Analysis of Adverse Drug Reactions Caused by Chinese Patent Medicine Treatment Based on Kidney Damp-heat Syndrome and Damp-turbidity Syndrome

Wei MU, Guoqiang LIANG

1. Joint Logistics Support Force of the Chinese People’s Liberation Army, 904th Hospital, Wuxi 214044, China; 2. Clinical Pharmaceutical Laboratory of Traditional Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215009, China

Abstract [Objectives] To determine relationship of the adverse drug reaction (ADR) occurrence of the single use and combined use of Huangkui Capsule and Haikun Shenxi Capsule. [Methods] To determine relationship of the ADR occurrence of the single use and combined use of Huangkui Capsule and Haikun Shenxi Capsule. [Results] The main adverse drug reactions of the single use of Huangkui Capsule or Haikun Shenxi Capsule was severe diarrhea (n=7, n=9), however the combined use of the two resulted in more occurrence of adverse drug reactions (n=23) with significant difference in contrast to the single use group (P=0.001 5, P=0.006 9). [Conclusions] When traditional Chinese patent medicines are used in combination to treat kidney damp-heat syndrome and damp-turbid syndrome, it is necessary to pay close attention to the occurrence of adverse drug reactions, especially the digestive system.

Key words Huangkui Capsule, Haikun Shenxi Capsule, Adverse drug reaction (ADR), Diarrhea, Nephrotic syndrome

1 Introduction

The main component of Huangkui Capsule is hollyhock flower and it is the dried corolla ofAbelmoschusmanihot(L.). It is sweet and cold in nature, and belongs to the kidney and bladder meridians. It has been used for damp-heat retention, edema of drenching turbidity, external treatment of carbuncle and swollen poison and scald caused by fire and water. The Huangkui Capsule has the effects of clearing damp-heat, detoxifying and detumescence. In clinic, it was usually applied in damp-heat syndrome of chronic nephritis with the symptoms of edema, lumbar pain, proteinuria, hematuria, yellow and greasy tongue fur,etc[1]. Pharmacological studies have shown that Huangkui Capsule can reduce the content of urinary protein and serum creatinine in animal models with glomerulonephritis[2]. Haikun Shenxi Capsule is mainly composed of fucoidan sulfate with the effect of removing turbidity and toxin. It has been used for treating dampness and turbidity syndrome for chronic renal failure with the symptoms of nausea, vomiting, poor appetite, abdominal distention, heavy-drowsy, little urine, edema, thick and greasy fur,etc[3]. Pharmacodynamic test shows that Haikun Shenxi Capsule can reduce the levels of serum creatinine and urea nitrogen, increase the content of serum albumin, and improve the pathological changes of renal tissue morphology in rats with renal failure. In addition, it can inhibit the type of delayed hypersensitivity induced by 2,4-dinitrochlorobenzene in mice, promote urination in normal or edematous rats, and increase renal blood flow in anesthetized dogs[4]. Both Huangkui Capsule and Haikun Shenxi Capsule can improve renal failure and be used for nephrotic syndrome caused by primary kidney disease or other diseases. However, in clinical setting, both Huangkui Capsule and Haikun Huangkui Capsule can cause adverse drug reaction (ADR) such as abdominal distension and discomfort, poor appetite,etc.in digestive system. Based on the data with ADR reports in our hospital, we conducted this study to explore and analyze the factors of ADR caused by the single or combined use of the Huangkui Capsule and Haikun Huangkui Capsule.

2 Materials and methods

We randomly selected 100 inpatient prescriptions of the single use of Huangkui Capsule and Haikun Huangkui Capsule from 2020-2022 in Suzhou TCM Hospital. We separately screened out 7 and 9 ADR reported cases of the single use of Huangkui Capsule or Haikun Huangkui Capsule. By the same way, we randomly selected 100 inpatient prescriptions of the combined use of Huangkui Capsule and Haikun Huangkui Capsule in 2021 in Suzhou TCM Hospital. We screened out 23 ADR reported cases of the combined use group. In addition, we performed both Chi-test and Fisher’s test for data analysis, and plotted graphs with the aid of GraphPad Prism 8.0 software.

3 Results and analysis

3.1 ADRs Statistics of Huangkui Capsule and Haikun Huangkui CapsuleBy the statistical analysis, the comparative results of the ADRs caused by the single use of Huangkui Capsule (n=7,χ2=147.9) or Haikun Huangkui Capsule (n=9,χ2=134.5), and the combined use of the two (n=23,χ2=58.52) showed significant differences (P<0.000 1), indicating that the occurrence of ADRs caused by the use of Huangkui Capsule or Haikun Huangkui Capsule were within the normal range in contrast with drug instructions. The greaterPvalue showed larger deviation from the normal range. Both the results from Chi-test and Fisher’s test supported this argument (Table 1 and Fig.1).

Table 1 ADRs statistics of Huangkui Capsule and Haikun Huangkui Capsule

Note: A. single use group of Huangkui Capsule, B. single use group of Haikun Huangkui Capsule, C. combined use group of Huangkui Capsule and Haikun Huangkui Capsule; **** denotes P<0.000 1.

3.2 Comparison of ADRs between the single and combined use of Huangkui Capsule and Haikun Huangkui CapsuleComparing with the ADRs of the single and combined use of Huangkui Capsule and Haikun Huangkui Capsule, we found that there was a significant difference in ADR occurrence between the single use group of Huangkui Capsule and the combined use group of the two (χ2=10.04,P=0.001 5) (Table 2 and Fig.2). ThePvalue of Fisher’s test was 0.002 5. Interestingly, the outcome was similar in the single use group of Haikun Huangkui Capsule and the combined use group of the two (χ2=7.292,P=0.006 9) (Table 2 and Fig.2). ThePvalue of Fisher’s test was 0.011 3. Subsequently, we hypothesized that if we considered the ADR occurrence of the single use of Huangkui Capsule or Haikun Huangkui Capsule as a whole, then comparing with those of the combined use group of the two, which showed that there was a significant difference between the virtual group and the combined use group of the two (χ2=8.589,P=0.003 4) (Table 2 and Fig.2). ThePvalue of Fisher’s test was 0.005 6 (Table 2).

Table 2 Comparison of ADRs between the single and combined use of Huangkui Capsule and Haikun Huangkui Capsule

Note: A. single use group of Huangkui Capsule, B. single use group of Haikun Huangkui Capsule, C. combined use group of Huangkui Capsule and Haikun Huangkui Capsule; Chi-test, P value.

4 Discussion

There are many records in Chinese medicine ancient books about hollyhock flower in treating kidney diseases such as Dusheng Powder recorded inPrescriptionsforUniversalRelief(Pu Ji Fang), made of 30 g hollyhock flower, fried as powder and took 3 g per meal for urolithiasis treatment. For another,MateriaMedicaofJiaYouReignrecorded that hollyhock flower made of powder dosage form can promote urination and baby birth, and treat for those who suffer from malignant sores and pus for a long time. Modern medicine research indicated that hollyhock flower had the functions of clearing away heat and dampness, removing toxins and expelling pus. It is made into Huangkui Capsule for better use in clinic, and contains multiple flavonoids compounds with the effects of anti-glomerulonephritis, clearing immune complexes in the circulatory system, reducing urinary protein, anti-platelet aggregation, protecting renal function and so on[5]. In clinic, Huangkui Capsule was used for the treatment of diabetic nephrotic syndrome frequently. However, it might induce the side effect of flatulence discomfort in upper abdomen or result in the occurrence of ADR with symptom of severe diarrhea. Therefore, as a kind of traditional Chinese patent medicine, occurrence of ADR in the use of Huangkui Capsule is unavoidable in clinical, and our results of data analysis also support this argument.

The main component of Haikun Huangkui Capsule is fucoidan sulfate, which is a biologically active substance extracted from kelp. It belongs to a water-soluble heteropolysaccharide with high adsorption, and can fully absorb toxic substances and excrete them from the body. Previous studies show that Haikun Huangkui Capsule can improve renal blood flow, resist renal fibrosis, promote the repair of damaged renal cells, and enhance the diuretic effect[6]. Currently, it has been widely used in clinic and has achieved remarkable results in the treatment of kidney diseases. Furthermore, it is reported that the combined use of Haikun Huangkui Capsules and Huangkui Capsules can significantly enhance the therapeutic effect of diabetic nephropathy syndrome. In addition, the instructions of Haikun Huangkui Capsule also clearly indicate that it might result in the occurrence of ADR in the digestive system. Therefore, our data also support such argument as the ADRs of Haikun Huangkui Capsules are common in clinical use.

The theory of Traditional Chinese medicine (TCM) believes that kidney disease belongs to the category of "consumption of labor" and "guange", with "hypofunction of spleen and kidney, dampness, heat, and toxin accumulating inside" as the main pathological changes. How to control proteinuria, improve the renal function of patients, and delay the deterioration of the kidney disease is the key factor of treatment in clinical[7]. At present, the combined use of multiple drugs is preferred for the treatment of various renal diseases in clinical setting. It is obvious that the combined use of multiple herbal medicine or Chinese patent medicine is common in TCM practice to enhance efficacy and reduce toxicity, which can reduce ADR occurrence and drug resistance induced by chemical drugs to a certain extent[8]. Huangkui Capsules are widely used in the treatment of chronic glomerulonephritis, IgA nephropathy, diabetic nephropathy and other diseases due to its effect of clearing dampness and heat, reducing swelling and detoxification[9-10]. Similarly, Haikun Huangkui Capsule is a commonly used traditional Chinese patent medicine for treatment of chronic kidney disease with significant advantages in improving renal function. Studies have shown that the combined use of Huangkui Capsules and Haikun Huangkui Capsules has a synergistic effect in the treatment of diabetic nephrotic[11]. However, sometimes the combined use of the two may increase the occurrence of ADR, because the ADRs of both the Huangkui Capsule and Haikun Huangkui Capsule happen in the digestive system such as severe diarrhea.

Our results show that the combined use of the two increased the occurrence of ADR in contrast to the single use group. Even the sum of ADRs caused by the single use of Huangkui Capsule or Haikun Huangkui Capsule is less than that of the combined use, showing significant differences in statistic (P=0.003 4).

In summary, the advantage of the combined use of Huangkui Capsule and Haikun Huangkui Capsule for the treatment of renal diseases is notable, but we cannot ignore the occurrence of ADR when they were in the combined use too. In this situation, physicians, nurses and clinical pharmacists should collaborate closely to instruct the patients to take medicine correctly to provide a guarantee for the safe medication of patients.