# Efficacy of Oxymatrine Plus Antiviral in the Treatment of Sepsis and Its Effect on the Levels of Endotoxin and Inflammatory Factors

Authors: Jinglin Zhao; Qi Wei; Shengchao Guo; Hao Wang; Chao Zhao; Caihong Hu; Cuicui Liu; Qingchun Dai; Rui Wang
Journal: Evidence-Based Complementary and Alternative Medicine
 (2022)

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## Abstract

Objective. To assess the clinical efficacy of oxymatrine plus antiviral therapy in the treatment of sepsis and its effects on the levels of endotoxin and inflammatory factors. Methodology. 90 patients with sepsis were selected for retrospective analysis and were assigned to receive either conventional treatment (control group) or oxymatrine plus antiviral treatment (study group). The clinical endpoint was treatment efficacy. Results. There were no significant differences in baseline patient profile between the two groups (P>0.05). The study group showed a higher efficiency versus the control group (P<0.05). Patients in the study group had a significantly shorter mechanical ventilation duration and ICU stay versus those in the control group (P<0.05). Both groups had reduced Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Marshall score, levels of endotoxin, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, C-reactive protein (CRP), and procalcitonin (PCT) after treatment, with lower results in the study group versus the control group (P<0.05). Conclusion. Oxymatrine plus antiviral therapy effectively improves clinical efficacy, reduces the levels of endotoxin and inflammatory factors, protects organ function, and boosts recovery. Further clinical trials are, however, required prior to general application in clinical practice.


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## Body

## 1. Introduction

Sepsis is a systemic inflammatory response syndrome induced by pathogenic bacteria and is one of the common complications of critically ill patients. Without timely and effective intervention, sepsis would further develop into septic shock, multiple organ failure, or even death [1–4]. Recent studies have found that inflammatory factors play a very important role in the pathophysiological process of sepsis. The inhibition of inflammatory factors such as endotoxin, tumor necrosis factor (TNF), interleukin (IL)-6, and IL -8 with an effective approach remains one of the vital challenges in the treatment of sepsis. Entecavir is currently used as a front-line antiviral drug in clinical practice. Despite the little effect of single drug medication, it shows high effectiveness in inhibiting endotoxin and inflammatory factors when combined with oxymatrine [5–8]. At present, the two drugs are mostly used for the treatment of chronic hepatitis B and liver cirrhosis. However, their application in the treatment of sepsis is marginally explored. Hence, oxymatrine plus antiviral treatment in sepsis was investigated in this study to scientifically evaluate its therapeutic effect.


## 2. Data and Methodology

### 2.1. Screening and Grouping

A retrospective analysis was performed on 90 patients with sepsis admitted to this hospital from January 2019 to December 2020, and they were assigned via different treatment methods to a control group (n = 45) and a study group (n = 45). The study was approved by the Ethics Committee of the Cangzhou Central Hospital, no. CZ971-1.


### 2.2. Diagnosis

Sepsis is diagnosed if the patient exhibits clinical bacteriological symptoms with highly suspicious infection and meets any two of the first four following conditions and the fifth condition: (1) Body temperature exceeds 39 C or lower than 35.5 C, which lasts for more than three days; (2) heart rate exceeds 120 beats/min; (3) white blood cell count exceeds 12.0 × 109/L or less than 4.0 × 109/L; (4) respiratory frequency exceeds 28 times/min; (5) clinical manifestations include irritability, depression or delirium, diarrhea, and abdominal distension or gastrointestinal bleeding.


### 2.3. Inclusion Criteria

Patients whose clinical manifestations and laboratory tests results met the diagnostic criteria of sepsis; with a score of acute physiology and chronic health evaluation II (APACHE II) [9] >12 points; with a Marshall score of ≥6 points; and with complete clinical data. Patients and their families were informed of the purpose and process of the study.


### 2.4. Exclusion Criteria

Patients with chronic organ dysfunction; with immune system diseases; with treatment duration of less than one week; with extremely unstable conditions or death during treatment; with contraindication to oxymatrine and antiviral therapy were excluded.


### 2.5. Methodology

Patients in the control group received conventional treatments. Patients received early removal of infected lesions, effective antibiotics treatment [9, 10], and symptomatic and supportive treatment measures for damage to different organs and systems, such as early cycle resuscitation, mechanical ventilation, metabolic support, kidney replacement, and anticoagulation [11, 12]. A similar conventional treatment protocol was introduced to the study group.The eligible patients in the study group received oxymatrine and antiviral treatment. They received 0.3 g oxymatrine tablets (Shandong Xinhua Pharmaceutical Co. Ltd., approval no. H20090019) orally three times daily, with one tablet containing 0.1 g oxymatrine. The dosage was properly adjusted in accordance with the doctor’s advice. Entecavir capsule (0.5 mg) was orally administrated daily (Jiangxi Qingfeng Pharmaceutical Co. Ltd., approval no. H201300ll). The treatment of both groups lasted for 4 weeks.


### 2.6. Outcome Measures

The baseline data including age, gender, body temperature, heart rate, systolic and diastolic blood pressure, urine volume, serum lactate dehydrogenase (LHD), troponin (cTnl), creatine kinase isoenzyme (CK-MK), leukocyte level, hypertension, diabetes, and hyperlipidemia were collected. The mechanical ventilation duration and ICU stay of the patients were recorded in detail.The APACHE II consisted of three parts: acute physiology, age, and chronic health, with a full score of 71 points. A higher score indicated more serious conditions of the patient. The Marshall scoring scale was used to assess the multiple organ function status of the patient, with a total score of 24 points. A higher score signified more severe organ dysfunction.Clinical efficacy: markedly effective: clinical symptoms of the patients disappeared, and the APACHE II score was reduced by ≥70%. Effective: clinical symptoms were improved, and the APACHE II score was reduced by 30%–70%; Ineffective: clinical symptoms showed no improvement or even worsen, and the APACHE II score decreased by <30%. Total efficacy = (markedly effective cases + effective cases)/total number of cases × 100%.Serum levels of TNF-α, IL-6, and IL-8 were determined using the ELISA, C-reactive protein (CRP) level was determined by nephelometry, procalcitonin (PCT) level was determined using an automatic biochemical analyzer, and the endotoxin level was determined using the gel method.


### 2.7. Statistical Processing

The data of this study were analyzed using the SPSS22.0 software, and GraphPad Prism 7 (GraphPad Software, San Diego, USA) was used to plot the graphics. The research included the counting data and measurement data. The counting data are expressed as (n (%)) and analyzed using the chi-square test, and the measurement data are expressed as (mean ± SD) and analyzed using thet-test, respectively. Differences were considered statistically significant at P<0.05.


## 2.1. Screening and Grouping

A retrospective analysis was performed on 90 patients with sepsis admitted to this hospital from January 2019 to December 2020, and they were assigned via different treatment methods to a control group (n = 45) and a study group (n = 45). The study was approved by the Ethics Committee of the Cangzhou Central Hospital, no. CZ971-1.


## 2.2. Diagnosis

Sepsis is diagnosed if the patient exhibits clinical bacteriological symptoms with highly suspicious infection and meets any two of the first four following conditions and the fifth condition: (1) Body temperature exceeds 39 C or lower than 35.5 C, which lasts for more than three days; (2) heart rate exceeds 120 beats/min; (3) white blood cell count exceeds 12.0 × 109/L or less than 4.0 × 109/L; (4) respiratory frequency exceeds 28 times/min; (5) clinical manifestations include irritability, depression or delirium, diarrhea, and abdominal distension or gastrointestinal bleeding.


## 2.3. Inclusion Criteria

Patients whose clinical manifestations and laboratory tests results met the diagnostic criteria of sepsis; with a score of acute physiology and chronic health evaluation II (APACHE II) [9] >12 points; with a Marshall score of ≥6 points; and with complete clinical data. Patients and their families were informed of the purpose and process of the study.


## 2.4. Exclusion Criteria

Patients with chronic organ dysfunction; with immune system diseases; with treatment duration of less than one week; with extremely unstable conditions or death during treatment; with contraindication to oxymatrine and antiviral therapy were excluded.


## 2.5. Methodology

Patients in the control group received conventional treatments. Patients received early removal of infected lesions, effective antibiotics treatment [9, 10], and symptomatic and supportive treatment measures for damage to different organs and systems, such as early cycle resuscitation, mechanical ventilation, metabolic support, kidney replacement, and anticoagulation [11, 12]. A similar conventional treatment protocol was introduced to the study group.The eligible patients in the study group received oxymatrine and antiviral treatment. They received 0.3 g oxymatrine tablets (Shandong Xinhua Pharmaceutical Co. Ltd., approval no. H20090019) orally three times daily, with one tablet containing 0.1 g oxymatrine. The dosage was properly adjusted in accordance with the doctor’s advice. Entecavir capsule (0.5 mg) was orally administrated daily (Jiangxi Qingfeng Pharmaceutical Co. Ltd., approval no. H201300ll). The treatment of both groups lasted for 4 weeks.


## 2.6. Outcome Measures

The baseline data including age, gender, body temperature, heart rate, systolic and diastolic blood pressure, urine volume, serum lactate dehydrogenase (LHD), troponin (cTnl), creatine kinase isoenzyme (CK-MK), leukocyte level, hypertension, diabetes, and hyperlipidemia were collected. The mechanical ventilation duration and ICU stay of the patients were recorded in detail.The APACHE II consisted of three parts: acute physiology, age, and chronic health, with a full score of 71 points. A higher score indicated more serious conditions of the patient. The Marshall scoring scale was used to assess the multiple organ function status of the patient, with a total score of 24 points. A higher score signified more severe organ dysfunction.Clinical efficacy: markedly effective: clinical symptoms of the patients disappeared, and the APACHE II score was reduced by ≥70%. Effective: clinical symptoms were improved, and the APACHE II score was reduced by 30%–70%; Ineffective: clinical symptoms showed no improvement or even worsen, and the APACHE II score decreased by <30%. Total efficacy = (markedly effective cases + effective cases)/total number of cases × 100%.Serum levels of TNF-α, IL-6, and IL-8 were determined using the ELISA, C-reactive protein (CRP) level was determined by nephelometry, procalcitonin (PCT) level was determined using an automatic biochemical analyzer, and the endotoxin level was determined using the gel method.


## 2.7. Statistical Processing

The data of this study were analyzed using the SPSS22.0 software, and GraphPad Prism 7 (GraphPad Software, San Diego, USA) was used to plot the graphics. The research included the counting data and measurement data. The counting data are expressed as (n (%)) and analyzed using the chi-square test, and the measurement data are expressed as (mean ± SD) and analyzed using thet-test, respectively. Differences were considered statistically significant at P<0.05.


## 3. Results

### 3.1. Baseline Data

There were no statistical differences in the baseline data between the two groups (P>0.05) (Table 1).Table 1
General information of two groups (n = 45).
IndicatorsControl groupStudy groupT/X2P valueGender (male/female)28/1725/200.4130.520Age (years)63.49 ± 7.4164.18 ± 8.350.4150.679Body temperature (°C)39.12 ± 0.2539.08 ± 0.310.6740.502Heart rate (beats/min)132.15 ± 19.94131.87 ± 19.730.0670.947Systolic blood pressure (mm·Hg)71.55 ± 3.4871.69 ± 3.500.1900.850Diastolic blood pressure (mm·Hg)50.84 ± 3.6151.11 ± 3.850.3430.732Urine volume (ml/h)20.88 ± 4.2921.30 ± 4.410.4580.648LDH (U/L)605.47 ± 81.09609.41 ± 78.420.2340.815cTnl (μg/L)3.04 ± 0.512.97 ± 0.530.6380.525CK-mb (U/Lz)402.35 ± 68.91398.76 ± 67.550.2500.803White blood cell level (×109/L)16.28 ± 0.7416.32 ± 0.690.2650.792Hypertension23 (51.11)24 (53.33)0.0450.833Diabetes19 (42.22)17 (37.78)0.1850.667High blood lipid13 (28.89)15 (33.33)0.2070.649


### 3.2. Clinical Efficacy

The total efficacy of the patients in the study group was higher than that in the control group (P<0.05) (Figure 1).Figure 1
Statistics of clinical efficacy in two groups (n = 45, %). Note: The abscissa indicates the evaluation dimension, and the ordinate indicates the percentage (%). In the control group, there were 11 ineffective cases, 18 effective cases, 16 markedly effective cases, and 34 total effective cases. In the study group, there were 2 ineffective cases, 16 effective cases, 27 markedly effective cases, and 43 total effective cases. ∗indicates a significant difference in the total effective rate between the two groups (t = 7.283, P=0.007).


### 3.3. Mechanical Ventilation Duration and ICU Stay

Patients in the study group had a shorter mechanical ventilation duration and ICU stay than the control group (P<0.05) (Table 2).Table 2
Mechanical ventilation time and ICU stay in two groups (x ± s).
GroupnMechanical ventilation time (d)ICU stay (d)Control group4514.28 ± 3.7118.26 ± 4.53Study group4511.04 ± 4.0813.22 ± 3.17t3.9416.115P value<0.001<0.001


### 3.4. Apache II Score, Marshall Score, and Endotoxin

Both groups had reduced APACHE II score, Marshall score, and levels of endotoxin after treatment, with lower results in the study group versus the control group (P<0.05) (Table 3).Table 3
APACHE II scores, Marshall scores, and endotoxin levels of two groups.
IndexTimeControl group (n = 45)Study group (n = 45)tP valueAPACHE II scoresPretreatment23.56 ± 7.2423.60 ± 7.263.7450.212After treatment15.74 ± 3.8111.06 ± 2.297.062<0.001Marshall scoresPretreatment13.05 ± 2.4313.11 ± 2.544.5410.214After treatment7.83 ± 1.815.68 ± 1.376.354<0.001Endotoxin levelsPretreatment7.06 ± 1.286.95 ± 1.335.2410.325After treatment3.91 ± 1.072.23 ± 0.927.986<0.001


### 3.5. Inflammatory Factors Levels

The levels of inflammatory factors such as TNF-α, IL-6, IL-8, CRP, and PCT in the treatment group were lower than those in the control group (P<0.05) (Table 4).Table 4
Inflammatory factor levels in two groups.
IndicatorsControl group (n = 45)Study group (n = 45)PretreatmentAfter treatmentPretreatmentAfter treatmentTNF-α (ng/L)142.14 ± 27.59119.30 ± 24.57142.08 ± 25.8186.72 ± 26.09∗IL-6 (ng/L)76.21 ± 6.8560.35 ± 7.1675.98 ± 7.1126.93 ± 8.06∗IL-8 (ng/L)63.39 ± 17.1050.61 ± 12.3963.44 ± 19.0527.84 ± 13.52∗CRP (mg/L)77.69 ± 7.4849.30 ± 5.6278.02 ± 7.8327.19 ± 3.26∗PCT (μg/L)5.95 ± 2.332.87 ± 1.155.88 ± 3.040.83 ± 0.32∗∗P<0.05 as compared with the control group after treatment.


## 3.1. Baseline Data

There were no statistical differences in the baseline data between the two groups (P>0.05) (Table 1).Table 1
General information of two groups (n = 45).
IndicatorsControl groupStudy groupT/X2P valueGender (male/female)28/1725/200.4130.520Age (years)63.49 ± 7.4164.18 ± 8.350.4150.679Body temperature (°C)39.12 ± 0.2539.08 ± 0.310.6740.502Heart rate (beats/min)132.15 ± 19.94131.87 ± 19.730.0670.947Systolic blood pressure (mm·Hg)71.55 ± 3.4871.69 ± 3.500.1900.850Diastolic blood pressure (mm·Hg)50.84 ± 3.6151.11 ± 3.850.3430.732Urine volume (ml/h)20.88 ± 4.2921.30 ± 4.410.4580.648LDH (U/L)605.47 ± 81.09609.41 ± 78.420.2340.815cTnl (μg/L)3.04 ± 0.512.97 ± 0.530.6380.525CK-mb (U/Lz)402.35 ± 68.91398.76 ± 67.550.2500.803White blood cell level (×109/L)16.28 ± 0.7416.32 ± 0.690.2650.792Hypertension23 (51.11)24 (53.33)0.0450.833Diabetes19 (42.22)17 (37.78)0.1850.667High blood lipid13 (28.89)15 (33.33)0.2070.649


## 3.2. Clinical Efficacy

The total efficacy of the patients in the study group was higher than that in the control group (P<0.05) (Figure 1).Figure 1
Statistics of clinical efficacy in two groups (n = 45, %). Note: The abscissa indicates the evaluation dimension, and the ordinate indicates the percentage (%). In the control group, there were 11 ineffective cases, 18 effective cases, 16 markedly effective cases, and 34 total effective cases. In the study group, there were 2 ineffective cases, 16 effective cases, 27 markedly effective cases, and 43 total effective cases. ∗indicates a significant difference in the total effective rate between the two groups (t = 7.283, P=0.007).


## 3.3. Mechanical Ventilation Duration and ICU Stay

Patients in the study group had a shorter mechanical ventilation duration and ICU stay than the control group (P<0.05) (Table 2).Table 2
Mechanical ventilation time and ICU stay in two groups (x ± s).
GroupnMechanical ventilation time (d)ICU stay (d)Control group4514.28 ± 3.7118.26 ± 4.53Study group4511.04 ± 4.0813.22 ± 3.17t3.9416.115P value<0.001<0.001


## 3.4. Apache II Score, Marshall Score, and Endotoxin

Both groups had reduced APACHE II score, Marshall score, and levels of endotoxin after treatment, with lower results in the study group versus the control group (P<0.05) (Table 3).Table 3
APACHE II scores, Marshall scores, and endotoxin levels of two groups.
IndexTimeControl group (n = 45)Study group (n = 45)tP valueAPACHE II scoresPretreatment23.56 ± 7.2423.60 ± 7.263.7450.212After treatment15.74 ± 3.8111.06 ± 2.297.062<0.001Marshall scoresPretreatment13.05 ± 2.4313.11 ± 2.544.5410.214After treatment7.83 ± 1.815.68 ± 1.376.354<0.001Endotoxin levelsPretreatment7.06 ± 1.286.95 ± 1.335.2410.325After treatment3.91 ± 1.072.23 ± 0.927.986<0.001


## 3.5. Inflammatory Factors Levels

The levels of inflammatory factors such as TNF-α, IL-6, IL-8, CRP, and PCT in the treatment group were lower than those in the control group (P<0.05) (Table 4).Table 4
Inflammatory factor levels in two groups.
IndicatorsControl group (n = 45)Study group (n = 45)PretreatmentAfter treatmentPretreatmentAfter treatmentTNF-α (ng/L)142.14 ± 27.59119.30 ± 24.57142.08 ± 25.8186.72 ± 26.09∗IL-6 (ng/L)76.21 ± 6.8560.35 ± 7.1675.98 ± 7.1126.93 ± 8.06∗IL-8 (ng/L)63.39 ± 17.1050.61 ± 12.3963.44 ± 19.0527.84 ± 13.52∗CRP (mg/L)77.69 ± 7.4849.30 ± 5.6278.02 ± 7.8327.19 ± 3.26∗PCT (μg/L)5.95 ± 2.332.87 ± 1.155.88 ± 3.040.83 ± 0.32∗∗P<0.05 as compared with the control group after treatment.


## 4. Discussion

Sepsis is commonly seen in pneumonia, peritonitis, hepatitis, urinary system infection, meningitis, and abscess with pathogenic bacteria including bacteria, fungi, and viruses [13–16]. Large amounts of inflammatory cytokines and tissue factors released by systemic inflammatory reactions may lead to body damage, resulting in life-threatening organ dysfunction. Effective measures to inhibit the release of proinflammatory mediators can alleviate the inflammatory response in sepsis patients and ameliorate their prognosis and recovery. To our knowledge, oxymatrine is an alkaloid extracted from Sophora L. of Leguminosae, and its main ingredients can inhibit virus replication, induce endogenous interferon, and increase white blood cells to counter tumors. The research by Jiang et al. [17] revealed a similar clinical efficacy of oxymatrine to interferons. Entecavir is frequently used for the treatment of chronic hepatitis B given its inhibitory effect on virus activity. Relevant studies have demonstrated that the combination of the two significantly mitigated inflammatory response and endotoxin.Here, the study group showed a higher total efficacy and a markedly shorter mechanical ventilation duration and ICU stay than the control group, demonstrating that oxymatrine plus antiviral therapy could mitigate clinical symptoms of patients with sepsis and boost their prognosis and curative effect. In addition, both groups had lower APACHE II scores, Marshall scores, endotoxin, TNF-α, IL-6, IL-8, CRP, and PCT levels after treatment, with better results observed in the study group than the control group. Endotoxin, an important pathogenic factor causing sepsis, stimulates monocytes to produce a variety of proinflammatory factors, thus releasing inflammatory factors through a series of phosphorylation pathways. These inflammatory factors further prompt the release of inflammatory mediators and the generation of hydrolase and oxygen-free radicals, leading to typical symptoms of sepsis such as pathological coagulation, vasodilation, and organ dysfunction [18–21]. All these results indicated that oxymatrine plus antiviral therapy could effectively reduce the levels of endotoxin and inflammatory reactions in patients and protect organ function.Relevant animal experiments confirmed that oxymatrine could significantly improve the white blood cell level of healthy rabbits and rabbits with low white blood cells due to radiation. In addition, it also has a certain protective effect on toxic liver injury caused by carbon tetrachloride and D-galactose and improves mouse leukopenia caused by mitomycin C. As an antiviral traditional Chinese medicine, oxymatrine improves various serum indexes of liver fibrosis, regulates immune function, and induces endogenous interferon. It is reported that oxymatrine plus immunoregulatory drugs are particularly effective for patients with antiviral indications and intolerance or unwillingness to receive interferons and nucleotide treatment. During the treatment of sepsis, oxymatrine inhibits the excessive release of inflammatory mediators and reduces their damage to the body tissue. Entecavir is particularly suitable for the treatment of histological lesions such as active viral replication, increased serum ALT, and moderate or severe inflammation, which is attributable to its significant reduction of endotoxin, regulation of immune function, inhibition of the release of inflammatory factors so as to protect vascular endothelial cells [22–25].Protein phosphatae2A (PP2A) is the major serine/threonine protein phosphatase in eukaryotic organisms. It has many different genetically encoded subunits and is composed of different PP2A holoenzymes, which are involved in the cell cycle, DNA replication, signal transduction, cell differentiation, and malignant cell transformation. PP2A interacts with other phosphatases and kinases in the signal transduction cascade, constituting a regulatory macromolecule that regulates downstream signaling and can also negatively regulate signaling by reversibly phosphorylating proteins that are already phosphorylated. PP2A is a key endogenous regulator of inflammatory cell signaling and plays an important role in the molecular mechanism of sepsis-induced vascular endothelial cell dysfunction, constituting a useful pharmacological target for the treatment of sepsis.


## 5. Conclusion

In summary, oxymatrine plus antiviral therapy can effectively improve clinical efficacy, reduce the levels of endotoxin and inflammatory factors, protect organ function, and boost body recovery. However, there are still some limitations in this study: (1) the follow-up was short, and there was a lack of statistical analysis on the effective survival rate of patients with sepsis; (2) this study was single-centered with small sample size; (3) entecavir is the only antiviral drug studied, and selection of antiviral drugs should be tailored based on the patient’s condition in clinical practice.



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