Network meta-analysis of heat-clearing and detoxifying oral liquid of Chinese medicines in treatment of children's hand-foot-mouth disease: A protocol for systematic review and meta-analysis.

BACKGROUND: Hand-foot-mouth is a viral infectious disease characterized by fever, hand foot rash and oral mucosal herpes caused by a variety of enteroviruses. It is often found in preschool children, and its immune system is not well developed, so it is very susceptible to infection by pathogens and epidemics, resulting in rapid progress of the disease. At present, the commonly used Chinese patent medicine oral liquid in our country has good clinical efficacy of antiviral, antibacterial, antiphlogistic and improving immunity, but there is no evidence to compare the clinical efficacy and safety of a variety of oral liquid of Chinese patent medicine. Therefore, this study is aim to use the network meta-analysis to integrate the clinical relevant evidence of direct and indirect comparative relationship, and to conduct quantitative comprehensive statistical analysis and sequencing after the aggregation of different Chinese patent medicine oral liquid with the same evidence body, and then the best clinical medication scheme is selected, which can provide reference value and evidence-based theoretical evidence for clinical optimization of drug selection. METHODS: Comprehensive retrieval of CNKI, VIP, CBM, and WANFANG database and the Cochrane Library, PubMed, Web of Science and EMBASE database. Search and publish the clinical RCT of these 7 kinds of oral liquid of Chinese patent medicine compared with ribavirin or oral liquid of Chinese patent medicine. The retrieval time is from the establishment of the database to October 31st, 2021. The 2 first authors will screen the literatures that meets the inclusion criteria, extract the data independently according to the predesigned rules, and evaluate the literature quality and bias risk of the included research according to the Cochrane manual standard. Data merging and network meta-analysis were carried out with R programming software to evaluate the ranking probability of all interventions. RESULTS: This network meta-analysis and probability ranking will identify the best Chinese patent medicine oral liquid treatment for Hand-foot-mouth. CONCLUSION: This study will provide systematic evidence-based medicine evidence for Chinese patent medicine oral liquid treatment for Hand-foot-mouth, and help clinicians, patients with poststroke depression and decision-makers to make more effective, safer and economic optimal treatment plan in the decision-making process. REGISTRATION NUMBER: INPLASY202210032. The protocol for this systematic review was registered on INPLASY and is available in full on the inplasy.com (https://inplasy.com/inplasy-2022-1-0032/).

Antidepressant Sertraline Is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry through Neutralization of Endolysosomal Acidification.

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs as of yet to treat EV71 infections. In this study, we conducted antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug's antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be greatly relieved by exposing virus-infected cells to extracellular low-pH culture media. Ultimately, we have identified a use for an FDA-approved antidepressant in broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.

Regulation of RDN on Th1/ILC1 cell imbalance in HFMD patients caused by EV71 infection.

Enterovirus 71 (EV71) infection is more likely to cause hand, foot and mouth disease (HFMD) in children, which can lead to neurogenic complications and higher mortality. As a commonly used clinical medicine, Reduning injection (RDN) helps to shorten the symptoms of patients with HFMD and facilitate the early recovery of children. However, the regulatory mechanism of RDN on the HFMD immune system disorder caused by EV71 remains to be discussed. This study collected detailed treatment data of 56 children with HFMD who entered the affiliated Children's Hospital of Nanjing Medical University during 2019. Retrospective analysis of clinical data showed that the symptoms of the RDN treatment group were improved compared with the untreated group. To explore its mechanism, the relevant detection indicators were detected by flow cytometry, enzyme-linked immunosorbent assay and real-time quantitative PCR. It was found that the number and function of innate immune (ILCs) and adaptive immunity (Th1, Th2 and secreted cytokines) were reduced, suggesting that RDN plays a role by regulating cellular immunity. The in vitro differentiation inhibition test further confirmed that RDN affected Th1 differentiation by inhibiting the expression of transcription factors on the basis of Th1 cell differentiation in vitro.

Recent advances of enterovirus 71 [Formula: see text] targeting Inhibitors.

With CA16, enterovirus-71 is the causative agent of hand foot and mouth disease (HFMD) which occurs mostly in children under 5 years-old and responsible of several outbreaks since a decade. Most of the time, HFMD is a mild disease but can progress to severe complications such as meningitis, brain stem encephalitis, acute flaccid paralysis (AFP) and even death; EV71 has been identified in all severe cases. Therefore, it is actually one of the most public health issues that threatens children's life. [Formula: see text] is a protease which plays important functions in EV71 infection. To date, a lot of [Formula: see text] inhibitors have been tested but none of them has been approved yet. Therefore, a drug screening is still an utmost importance in order to treat and/or prevent EV71 infections. This work highlights the EV71 life cycle, [Formula: see text] functions and [Formula: see text] inhibitors recently screened. It permits to well understand all mechanisms about [Formula: see text] and consequently allow further development of drugs targeting [Formula: see text]. Thus, this review is helpful for screening of more new [Formula: see text] inhibitors or for designing analogues of well known [Formula: see text] inhibitors in order to improve its antiviral activity.

Effect of heat-clearing and detoxifying Chinese medicines combined with conventional therapy on mild hand, foot, and mouth disease with fever: An individual patient data meta-analysis.

BACKGROUND: In China, heat-clearing and detoxifying Chinese medicines combined with conventional therapy are commonly applied to treat the mild hand, foot, and mouth disease (HFMD). However, there is lack of solid evidence on the efficacy and safety of such therapies. METHODS: We conducted a pooled analysis with individual patient data from 5 strictly randomized controlled clinical trials to assess the efficacy and safety of this combination therapy for mild HFMD. An intention-to-treat analysis was performed. A 2-stage meta-analysis method was adopted to analyze the pooled effect size. RESULTS: In total, 947 patients were included. Compared with conventional therapy, the combination therapy significantly reduced the progression rate of HFMD from mild to severe (odds ratio [OR] 0.43, 95% confidence interval [CI]: 0.22 to 0.83, P = .01). Meanwhile, the healing time of skin rash and oral ulcer in the combination therapy group was significantly shorter than that of conventional therapy. The overall hazard ratio (HR) of healing time of the skin rash or oral ulcer was 1.22 (95%CI: 1.04 to 1.43; P = .02). However, except Jinlianqingre effervescent tablets, the combination therapy cannot shorten the time to fever resolution (HR 1.12, 95%CI: 0.97 to 1.29, P = .14). Because of the heterogeneity, Jinlianqingre effervescent tablets were analyzed separately and the HRs of the time to fever resolution and the healing time of skin rash or oral ulcer were 3.88 (95%CI: 3.19 to 4.72; P < .0001) and 3.79 (95%CI: 2.81 to 5.11; P < .0001), respectively. There were 30 adverse events reported in total; 2 cases were related to Chinese medicines. CONCLUSION: In conclusion, the heat-clearing and detoxifying Chinese medicines on top of conventional therapy can effectively reduce the progressive rate of mild HFMD and improve healing of skin and oral mucosal lesions. More studies are needed for the time to fever resolution.

Virucidal activity and the antiviral mechanism of acidic polysaccharides against Enterovirus 71 infection in vitro.

Enterovirus 71 (EV71) is the predominant pathogen for severe hand, foot, and mouth disease (HFMD) in children younger than 5 years, and currently no effective drugs are available for EV71. Thus, there is an urgent need to develop new drugs for the control of EV71 infection. In this study, LJ04 was extracted from Laminaria japonica using diethylaminoethyl cellulose-52 with 0.4 mol/l NaCl as the eluent, and its virucidal activity was evaluated based on its cytopathic effects on a microplate. LJ04 is composed of fucose, galactose, and mannose and mainly showed good virucidal activity against EV71. The antiviral mechanisms of LJ04 were the direct inactivation of the virus, the blockage of virus binding, disruptions to viral entry, and weak inhibitory activity against the nonstructural protein 3C. The two most important findings from this study were that LJ04 inhibited EV71 proliferation in HM1900 cells, which are a human microglia cell line, and that LJ04 can directly inactivate EV71 within 2 hr at 37°C. This study demonstrates for the first time the ability of a polysaccharide from L. japonica to inhibit viral and 3C activity; importantly, the inhibition of 3C might have a minor effect on the antiviral effect of LJ04. Consequently, our results identify LJ04 as a potential drug candidate for the control of severe EV71 infection in clinical settings.

Assessing the efficacy and safety of magnesium sulfate for management of autonomic nervous system dysregulation in Vietnamese children with severe hand foot and mouth disease.

BACKGROUND: Brainstem encephalitis is a serious complication of hand foot and mouth disease (HFMD) in children. Autonomic nervous system (ANS) dysregulation and hypertension may occur, sometimes progressing to cardiopulmonary failure and death. Vietnamese national guidelines recommend use of milrinone if ANS dysregulation with Stage 2 hypertension develops. We wished to investigate whether magnesium sulfate (MgSO4) improved outcomes in children with HFMD if used earlier in the evolution of the ANS dysregulation (Stage 1 hypertension). METHODS: During a regional epidemic we conducted a randomized, double-blind, placebo-controlled trial of MgSO4 in children with HFMD, ANS dysregulation and Stage 1 hypertension, at the Hospital for Tropical Diseases in Ho Chi Minh city. Study participants received an infusion of MgSO4 or matched placebo for 72 h. We also reviewed data from non-trial HFMD patients in whom milrinone failed to control hypertension, some of whom received MgSO4 as second line therapy. The primary outcome for both analyses was a composite of disease progression within 72 h - addition of milrinone (trial participants only), need for ventilation, shock, or death. RESULTS: Between June 2014 and September 2016, 14 and 12 participants received MgSO4 or placebo respectively, before the trial was stopped due to futility. Among 45 non-trial cases with poorly controlled hypertension despite high-dose milrinone, 33 received MgSO4 while 12 did not. There were no statistically significant differences in the composite outcome between the MgSO4 and the placebo/control groups in either study (adjusted relative risk (95%CI) of [6/14 (43%) vs. 6/12 (50%)], 0.84 (0.37, 1.92), p = 0.682 in the trial and [1/33 (3%) vs. 2/12 (17%)], 0.16 (0.01, 1.79), p = 0.132 in the observational cohort). The incidence of adverse events was similar between the groups. Potentially toxic magnesium levels occurred very rarely with the infusion regime used. CONCLUSION: Although we could not demonstrate efficacy in these studies, there were no safety signals associated with use of 30-50 mg/kg/hr. MgSO4 in severe HFMD. Intermittent outbreaks of HFMD are likely to continue across the region, and an adequately powered trial is still needed to evaluate use of MgSO4 in controlling hypertension in severe HFMD, potentially involving a higher dose regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 AUG 2013). Trial sponsor: University of Oxford.

[Effects of L-carnitine on serum levels of brain natriuretic peptide and N-terminal pro-brain natriuretic peptide and cardiac function in children with severe hand-foot-mouth disease].

OBJECTIVE: To observe the effects of L-carnitine treatment on serum levels of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) and cardiac function in children with heart dysfunction and severe hand-foot-mouth disease (HFMD). METHODS: A total of 120 children with severe HFMD were enrolled and randomly and equally divided into routine treatment group and L-carnitine treatment group. Thirty healthy children served as the control group. HFMD patients were given anti-fever and antiviral treatment as the basic treatment, while the patients in the L-carnitine treatment group were given L-carnitine as an adjuvant treatment to the basic treatment. Treatment outcomes were observed in the two groups. For all the subjects, serum levels of BNP and NT-proBNP and cardiac function parameters including left ventricular ejection fraction (LVEF), fractional shortening (FS), and cardiac index (CI) were measured at different time points before and after treatment. RESULTS: Before treatment, HFMD patients had significantly higher serum levels of BNP and NT-proBNP and heart rate but significantly lower LVEF, FS, and CI compared with the control group (P<0.05). After treatment, the L-carnitine treatment group had a significantly higher response rate than the routine treatment group (P<0.05). After 3 days of treatment, the serum levels of BNP and NT-proBNP, LVEF, FS, and CI were significantly reduced in the L-carnitine group (P<0.05); the L-carnitine group had significantly lower serum levels of BNP and NT-proBNP, LVEF, FS, and CI than the routine treatment group (P<0.05); there were no significant differences in the serum levels of BNP and NT-proBNP, LVEF, FS, or CI between the L-carnitine treatment and control groups (P>0.05). After 5 days of treatment, there were no significant differences in the serum levels of BNP and NT-proBNP, LVEF, FS, or CI between the L-carnitine treatment and routine treatment groups (P>0.05). Heart rate recovery was significantly slower in the routine treatment group than in the L-carnitine treatment group (P<0.05). CONCLUSIONS: As an adjuvant therapy for severe HFMD, L-carnitine treatment has satisfactory short-term efficacy in reducing the serum levels of BNP and NT-proBNP and improving cardiac function, thus improving clinical outcomes.

Andrographolide sulfonate reduces mortality in Enterovirus 71 infected mice by modulating immunity.

Outbreaks of hand, foot and mouth disease (HFMD), which is caused by Enterovirus 71 (EV71), have erupted in recent years. Andrographolide sulfonate (Trade name: Xiyanping injection) has been recommended to treat severe HFMD in China because of its conventional antithermic and antitoxic activities, but its actual mechanism has not been revealed clearly until now. To explore its therapeutic efficacy and mechanism, a Xiyanping injection treatment mouse model was established. Based on the therapeutic model, routine clinical parameters and histopathologic changes were investigated, in the same time, viral loads, immune cells, inflammatory molecules and cell signaling pathways were determined. Xiyanping injection treatment protected mice from lethal EV71 challenge in a therapeutic regimen-dependent manner, which may mostly depend on its direct immunomodulatory activities on neutrophil and T lymphocyte. Reduced inflammatory molecular production of neutrophil and elevated T lymphocyte activity may result from its marked inhibition of some signaling pathways. Taken together, Xiyanping injection was an effective treatment for severe HFMD by improving hosts' immunity.

Efficacy of Scutellaria baicalensis for the Treatment of Hand, Foot, and Mouth Disease Associated with Encephalitis in Patients Infected with EV71: A Multicenter, Retrospective Analysis.

This study aimed to evaluate the clinical efficacy and safety of using the traditional Chinese herbal medicine Scutellaria baicalensis for the treatment of severe HFMD in 725 patients aged >1 year in a multicenter, retrospective analysis. The patients were divided into the S. baicalensis and ribavirin groups, and the temperatures, presence or absence of skin rashes and oral lesions, nervous system (NS) involvement, and viral loads of the patients, as well as the safety of the treatments, were evaluated. The median duration of fever, median time to NS involvement, and the number of patients with oral ulcers and/or vesicles, as well as skin rashes, were decreased in the S. baicalensis group compared with the ribavirin group. In addition, the EV71 viral loads were decreased in the S. baicalensis group, suggesting that S. baicalensis exerted more potent antiviral effects compared with ribavirin. The present study demonstrated that S. baicalensis was suitable for the treatment of severe HFMD in patients aged >1 year, since it was shown to rapidly relieve fever, attenuate oral lesions and rashes, and improve NS involvement. Furthermore, it was demonstrated to be relatively safe for topical application.

[Real world analysis to explore Xiyanping injection combined with other drugs for hand-foot-mouth disease].

Integrated network analysis was used in this paper to analyze Xiyanping injection combined therapy for hand-foot-mouth disease based on the registered research data of 3 204 cases. It was found that the drug combination therapy was almost consistent with the guidelines for the diagnosis and treatment of hand foot mouth disease, but there were some problems to be noticed: there were too many applications of antibiotics, more than the need in preventing secondary infection; and ribavirin was not necessary for use. This article showed that the clinical antibacterial and antiviral values of Xiyanping injection has not been well recognized for hand-foot-mouth disease.

Clinical Efficacy of Andrographolide Sulfonate in the Treatment of Severe Hand, Foot, and Mouth Disease (HFMD) is Dependent upon Inhibition of Neutrophil Activation.

Andrographolide sulfonate treatment has been shown to improve clinical severe hand, foot, and mouth disease (HFMD) efficacies when combined with conventional therapy. However, the mechanisms for its therapeutic effects remain elusive. In this study, we aimed to investigate whether andrographolide sulfonate exerts its efficacy by acting on neutrophil activation. We obtained serial plasma samples at two time points (before and after 5 days of therapy) from 28 HFMD patients who received conventional therapy and 18 patients who received combination therapy (andrographolide sulfonate plus conventional therapy). Then, we measured plasma myeloperoxidase (MPO), S100A8/A9, histone, and inflammatory cytokine levels. Furthermore, we examined if andrographolide sulfonate had direct effects on neutrophil activation in vitro. We observed that MPO and S100A8/A9 levels were markedly elevated in the HFMD patients before clinical treatment. At 5 days post-medication, the MPO, S100A8/A9, histone, and interleukin-6 levels were markedly lower in the combination therapy group compared with the conventional therapy group. In vitro studies showed that andrographolide sulfonate inhibited lipopolysaccharide-stimulated neutrophil activation, demonstrated by the decreased production of reactive oxygen species and cytokines. These data indicate that neutrophil activation modulation by andrographolide sulfonate may be a critical determinant for its clinical HFMD treatment efficacy. Copyright © 2015 John Wiley & Sons, Ltd.

Therapeutic effect of Jinzhen oral liquid for hand foot and mouth disease: a randomized, multi-center, double-blind, placebo-controlled trial.

BACKGROUND: No specific antiviral agent against hand foot and mouth disease (HFMD) is available for clinical practice today. OBJECTIVE: To evaluate the efficacy and safety of Jinzhen oral solution in treating uncomplicated HFMD. METHODS: In this randomized, double-blind, placebo-controlled trial, 399 children aged 1 to 7 years with laboratory confirmed HFMD were randomized to receive Jinzhen oral liquid or placebo 3 times daily for 7 days with a 3-day follow-up. The primary outcomes were time to the first disappearance of oral ulcers and vesicles on hand or foot and time to the first normalization of temperature (fever clearance). RESULTS: There were 199 children enrolling into the Jinzhen group including 79 with fever and 200 into the placebo group including 93 with fever. Jinzhen reduced the time to the first disappearance of oral ulcers and vesicles on hand or foot to 4.9 days (95% CI, 4.6 to 5.2 days), compared with 5.7 days (95% CI, 5.4 to 6.0 days) in the placebo group (P = 0.0036). The median time of fever clearance was shorter in the 79 children who received Jinzhen (43.41 hrs, 95% CI, 37.05 to 49.76) than that in the 93 children who received placebo (54.92 hrs, 95% CI, 48.16 to 61.68) (P = 0.0161). Moreover, Jinzhen reduced the risk of symptoms by 28.5% compared with placebo (HR, 0.7150, 95% CI, 0.5719 to 0.8940, P = 0.0032). More importantly, treatment failure rate was significantly lower in the Jinzhen group (8.04%) compared with that in the placebo group (15.00%) (P = 0.0434). The incidence of serious adverse events did not differ significantly between the two groups (9 in Jinzhen group vs. 18 in placebo, P = 0.075). CONCLUSIONS: Children with HFMD may benefit from Jinzhen oral liquid treatment as compared with placebo. TRIAL REGISTRATION: Chinese Clinical Trial Registry (http://www.chictr.org/en/) ChiCTR-TRC-10000937.

A double-blind comparative study of Chinese herbal medicine Jinlianqingre Effervescent Tablets in combination with conventional therapy for the treatment of uncomplicated hand, foot, and mouth disease.

Chinese herbal medicine Jinlianqingre Effervescent Tablets (JET) are the recommended control measure for uncomplicated hand, foot, and mouth disease (HFMD) by the Ministry of Health of China. However, high-quality evidence to support this recommendation is limited. A total of 288 patients ranging in age from 1 to 13 years were randomly assigned to JET in combination with conventional therapy (mainly including the reduction of temperature by applying physical cooling paste or warm bathing), or conventional therapy with placebo group for 7 days. The objective was to test the hypothesis that JET combination therapy is more effective than conventional therapy for uncomplicated HFMD. A randomized, double-blind, placebo-controlled trial was designed. Our study showed that, compared with conventional therapy, the median time to fever resolution was significantly shorter in the JET combination therapy (8 vs. 80 h; p < 0.0001); the risk of fever resolution increased in the JET combination therapy [hazard ratio, 19.8; 95% confidence interval (CI), 12.8 to 30.7]; the median healing time of rash or oral ulcer was significantly shorter in the JET combination therapy (14 vs. 74 h; p < 0.0001); and the median symptom score for skin or oral mucosa lesions improved more rapidly in the JET combination therapy during the follow-up period. The median duration of hospital stay was 6 days in the JET combination therapy and 7 days in the conventional therapy (p < 0.0001). No significant adverse events and complications were found in both groups. The addition of JET to conventional therapy reduced fever clearance time, healing time of skin or oral mucosa lesions, and duration of hospital stay in children with uncomplicated HFMD.

[Hand, foot and mouth disease--more than a harmless "childhood disease"]. / Hand-fuss-Mund-Krankheit--weit mehr als eine harmlose "Kinderkrankheit".

Hand, foot and mouth disease (HFMD) is a highly contagious, world-wide distributed viral illness that affects predominantly children. It is caused by several enteroviruses, such as coxsackieviruses A6, A10, A16 and enterovirus 71. In most cases, HFMD follows a benign and self-limiting course. After an incubation period of 3 to 10 days, fever and sore throat, the first symptoms of the disease, appear. A few days later, maculopapular or vesicular eruptions form on the palms and soles as well as in the oral cavity. Since the year 2000, several large HFMD outbreaks have been reported in many Asian regions such as China, Malaysia and Vietnam. In some of these outbreaks, high incidences of severe progressive HFMD forms with some fatalities were observed. Such diseases have been caused primarily by enterovirus 71 strains and were characterized frequently by sudden onset of fever, encephalitis/meningitis and severe respiratory symptoms such as pulmonary edema. Further severe neurological and cardiac complications have also been observed during these outbreaks. Recently, some HFMD outbreaks caused by the coxsackievirus A6 have been reported in several parts of the world. These illnesses also affected adults and were characterized by more severe symptoms of "classical" HFMD. In addition, outbreaks of coxsackievirus-A6-associated HFMD in many countries were associated with onychomadesis, with the loss of nails occurring up to two months after initial symptoms. Treatment of "classical" HFMD is usually symptomatic, a generally recommended antiviral therapy does not exist. In severe HFMD cases, suitable treatment also encompasses mechanical ventilation, as well as the additional application of antiviral agents such as ribavirin. In the last years, several novel agents with good in vitro and in vivo activity against enteroviruses have been developed. A vaccine against HFMD is not yet available.

Glycyrrhizic acid as the antiviral component of Glycyrrhiza uralensis Fisch. against coxsackievirus A16 and enterovirus 71 of hand foot and mouth disease.

ETHNOPHARMACOLOGICAL RELEVANCE: The radices of Glycyrrhiza uralensis Fisch. and herbal preparations containing Glycyrrhiza spp. have been used for thousands of years as an herbal medicine for the treatment of viral induced cough, viral hepatitis, and viral skin diseases like ulcers in China. Glycyrrhizic acid (GA) is considered the principal component in Glycyrrhiza spp. with a wide spectrum of antiviral activity. AIM: The present study attempt to validate the medicinal use of Glycyrrhiza uralensis for hand, foot and mouth disease (HFMD) and further to verify whether GA is an active antiviral component in the water extract of Glycyrrhiza uralensis. MATERIALS AND METHODS: Radices of Glycyrrhiza uralensis Fisch. were extracted with hot water. The chemical contents of the extract were profiled with HPLC analysis. The antiviral activity of the extract and the major components was evaluated against infection of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) on Vero cells. The cytopathic effect caused by the infection was measured with MTT assay. Infectious virion production was determined using secondary infection assays and viral protein expression by immunoblotting analysis. RESULTS: The extract at 1000 µg/ml suppressed EV71 replication by 1.0 log and CVA16 by 1.5 logs. The antiviral activity was associated with the content of GA in the extract since selective depletion of GA from the extract by acid precipitation resulted in loss of antiviral activity. In contrast, the acid precipitant retained antiviral activity. The precipitant at a concentration of 200 µg/ml inhibited EV71 and CVA16 replication by 1.7 and 2.2 logs, respectively. Furthermore, GA dose-dependently blocked viral replication of EV71 and CVA16. At 3 mM, GA reduced infectious CVA16 and EV71 production by 3.5 and 2.2 logs, respectively. At 5mM, CVA16 production was reduced by 6.0 logs and EV71 by 4.0 logs. Both EV71 and CVA16 are members of Enterovirus genus, time-of-drug addition studies however showed that GA directly inactivated CVA16, while GA anti-EV71 effect was associated with an event(s) post virus cell entry. CONCLUSIONS: This study validated the medicinal usefulness of radices Glycyrrhiza uralensis against the etiological agents of HFMD. In addition to the identification of GA as the antiviral component of Glycyrrhiza uralensis against EV71 and CVA16 infection, this study also reveals that GA inhibits EV71 and CVA16 with distinct mechanisms.

Reduning injection for fever, rash, and ulcers in children with mild hand, foot, and mouth disease: a randomized controlled clinical study.

OBJECTIVE: To assess the efficacy and safety of Reduning injection for fever, rash, and ulcers in children with mild hand, foot, and mouth disease (HFMD). METHODS: A stratified-block randomized, double-blind, parallel-controlled, and multicenter clinical trial was conducted with 360 patients in five hospitals across China: Quanzhou Children's Hospital, Shijiazhuang No. 5 Hospital, Shanghai Public Health Centre, Hunan Provincial Children's Hospital, and Kaifeng Children's Hospital. Patients were randomized into three groups with 120 in each. Group A was treated with Western Medicine, group B with Reduning injection, a Chinese herbal medicine, and group C with both Reduning injection and Western Medicine. Results were compared for treatment efficacy and safety on HFMD. The clinical outcomes were observed as follows: fever and onset time of antifebrile effect (time to bring the body temperature down > or = 0.5 degrees C after medication); cumulative time for fever recovery (body temperature recovering to normal and lasting more than 24 h without medication); cumulative time for rash disappearance (without new rashes or ulcers appearing and the original ones fading away); and cumulative time for mouth ulcer disappearance. RESULTS: For the onset time of the antifebrile effect, there was no statistical difference between groups A and B (P > 0.05) and groups B and C (P > 0.05). However, there was a statistical difference between groups A and C (P < 0.05), and the effect in group C was the best. For the cumulative time for rash disappearance, there was no statistical difference between groups A and B (P > 0.05). There were statistical differences between groups A and C, and groups B and C (P < 0.05), and the effect in group C was the best. For the cumulative time for mouth ulcers disappearance, there were no statistical differences among the three groups (P > 0.05). CONCLUSION: Reduning injection with Western Medicine for symptomatic treatment is most effective for mild HFMD. No adverse reactions were observed.

[Effect of reducing injection on HFMD in children: a randomized controlled trial].

OBJECTIVE: To study the clinical effects of Reduning Injection on ordinary hand, foot and mouth disease (HFMD) in children. METHODS: 76 children with confirmed diagnosis of HFMD were randomly assigned to 3 groups by the center randomization method, i.e., the Western medicine group (WM, 24 cases, treated with Ribavirin Injection or antibiotics), the Reduning Injection group (RI, 26 cases, treated with Reduning Injection), and the combination group (26 cases, treated with the combination of Reduning injection with Ribavirin Injection or antibiotics). The therapeutic course lasted for 3 to 7 days. A 3-day follow-up study was performed by the end of the treatment. The blood routines, the liver function, the renal function, the fasting blood glucose, the pyretolysis effect initiating time, the time for the body temperature recovery, and the rash subside time were observed in the three groups. RESULTS: (1) Of 76 patients, 13 dropped out, with the final effective case being 63. Of them, there were 19 cases in the WM group, 22 in the RI group, and 22 in the combination group. (2) Compared with the WM group, the pyretolysis effect initiating time and the time for the body temperature recovery were both significantly shortened in the RI group and the combination group (P<0.05, P<0.01). (3) There was no significant difference in the rash subside time among the three groups (P>0.05). But there was shortening tendency in the RI group and the combination group. (4) One child in the RI group dropped out from this study due to a mild rash, and no adverse drug reaction occurred in the other two groups. CONCLUSIONS: RI had some advantages in treatment of HFMD such as fasting pyretolysis effect initiating time, shorter time for the body temperature recovery, higher safety. Besides, it also could accelerate the subside of skin rashes to some extent.

[Studies on anti-EV71 virus activity of traditional Chinese medicine and its clinical application in treatment of HFMD].

Hand-foot-and-mouth disease is caused by intestinal virus infection. The viruses coxsackie A16 (CA16) and enterovirus 71 (EV71) are the main pathogens. Between them, the virus EV71 is more dangerous and easier to cause serious complications, which leads to death or disability. Currently, there are no effective antiviral drugs to treat EV71 infection. Therefore, developing an effective drug against EV71 virus activity is significant. It has a huge potency of screening the anti-EV71 components and developing the new drugs from the abundant traditional Chinese medicines (TCMs). Meanwhile, since hand-foot-and-mouth disease spread in Shanghai in 1981, a growing number of reports on TCMs treatment in clinic have been published. In addition, most of treatments with various ways are effective, which play a positive role on improving clinic treatment and controlling diseases. Moreover, special clinic advantages and features of TCMs were obviously shown.