Clinical Efficacy and Application Progress of Reduning Injection in Children with Viral Encephalitis

Yuanyuan ZOU, Hongying ZHANG, Zhiyong XU, Ziyi PAN, Changsheng DENG, Jianping SONG, Qi WANG*

1. Guangzhou University of Chinese Medicine, Guangzhou 510006, China; 2. Institute of Science and Technology, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

Abstract Viral encephalitis in children caused by multiple viral infections, as a common central nervous system disease in pediatrics, has a high incidence in China. Its clinical symptoms usually include infection, poisoning, intracranial hypertension, and disturbance of consciousness. In severe cases, it can even endanger the lives of patient children. At present, the clinical treatment of the viral encephalitis mainly uses traditional Chinese medicine preparations such as Reduning Injection. The efficacy is significant. It can not only relieve the uncomfortable symptoms in a short time, but also has low incidence of adverse reactions. In this study, the factors that cause viral encephalitis in children were analyzed, and the efficacy, pharmacological action and clinical application of Reduning Injection were comprehensively elaborated, to provide a reference for clinical doctors to rationally treat viral encephalitis in children.

Key words Reduning Injection, Children, Viral encephalitis, Clinical effects

1 Introduction

Viral encephalitis, also known as sporadic encephalitis[1], is a common neurological disease in pediatrics. It is caused by inflammatory lesions in the brain parenchyma of patients due to multiple viral infections. The clinical manifestations of children with viral encephalitis mainly include headache, vomiting, unresponsiveness, convulsions, fever, disturbance of consciousness,etc. In serious cases, it may even endanger the life of children. The incidence rate of viral encephalitis in children is high, it may occur throughout the year, and the incidence of its complications is also high. Therefore, in order to effectively alleviate the symptoms of children and better recover, it is important to provide active, effective and reasonable treatment. Reduning Injection is a pure Chinese medicine preparation with anti-inflammatory, anti-virus, heat-clearing and immune-enhancing effects. In the clinical treatment of viral encephalitis in children, it has shown a unique effect and is widely used in children with low immunity[2]. It is a new drug for the treatment of viral encephalitis in children.

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2 Introduction of viral encephalitis in children

Viral encephalitis in children usually occurs in summer and autumn. The pathogenic virus enters the patient’s body from the respiratory or digestive tract. The type of viral encephalitis is related to the host response in the patient’s body. Many types of viruses can induce viral encephalitis in children. The interoviruses account for the majority, such as polio virus, coxsackie virus A, coxsackie virus B, mumps virus, Echo virus, herpes Viruses and adenoviruses, as well as herpes viruses such as herpes simplex virus and varicella-zoster virus[3]. These viruses can directly invade the surrounding blood vessels or invade the nerve cells of the brain tissue, leading to diffuse or local neuronal function decline, which in turn causes damage to the brain tissue cells, leading to vomiting, varying degrees of disturbance of consciousness, fever, and central nervous system infection symptoms such as persistent or repeated seizures, limb disorders, and mental disorders[4]. Compared with other pediatric diseases, the condition of children viral encephalitis is more complicated. It is generally believed to be related to the location, scope and extent of the disease in clinical practice, and the course of the disease is usually 2-3 weeks. Although the disease is a self-limiting disease, many complications can occur during the onset, including edema and increased intracranial pressure. If no prompt treatment is taken, it will cause the spread of virus infection, seriously affect the quality of life of the children, and even threaten their lives.

3 Antiviral drug treatment

So far, there is still no specific antiviral drug for the treatment of viral encephalitis in children. Extensive studies have evaluated the efficacy and safety of western medicine and traditional Chinese medicine in the treatment of children with viral encephalitis. The treatment often uses conventional methods such as lowering intracranial pressure, antiviral, antipyretic, sedation, anticonvulsant, antibiotics and brain cell nutrient solutions. For its treatment, the most common antiviral drugs in clinical treatment are Ribavirin and Reduning[5]. As a common broad-spectrum antiviral drug in the clinic, Ribavirin can quickly phosphorylate the virus-infected cells after entering the patient body, thereby changing the direction of virus adsorption. Besides, Ribavirin is effective against a variety of DNA and RNA viruses, can reduce the level of guanosine triphosphate (GTP), and also can reduce the production of interferon in the body, thereby inhibiting the reproduction and release of viruses in children. Although Ribavirin has significant antiviral ability, some scholars have found that it is not suitable for patients with severe anemia or hepatic Insufficiency. Ribavirin may cause different degrees of myocardial damage in patients with anemia; it may also cause increased blood bilirubin, decreased hemoglobin indicators, and interfere with clinical diagnosis; it may even cause clinical discomfort symptoms such as abdominal pain, diarrhea, gastrointestinal bleeding or general skin rash in children[6]. In addition, some studies have shown that the use of Ribavirin in children will cause varying degrees of damage to the normal functions of the myocardium, liver and kidney of children who are still developing, resulting in a decrease in white blood cells in the body; some children may even show symptoms such as weakness of limbs, dizziness, depression, headache,etc. Ribavirin has a significant antiviral effect, but it has many adverse reactions, which can cause a decrease in red blood cells, a decrease in hemoglobin, and a certain toxic effect on various systems, and the treatment effect for children infected with adenovirus and respiratory syncytial virus is not obvious, so the treatment is subject to certain restrictions, and safer and more effective drugs are needed to substitute for adjuvant treatment.

4 Traditional Chinese Medicine preparation: Reduning Injection

4.1 Ingredients and efficacy of Reduning InjectionAs a Class II new drug in China, Reduning Injection is a pure Chinese medicine preparation developed on the basis of empirical prescriptions. It is separated, extracted, purified and refined by modern technology. The main ingredients of Reduning Injection include Artemisiae Annuae Herba, Lonicerae Japonicae Flos, and Gardeniae Fructus. Reduning Injection has effects of clearing away heat and detoxification, expelling wind, resisting inflammation and virus, and improving the immunity.

4.3 Adverse reactions of Reduning Injection

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Reduning Injection can significantly inhibit inflammatory mediators such as interleukin-1 (IL-1), interleukin-6 (IL-6), endothelin-1 (ET-1), prostaglandin E2 (PGE2). It can lower body temperature by reducing the level of cyclic adenosine monophosphate (cAMP) in the cerebrospinal fluid and hypothalamus, and reducing the level of IL-1β and tumor necrosis factor-α (TNF-α) in the serum. Besides, it can inhibit the expression of matrix metalloproteinase-2 (MMP-2), TNF-α and IL-6 in the serum, reduce the aggregation of neutrophils, and exert antipyretic and anti-inflammatory effects. Reduning Injection can directly kill the virus and inhibit its reproduction. Its organic acid components can inhibit the activity of viral neuraminidase (NA), and inhibit the adsorption of viruses to cells by interacting with multiple proteins in the links of virus adsorption, uncoating, replication, and release, thereby protect cells from virus attack, and block target cells that have been infected by virus, and exert the direct antiviral effect of the drug. In addition, Reduning Injection can also increase the phagocytic ability of macrophages and neutrophils; through increasing the level of γ-interferon (IFN-γ), it can reduce the levels of TNF-α, IL-6,etc., regulate the levels of various inflammatory mediators in children, accordingly enhancing the immunity of children and exerting the indirect antiviral effect of the drug. Pharmacokinetic studies have shown that Reduning Injection is easier to enter the body of the patient children through the blood-brain barrier to exert its efficacy. With the continuous increase in the dosage of Reduning Injection, the clinical treatment effect is more significant, it can actively and effectively compensate for the resistance defects caused by antibiotics; compared with Ribavirin, the application of Reduning Injection is wider[5, 10].

4.3.1Main symptoms of adverse reactions. Although Reduning Injection can achieve better curative effect in the treatment of viral encephalitis in children, it contains some common sensitizers that may cause allergic reactions in the body. Lonicerae Japonicae Flos contains chlorogenic acid which will produce an immune complex when combined with amino acids in the human body, causing the body to have an allergic reaction to the drug. Besides, the components of the drug in the Injection are relatively complex, and a small amount of impurities may be mixed in the process of its manufacture, or the quality of the drug may be changed due to the incorrect storage process, which will affect the metabolic process of the drug in the body, resulting in occurrence of varying degrees of adverse effects. If this drug is used in large amounts in clinical treatment, it is very likely to cause symptoms of allergic reactions in the body. In mild cases, local skin itching, rash, exudative erythema, and maculopapular rash on the neck and face may occur appear to damage to the skin and accessories[12]; in severe cases, clinical symptoms such as irritability and chills, rapid breathing, generalized rubella and cold limbs may occur, and it may even cause anaphylactic shock in children, which will adversely affect the normal recovery and prognosis of children. A few children will also show relatively serious adverse reactions, such as acute laryngeal edema. In this case, if it is not handled in time, it will directly lead to child death.

In the ingredients, Artemisiae Annuae Herba is bitter in taste and cold in nature, can clear away heat and dispel the summer heat, remove the steaming bone (a subjective feeling of fever deep in the body, which appears to emanate from the bone or marrow) and treat malaria. Clinically, Artemisiae Annuae Herba is usually used to treat heat-induced diseases, such as blood heat, malaria, and summer heat. Modern pharmacological research has shown that the volatile components of coumarins and flavonoids contained in Artemisiae Annuae Herba have certain antiviral, analgesic and antipyretic, antibacterial, anti-inflammatory and anti-inflammatory effects and can enhance human immunity; as a new type of low-toxicity and high-efficiency immunomodulator, artemisinin can regulate the differentiation of helper T cells (Th1 /Th2 cells), inhibit the proliferation of T lymphocytes, reduce the level of IgG in the serum of children and inhibit the production of antibodies in patients, to play its immunosuppressive effect[7]. Lonicerae Japonicae Flos is sweet in taste and cold in nature, and has effects of clearing away heat and detoxification, expelling carbuncle and eliminating abscess, and dispelling the exterior pathogen. Clinically, it is often used for treating erysipelas, abscess and pustule, warm diseases, and wind-heat cold. In the prescription of Reduning Injection, it can assist Artemisiae Annuae Herba in improving the functions of clearing away the heat and dispersing wind heat. In addition, organic acids and iridoid glycosides, as extracts of Lonicerae Japonicae Flos, have clinically significant anti-inflammatory and antiviral effects and can enhance the phagocytic function of white blood cells, accelerate lymphocyte transformation, promote the release of adrenal cortex hormones[8], inhibit a variety of pathogenic microbial flora such asStaphylococcusaureus,Salmonellatyphi,EscherichiacoliandPseudomonasaeruginosa, inhibit the synthesis and release of inflammatory mediators in inflammatory parts, reduce inflammation, and eliminate pathogens[9], and also inhibit the activity of respiratory syncytial virus, adenovirus and Coxsackie virusinvitro. The Gardeniae Fructus in the preparation has the effects of purging fire and eliminating troubles, clearing away heat and dampness, cooling blood and detoxification. Geniposide in Gardeniae Fructus can directly neutralize endotoxins in children’s body, reduce the damage to normal cells caused by endotoxins, nitric oxide and oxygen free radicals, and protect the integrity of important organ cells, and has obvious inhibitory effects on many kinds of viruses. As the main components of Gardeniae Fructus, ursolic acid, geniposide and deshydroxy geniposide have the effects of inhibiting central nervous system excitement, and also have anti-virus and infection effects. It has significant inhibitory effects onS.aureusandS.typhi. Therefore, Reduning Injection obtained after extraction and purification by modern technology enables these three traditional Chinese medicines, can exert a powerful synergistic effect, not only enhances the immunosuppressive and anti-inflammatory effects against a variety of viruses, but also strengthens the growth inhibitory effect on a variety of bacterial strains, can significantly enhance the body’s immune function and improve the body’s antiviral ability.

4.2 Therapeutic effect of Reduning Injection on viral encephalitis in childrenIn a study of 100 children with viral encephalitis in children treated with Reduning Injection, all the children included in the trial had clinical symptoms such as varying degrees of fever, limb twitching, vomiting, dizziness, and disturbance of consciousness,, and there is no statistically significant difference between individuals[5]. This study randomly divided children into an experimental group and a control group, with 50 cases in each group. The ages of the experimental group and the control group were 6.2 months to 11.5 years and 5.7 months to 12.5 years, respectively; the average ages were (4.1 ± 1.2) years and (3.9 ± 0.8) years, respectively; female cases were 23 and 29, and male cases were 27 and 21, respectively. In the comparison of general data such as gender and age of the experimental group and the control group, there was no statistically significant difference and it was comparable. This study mainly compared the curative effect of Ribavirin and Reduning Injection on children with viral encephalitis. All children included in the study were given a comprehensive treatment plan combining hormones and antibiotics according to their respective conditions. The experimental group was supplemented with traditional Chinese medicine Reduning Injection (Jiangsu Kanion Pharmaceutical Co., Ltd., National Medicine Permit No.Z20050217) on the basis of comprehensive treatment, at a dosage of 10 mg/time, once daily. The control group was treated with Ribavirin (Cisen Pharmaceutical Co., Ltd., National Medicine Permit No. H34023781) on the basis of comprehensive treatment, at a dosage of 10 mg/time, 2 times daily. The clinical treatment course of the two groups of the study was 7-10 d, and the dosage of the drugs can be adjusted according to the children’s real-time disease progression (the principles of the two groups of drugs were still the same). The clinical efficacy of the two groups of children was compared after the treatment cycle. The results of the study showed that there was no statistically significant difference between the Reduning Injection group and the Ribavirin group in the number of clinically vomiting patients. However, in terms of clinical treatment effects such as convulsions, dizziness, fever, and unconsciousness, the Reduning Injection group showed significant advantages. The study showed that the use of Reduning Injection for the treatment of children with viral encephalitis has a significant clinical effect and can reduce the incidence of adverse reaction events. Another scholar conducted a similar study, and divided 69 children with viral encephalitis in children randomly into an experimental group and a control group. Thirty four children in the control group received Ribavirin for conventional treatment, and 35 children in the experimental group, the conventional treatment was supplemented by intravenous drip of Reduning Injection. The treatment cycle of the two groups was 5-7 d. The indicators were observed for dizziness and vomiting, limb twitching, fever, and disturbance of consciousness[11]. The results of the study showed that the effective rate of treatment in the experimental group was 97.1%, which was significantly better than 76.5% in the control group; and the improvement time of the clinical observation indicator symptoms of the children in the experimental group was significantly shorter than that of the control group. These indicate that using Reduning Injection to assist the treatment of viral encephalitis in children not only has a short treatment cycle but also has significant clinical effects.

4.3.2Treatment measures for adverse reactions. Although there are many adverse reactions that may be caused from using Reduning Injection, most of them can be prevented and reduced. Generally, clinicians should accurately understand the child’s medical history, family history, and previous treatment conditions and requirements before using Reduning Injection. For children with a history of drug allergy, they should try to avoid their medication; for patients with weak physical fitness, it is necessary to choose other drugs for treatment to avoid causing adverse reactions. Since the components of Reduning Injection are complex, it should be used in combination with other drugs in clinical treatment of children, avoid using the drug alone in clinical practice, and it should be used in small doses in a short period of time to achieve the desired therapeutic effect, and it is also necessary to avoid the occurrence of drug allergic reactions. After in-depth study on the clinical dosage and methods of Reduning Injection, some scholars suggested that when choosing this drug for clinical treatment, it must first be specially diluted to ensure that the concentration before use is within the normal range and during the medication period, and do not change the dosage of the drug at will, but should use the drug according to the child’s conditions and the drug instructions[13]. At the same time, in the process of intravenous infusion in children, nursing staff should be instructed to closely observe the child’s state. If it is used in combination with other drugs, in order to avoid mixed reactions of multiple drugs, after the intravenous infusion of Reduning Injection, the Injection tube needs to be flushed with 5% glucose Injection before infusion of the next drug. Because the adverse reactions of Reduning Injection generally occur early, the nursing staff should closely observe the various reactions of the child before the infusion. When the infusion starts, the speed of the infusion should be slowed down as much as possible, and under the premise that adverse reaction does not occur, slowly restore the normal infusion rate, but various emergency medicines are still needed to prevent accidents. When the patient children have symptoms such as slight chest tightness during treatment, ask the patient to take adequate rest; when the patient children have itching or rashes, they can be relieved by intravenous drip of dexamethasone; when the patient children have generalized skin redness and rash, the infusion should be stopped immediately and anti-allergic drugs should be given. When physicians use drugs to treat diseases in the clinic, they must strictly abide by theBasicPrinciplesofClinicalUseofTraditionalChineseMedicineInjections, conduct dialectical treatment, and correctly grasp the indications, dosage and course of drug treatment, ensure that the drug use is consistent with the disease conditions, and reduce and avoid adverse reactions.

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5 Conclusions

Reduning Injection not only has antiviral and antibacterial effects, but also increases the body’s immunity. Reduning Injection, whether used alone or in combination with other antibiotics, can exert strong anti-inflammatory and antiviral effects. This Injection is not only suitable for the clinical treatment of children with viral encephalitis, but also can relieve various symptoms of children with respiratory infections viral enteritis, mumps and other diseases in a short period of time, significantly shorten the disease treatment cycle, and reduce the incidence of adverse reactions. In clinical medication, physicians should grasp the reasonable dose, concentration and time of medication, to obtain the ideal therapeutic effect. Besides, in normal life, in order to reduce the probability of children suffering from viral encephalitis and enhance immunity, parents should lead them to actively participate in various physical exercises to improve their physical fitness.