved, and the effective rate was 100.0%.In 200 patients, 7 patients(3.5%)had abdominal discomfort after taking the medicine, mainly manifested in nausea, infraxiphoid fullness, stomach noise, dull pain, increased stool times and increased intestinal farting.By reducing the number of tablets taken each time, the adverse reactions can disappear.

3.5 Typical casesCase 1: patient A, female, 49 years old, initial diagnosis on November 27, 2018.Chief complaint: fatigue and pale complexion for more than 20 years.For more than 20 years, she has been weak, short of breath, pale, normal meat intake and occasionally drinking tea, no menorrhagia, no gastrointestinal diseases, no liver and kidney diseases, and no hand and foot joint pain.Physical examination: pale, no abnormality in other parts.Blood routine showed hypochromic anemia, and iron deficiency anemia was diagnosed.Jianpi Shengxue tablets were given, 3 tablets/time, 3 times/d, oral administration after meals, and therapy results were shown in Fig.4A and Fig.4B.Case 2: patient B, female, 36 years old, initial diagnosis on February 23, 2018.The chief complaint was dizziness, fatigue, pale face for 1 month, normal menstruation, normal meat intake, no tea drinking, no hemorrhoids bleeding, no gastrointestinal diseases, no tumors and rheumatic immune diseases.Physical examination: pale, no abnormality in other parts, and she was diagnosed as microcytic hypochromic anemia by blood routine.Treatment process was shown in Fig.4C and Fig.4D.

Note: Changes of hemoglobin, erythrocyte parameters and iron metabolism indexes in patients A(Fig.A and B)and B(Fig.C and D).

4 Discussion

Iron deficiency anemia is the most common type of anemia.The common reasons are reduced iron-containing food intake, such as long-term vegetarian diet, dislike of meat; impaired gastrointestinal absorption, such as chronic diarrhea and inflammatory bowel disease; excessive iron loss, such as gastrointestinal ulcer bleeding, tumor, hemorrhoid bleeding, long-term dialysis and repeated blood donation; increased demand and insufficient nutrition sources, such as the growth and development stage of infants and pregnant women[7].In traditional Chinese medicine, ancient doctors classified the disease as "yellow wilt", "yellow swelling", "consumptive disease" and "asthenia", which basically corresponded to mild, moderate and severe anemia of iron deficiency anemia.As far as the etiology is concerned, there are weakness of the spleen and stomach Qi, reduction of food nutrient transportation and transformation, and improper care after birth; blood loss due to blood syndrome and prolonged illness; low kidney function based on the theory of traditional Chinese medicine.

The decrease of hemoglobin content in red blood cells of iron deficiency anemia exceeds the decrease of red blood cell volume.Therefore, it presents microcytic hypochromic anemia, which is also one of the clues and bases for clinical diagnosis of the disease.The judgment index of microcytic hypochromic anemia is the abnormality of erythrocyte parameters: the red blood cell volume becomes smaller, and MCH and MCHC decrease.The occurrence of iron deficiency anemia is a gradual process.The first stage is the consumption of stored iron, which is characterized by the disappearance of extracellular iron in bone marrow, the decrease of iron granulocyte containing immature erythrocytes and the decrease of serum ferritin; further development will lead to decreased serum iron; and again further development, the synthesis of hemoglobin by red blood cells is insufficient, which is characterized by anemia, hemoglobin and erythrocyte reduction[8].Dizziness, weakness, pale complexion, palpitation, shortness of breath, abdominal distension, loss of appetite, hair loss and sparse menstruation may appear.TCM syndrome differentiation is internal and deficiency syndrome.The location of the disease is mainly in the spleen and kidney, often involving the heart and liver, and the spleen dominates the limbs.In the early stage, it is often manifested as limb fatigue, decreased spleen transport function, insufficient source of Qi and blood, and in the further development, it is manifested as insufficient heart and blood of insomnia and palpitation.When the amount of menstruation becomes less or the disease is caused by excessive menstruation, there will be insufficient performance of liver and kidney.Therefore, the disease often involves liver and kidney, namely the so-called "chronic disease will evenly damage kidney".

At present, the oral drugs for the treatment of iron deficiency anemia include Ferrous Succinate Tablet, Ferrous Sulfate Tablet and polysaccharide iron complex.These drugs all have gastric irritation to certain degree.In mild cases, they can cause gastric discomfort, dull pain and increase of the number of stools.In severe cases, they can cause nausea, vomiting and abdominal pain, so the patients have to interrupt the treatment[3,5].Therefore, there is an urgent need for oral iron with less adverse reactions and good curative effect.There is protein ferrous succinate oral liquid[9], ferrous lactate[10], and ferrous glycine chelate[11].Traditional Chinese medicine treatment of this disease mostly starts based on tonifying Qi and blood, strengthening spleen Qi, and assisting transportation.Blood tonifying decoction drugs such as Danggui Blood Tonifying Decoction, Guipi Decoction and Bazhen Decoction are commonly used in clinical treatment of this disease[12].Recently, the consensus of experts suggests adding "soap alum" and "calcined green alum" in these decoction[13], and the main chemical component of "soap alum" and "calcined green alum" is ferrous sulfate.

Jianpi Shengxue Tablet is a Chinese patent medicine with the functions of strengthening spleen and stomach Qi, nourishing blood and calming nerves, and contains ferrous sulfate[14].Iron deficiency anemia often has dizziness, fatigue, pale complexion, palpitation, shortness of breath, loss of appetite, abdominal distention and insomnia.The syndrome differentiation of traditional Chinese medicine is yellow wilt, and all patients had heart and spleen deficiency syndrome and Qi-blood deficiency syndrome.The efficacy of Jianpi Shengxue Tablet in the treatment of 200 patients with iron deficiency anemia was retrospectively summarized here, and it was found that all patients were benefited.Dizziness, fatigue, palpitation, shortness of breath, appetite, abdominal distention and insomnia were usually significantly improved in one week.After treatment with Jianpi Shengxue Tablet, 3 tablets per time, 3 times per day, orally for 2 weeks, the hemoglobin increased by 24.3% compared with that before treatment, and the hemoglobin could nearly reach normal at 4 weeks.

During the treatment with Jianpi Shengxue Tablet, the erythrocyte parameters gradually improved with the increase of hemoglobin.Erythrocyte volume, MCH and MCHC usually reached normal after 6 weeks of treatment, and the recovery time of erythrocyte cell parameters was slightly slower than that of hemoglobin.

The changes of iron metabolism indexes in iron deficiency anemia showed that the total iron binding capacity increased, and the serum iron and ferritin decreased[7].After therapy, total iron binding capacity gradually declined, and serum iron and ferritin rose.Among them, serum iron and ferritin were lower at the 8thweek than those at the 6thweek.The reason for this phenomenon may be the error caused by fewer cases entering the statistics, because only 5 patients reviewed serum iron and ferritin after 8 weeks of treatment, but whether there were other reasons was worthy of further study.Clinically, not all patients can be rechecked at the specified time.Some patients buy medicine or go to other medical institutions for treatment after the treatment improves.Some patients come back for follow-up but are unwilling to do laboratory examination.Some patients get better after treatment for several weeks and no longer take medicine for treatment due to various reasons, such as long journey, lack of attention or change to diet improvement at home.The longer the treatment time, the fewer cases of follow-up and blood reexamination.

Jianpi Shengxue tablet contains Codonopsis Radix, Poria, fried Macrocephalae Rhizoma, Radix Rhizoma Glycyrrhizae, Astmgali Radix, Rhizoma Dioscoreae, fried Galli Gigerii Endothelium Corneum, Vinegar tortoise shell, Radix Ophiopogonis, vinegar Schisandrae Chinensis Fructus, calcined keel, calcined Ostreae Concha, Jujubae Fructus, ferrous sulfate and vitamin C.Among them, Codonopsis Radix and Astmgali Radix replenish Qi, strengthen the spleen and stomach Qi, provide the source of biochemistry, replenish Qi and generate blood; Poria, Macrocephalae Rhizoma, and Rhizoma Dioscoreae help Codonopsis Radix and Astmgali Radix to strengthen the spleen and replenish Qi; Schisandrae Chinensis Fructus, Radix Ophiopogonis, vinegar tortoise shell and Jujubae Fructus nourish yin and blood; Galli Gigerii Endothelium Corneum can digest food and strengthen the stomach, so that various drugs can supplement without stagnation.Calcined keel and calcined Ostreae Concha can calm the nerves.Calcined Ostreae Concha can also inhibit the production of gastric acid, treat stomach pain and protect gastric mucosa.Radix Rhizoma Glycyrrhizae can supplement Qi, and coordinate various drugs, and the adding of ferrous sulfate could promote the formation of new blood[14].Vitamin C can also promote the absorption of ferrous.The prescription takes into account the common symptoms related to blood deficiency and Qi deficiency in iron deficiency anemia, as well as iron absorption and gastrointestinal stimulation injury.Analyzed from modern pharmacology, Codonopsis Radix, Poria, fried Macrocephalae Rhizoma, Radix Rhizoma Glycyrrhizae are the components of Sijunzi Decoction.They can play complex pharmacological effects through multiple signal pathways and multiple targets, and can regulate gastrointestinal movement, promote digestion and absorption, resist mucosal damage and improve intestinal mucosal immune function[15].The polysaccharide of Astmgali Radix has antioxidant damage.Rhizoma Dioscoreae is rich in allantoin[16], which can promote the regeneration of mucosal epithelial cells, stimulate the growth of healthy tissues, heal wounds, and protect gastric mucosa from damage[17].At present, compound allantoin tablets are commonly used to treat chronic gastritis and peptic ulcer, suggesting that Rhizoma Dioscoreae in Jianpi Shengxue Tablet plays an important role in protecting gastric mucosa from ferrous sulfate stimulation.Schisandrae Chinensis Fructus, Radix Ophiopogonis and tortoise shell nourishing liquid can calm the heart and the mind, and has the effects of sedation, anti-inflammatory, anti-oxidation and protecting peripheral nerves.Due to the comprehensive effect of various components, Jianpi Shengxue Tablet can quickly correct anemia, has less irritation to the stomach, and can also significantly improve sleep.

The incidence of adverse reactions was 3.5%, which was lower than 40% of ferrous succinate reported in the literature[5].The main adverse reactions were gastrointestinal irritation symptoms, such as nausea, infraxiphoid discomfort, abdominal distension and increased stool frequency.It is reported that Jianpi Shengxue Tablet has good curative effect and safety on iron deficiency anemia in pregnant women[18].Treating patients with acute ischemic stroke complicated with iron deficiency anemia, it can not only improve the symptoms of anemia, but also reduce the level of inflammatory mediators and the disability rate[19].It is suggested that Jianpi Shengxue Tablet has high safety and multiple action mechanisms, which may be the reason for its good efficacy and less adverse reactions.

In short, Jianpi Shengxue Tablet is indeed an ideal drug for the treatment of iron deficiency anemia.It has the characteristics of rapid hemoglobin increment, high effective rate, obvious improvement of anemia related symptoms and less adverse reactions.

ChineseversionofthispaperhasbeenpublishedintheWorldChineseMedicine.