CN116270853A

CN116270853A - Application of Thermoyanning in preparing medicine for treating children or teenagers SARS-CoV-2 asymptomatic or mild infection

Info

Publication number: CN116270853A
Application number: CN202211019640.8A
Authority: CN
Inventors: 杜成强
Original assignee: Tsing Hua De Ren Xi'an Happiness Pharmaceutical Co ltd
Current assignee: Tsing Hua De Ren Xi'an Happiness Pharmaceutical Co ltd
Priority date: 2022-08-24
Filing date: 2022-08-24
Publication date: 2023-06-23
Also published as: WO2024040799A1

Abstract

The invention relates to an application of a Thermoinflammatory Ning in preparing a medicine for treating asymptomatic or light-weight infection of children or teenagers SARS-CoV-2, which overcomes the problem that the evidence-based medicine for treating children's COVID-19 cases is still limited in the prior art, and can safely and effectively change the negative turning condition of the nucleic acid detection of the asymptomatic or light-weight infection of children or teenagers SARS-CoV-2, the Ct value of SARS-CoV-2ORF1ab or N gene, the hospitalization time, the new symptoms of asymptomatic infected persons, the symptom recovery rate and the disease progression proportion during observation. The invention comprises the application of the yanning in preparing the medicine for treating the asymptomatic or light infection of children or teenagers SARS-CoV-2 and the application of the yanning in preparing the medicine for changing the Ct value of SARS-CoV-2ORF1ab or N gene.

Description

Application of Thermoyanning in preparing medicine for treating children or teenagers SARS-CoV-2 asymptomatic or mild infection

Technical field:

the invention relates to an application of a traditional Chinese medicine composition, in particular to an application of Reyanning in preparing medicines for treating asymptomatic or light infection of SARS-CoV-2 of children or teenagers.

The background technology is as follows:

in the treatment of childhood covd-19, methods of treatment are limited. Three antiviral drugs have been urgently approved by the FDA: redox, ni Ma Ruiwei/ritonavir (Paxlovid) and Mo Nupi. These three drugs have been shown to be effective against SARS-CoV-2 VOC. Mild to moderate non-hospitalized patients are at higher risk of developing severe symptoms, and subsequent clinical studies confirm that antiviral drugs improve the clinical outcome of these patients. However, these drugs are only recommended for adult patients over 18 years of age. Paxlovid has been approved by the FDA for treatment of severe pediatric patients aged 12 and older, but requires more random trial data to verify their safety and effectiveness. Another antiviral drug, such as interferon- α, was proposed early, primarily based on clinical experience in treating other viral infections in children, to help alleviate the symptoms of COVID-19 in children and shorten the course of the disease. Nevertheless, evidence-based treatment for pediatric covd-19 cases remains limited.

The invention comprises the following steps:

the invention aims to provide an application of a Thermoinflammatory in preparing a medicine for treating asymptomatic or light infection of children or teenagers SARS-CoV-2, which overcomes the problem that the evidence-based therapeutic medicine for children's COVID-19 cases is still limited in the prior art, and can safely and effectively change the negative transfer condition of SARS-CoV-2 asymptomatic or light infection SARS-CoV-2 nucleic acid detection, ct value of SARS-CoV-2ORF1ab or N gene, hospitalization time, new symptoms of asymptomatic infected persons, symptom recovery rate and disease progression proportion during observation.

In order to achieve the above purpose, the invention adopts the following technical scheme:

application of Reyanning in preparing medicine for treating children or teenagers SARS-CoV-2 asymptomatic or mild infection is provided.

Application of Thermoyanning in preparing medicine for changing Ct value of SARS-CoV-2ORF1ab or N gene.

The Reyanning is prepared from water extracts of dandelion, giant knotweed, herba patriniae and barbed skullcap herb, wherein the weight ratio of the dandelion to the giant knotweed to the herba patriniae to the barbed skullcap herb is 1-3:1.

The Reyanning is prepared by the following preparation method: decocting the above four materials with water twice for 2 hr for 1 hr, filtering, concentrating the filtrate under reduced pressure to appropriate amount, mixing the concentrated solutions, centrifuging, filtering, adding steviosin 1.5g and ethylparaben 0.5g, heating to boil, and making into 1000 ml.

The dosage of the antipyretic is as follows: under 3 years old, 5ml each time, three times daily; 4-6 years old, 10ml each time, three times per day; 7-14 years old, 15ml each time, three times daily; 15-17 years old, 20ml each time, 4 times daily.

Compared with the prior art, the invention has the following advantages and effects:

1. the invention can safely and effectively change the negative transfer condition of SARS-CoV-2 nucleic acid detection of asymptomatic or light infection of children or teenagers, ct value of SARS-CoV-2ORF1ab or N gene, hospitalization time, new symptoms of asymptomatic infected people, symptom recovery rate and disease progress proportion during observation.

2. The therapeutic effect and safety of the Reyanning mixture on the treatment of COVID-19 with the age below 18 years. The data of the present invention show that the Reyanning mixture has good safety, can accelerate the negative rotation time of SARS-CoV-2, accelerate the elimination of viruses and rapidly relieve cough symptoms. Additional RYN treatment can significantly reduce the occurrence of wheezing symptoms. The course of the amikacin pandemic was significantly shortened compared to the previously reported viral turn-to-negative time (11.43 days) and hospitalization time (12.97 days).

Description of the drawings:

FIG. 1 is a flow chart of the present invention;

FIG. 2 is a graph showing the analysis of accounting negative conversion rate-KM;

FIG. 3 is a plot of the negative conversion rate of nucleic acids; (A) Two sets of nucleic acid to negative ratio comparisons within 3 days, (B) two sets of nucleic acid to negative ratio comparisons within 7 days;

FIG. 4 is a graph showing the change in SARS-CoV-2 viral load cycle threshold (Ct) during observation; (A) Ct value of ORF gene; (B) N gene Ct value;

FIG. 5 is a graph comparing discharge rates between two groups;

fig. 6 is a graph comparing symptom relief between two groups.

The specific embodiment is as follows:

the invention relates to an application of a febrifugal drug in preparing a drug for treating asymptomatic or light infection of SARS-CoV-2 of children or teenagers, comprising an application of the febrifugal drug in preparing a drug for changing Ct value of SARS-CoV-2ORF1ab or N gene. The Reyanning is prepared from water extracts of dandelion, giant knotweed, herba patriniae and barbed skullcap herb, wherein the weight ratio of the dandelion to the giant knotweed to the herba patriniae to the barbed skullcap herb is 1-3:1.

Experimental example:

1 study method

1.1 design of experiments

The study was a prospective, open label, random control trial. The study was conducted at the Shanghai New International Expandation center shelter hospital on

days

4, 2022, 15 to 5, 12 to evaluate the efficacy and safety of Reyanning (RYN) in treating asymptomatic or mild SARS-CoV-2 infection in children and adolescents. The study protocol was approved by the Jiujiang middle hospital ethical committee (accession number JJSZYYY 20220403). The test protocol complies with the GCP regulations and the declaration of Helsinki. The study was registered on the China clinical trial registration website (www.chictr.org/cn/, number: chiCTR 2200060292). Written informed consent of the parent or legal guardian of the subject was obtained.

1.2 study object

Children 1-17 years old, diagnosed with asymptomatic or mild infection of new coronaries within 48 hours after admission, were continuously recruited. Patients with written informed consent were included in the study. The following are excluded: (1) New coronatine pneumonia disease of common symptoms, severe symptoms or critical symptoms; (2) Patients with other primary respiratory diseases, such as asthma, congenital respiratory deformity, dysplasia of the lung, respiratory deformity; (3) Diseases involving vital organs (heart, brain, liver and kidney) and other hematopoietic, immune, endocrine, metabolic and nutritional diseases; (4) 3 months of internal reference to other clinical trials; (5) Allergic manifestations or previously reported allergies to test drugs and conventional western medicines. Including asthmatic children associated with viral infections.

The asymptomatic infections and the mild infections are classified according to the consensus of novel coronavirus infection diagnosis, treatment and prevention specialists for children. (1) asymptomatic infection: the SARS-CoV-2 nucleic acid detection result is positive, and the clinical manifestation and imaging characteristics of new coronaries in the whole disease process are absent. (2) mild infection: acute upper respiratory tract infection has no pneumonia imaging evidence, and is manifested by fever, cough, sore throat, fatigue, etc.

1.3 study of drugs

According to the randomized list, eligible subjects were randomly assigned to either the intervention group (RYN plus standard care) or the control group (standard care only, i.e., antiviral, antibacterial, symptomatic treatment, oxygen treatment, following the expert consensus document on pediatric new coronaries of pneumonia) at a 1:1 ratio. The randomized list was generated by an independent college who did not participate in the study using version SPSS 26.0. No blindness was established for the subjects and researchers. For the intervention group, each patient received RYN treatment for seven consecutive days while standard care was being performed. The approved doses for children are as follows: under 3 years old, 5ml each time, three times daily; 4-6 years old, 10ml each time, three times per day; 7-14 years old, 15ml each time, three times daily; 15-17 years old, 20ml each time, 4 times daily. After the treatment is finished, standard care is continued until discharge.

The yanning (RYN) mixture (100 ml/bottle, lot 220222) is available from Qinghua De Sian Happy pharmaceutical Co. According to the rule of the 2020 edition of Chinese pharmacopoeia, each 1000ml RYN is prepared from 372g dandelion, 372g polygonum cuspidatum, 372g patrinia and 186 g barbed skullcap herb. And controlling the quality of the medicinal materials and identifying the components by utilizing the fingerprint. The results show that the main components of the green glycoside are chlorogenic acid, caffeic acid, resveratrol glycoside, luteolin and emodin. The product was marketed in 2005 and approved by the national drug administration (approval document: Z20050493). High performance liquid chromatography analysis shows that the content and quality of the medicine accord with the reference standard of Chinese pharmacopoeia.

1.4 study endpoint

The main results of this study were:

(1) SARS-CoV-2 nucleic acid negative time

(2) Nucleic acid negative conversion ratio on day 3 and day 7

(3) The cycle threshold (Ct) value of the SARS-CoV-2ORF1ab gene or N gene tested in real-time fluorescent quantitative polymerase chain reaction (RT-PCR) (semi-quantitative analysis of SARS-CoV-2 viral load) was also used as the primary endpoint

Secondary results include

(4) Hospitalization time

(5) New symptoms in asymptomatic infected patients

(6) Rate of symptom recovery and rate of disease progression.

The SARS-CoV-2 nucleic acid is converted into negative by the continuous two times of nucleic acid sampling of the oropharynx swab, the Ct value of the ORF1ab gene and the N gene is more than or equal to 35, and the nucleic acid detection interval is at least 24 hours.

Discharge standard is (1) body temperature is recovered to be normal for more than 3 days; (2) the respiratory symptoms are obviously improved; (3) nucleic acid transformation is negative.

1.5 data acquisition

Data was collected using a pre-designed case report table, including demographics, disease severity, complications, concomitant medications, vaccination history, clinical outcome, and Adverse Events (AEs). The subject should report daily symptoms. Family members may also report for non-expressible child agents. The nurse samples the pharyngeal swabs daily prior to discharge. All pharyngeal swab specimens were transported from the sampling site to a nearby shelter laboratory (Shanghai, river Biotechnology Co., ltd., china) for RT-PCR detection. The viral load of the oropharynx is reflected by the Ct value of RT-PCR. AE is defined as any adverse medical event, whether or not related to the drug under study.

1.6 sample size

According to previous studies on clinical characteristics of the amikacin infected Shanghai, the mean time to negative SARS-CoV-2 was 7.46.+ -. 3.02 days. Given the exploratory nature of this study, the present invention assumes a SARS-CoV-2 negative conversion time of RYN of 6.5 days. The sample size required after calculation according to the formula was 192 cases. Assuming a shedding rate of 15%, 220 subjects must be enrolled per group. Therefore, the trial should be incorporated into 440 patients.

1.7 statistical analysis

For normally distributed data, the data are expressed as mean ± Standard Deviation (SD); for data that is not normally distributed, the data is represented as a median with a quarter-bit difference (IQR). The classification variable is expressed as frequency and ratio (%). The Mann-Whitney test was performed on continuous variables that were not normally distributed by comparing continuous variables that were normally distributed for the two treatment groups by independent sample t-test. Classification variables between the two groups were compared using chi-square test or Fisher's exact test. The cumulative probability of clinical outcome occurrence (as a "survival" measure) was estimated by the Kaplan-Meier method. For samples with Ct values below the lower detection limit, the Ct value was set to 45 for statistical purposes. For all analyses, the statistical significance difference was set to P <0.05 (bilateral test). Data analysis was performed using SPSS 26.0 (IBM Corp, USA).

2 results

2.1 baseline statistics

From day 15 of 4 of 2022 to day 12 of 5, 527 children infected with covd-19 were screened, 440 of which were included and randomly assigned to either the intervention group or the control group at a 1:1 ratio. Seven patients were excluded after randomization treatment. In this trial, 2 patients in the intervention group were withdrawn. Finally, the intervention group 214 patients and the control group 217 patients completed 7 days of treatment and were included in the efficacy analysis. Study flow chart (fig. 1) subject registration and study flow. Table 1 summarizes the baseline demographics and clinical characteristics of the subjects. There were no significant differences in demographic variables or baseline clinical characteristics in the two groups. There was a significant difference in the administration of expectorants between the two groups (p=0.04).

Table 1 baseline data and clinical features.

2.2 main results

The median negative switch time for the intervention group was 7 days (IQR: 4-9) and for the control group 8 days (IQR: 6-10). Kaplan-Meier analysis showed a reduced negative transition time (P < 0.001) for the intervention group (fig. 2).

By day 3 and day 7, the nucleic acid negative turnover rate was significantly higher in the intervening group than in the control group (day 3: 7.0% versus 2.8%, p=0.041; day 7: 60.3% versus 37.8%, P < 0.01) (fig. 3).

2.3 viral load

The viral load (expressed as Ct values) of the oropharynx of two groups of patients was obtained by RT-qPCR and the change in Ct values during observation was statistically analyzed (fig. 4). The Ct value is inversely proportional to viral load, with higher values indicating lower viral load.

The Ct values of the ORF1ab genes or the N genes were not statistically different between the two groups on day 1 (ORF 1ab genes: 33.05[27.19,45] vs.31.92[26.62,38.42], P=0.095; N genes: 32.77[26.62,45] vs.31.24[26.09,37.89], P=0.158). As treatment proceeds, the viral load level of the intervening group drops significantly and at day 6 to undetectable levels. The Ct values of the intervention group ORF1ab gene and the N gene were statistically increased on day 2 (ORF 1ab gene: 35.62[29.17,45] vs.34.22[28.41,39.41], p=0.03; N gene: 34.97[28.50,45] vs.33.51[27.70,38.25], p=0.024) compared to the control group, and on day 3 (ORF 1ab gene: 38[32.72,45] vs.35.81[29.96,45], p=0.003; N gene: 37.16[32.01,45] vs.35.26[29.09,45], p=0.01).

2.4 secondary results

The median hospitalization time for the intervention group was 9 days (IQR: 6-11), and for the control group was 9 days (IQR: 7-11). Kaplan-Meier analysis showed no significant difference in discharge rate between the two groups (p=0.105) (fig. 5). No disease progression cases were observed during the period. Of 292 infected persons who were asymptomatic at admission, 98 of the intervention groups and 101 of the control groups developed clinical symptoms during the observation period. The control group had a higher frequency of wheezing symptoms (0.7% vs13.0%, P < 0.001) than the intervention group, and there was no statistical difference between the other two groups with new symptoms (P > 0.05) (table 2). After 7 days of treatment, the cough symptom relief rate of the intervention group is obviously higher than that of the control group (82.2% vs.70.0%, p=0.02); fever (100% vs96.2%, p=0.06), sore throat (100% vs 100%), expectoration (73.1% vs58.6%, p=0.09), fatigue (82.4% vs76.5%, p=0.55), wheezing (100% vs.100%) symptoms were not statistically different between the two groups (fig. 6).

TABLE 2 New symptoms

2.5 Security

RYN can be considered a safe intervention since only a few AEs, for example 2 cases of diarrhea (0.9%), 6 cases of rash (2.8%), 9 cases of constipation (4.2%), 3 cases of chest distress (1.4%), 1 case of gum swelling (0.5%), 2 cases of conjunctivitis (0.9%), 1 case of joint pain (0.5%) are reported in the intervention group. There was no significant difference in AE incidence between the intervention group and the control group (table 3). All AEs were mild and could be treated symptomatically.

Table 3 adverse reactions.

Discussion 3

In the prospective, open label and random control test, the invention explores the curative effect and safety of the yanning mixture on the treatment of the COVID-19 with the age of less than 18 years. The data of the present invention show that the Reyanning mixture has good safety, can accelerate the negative rotation time of SARS-CoV-2, accelerate the elimination of viruses and rapidly relieve cough symptoms.

Children infected with SARS-CoV-2 are usually asymptomatic or slightly symptomatic, with fever and cough as the main symptoms. These results are consistent with the clinical features observed in this trial. In addition, 8% of infants reported wheezing. In the study of the present invention, the present invention also found that 8 patients had wheezing prior to group entry and 21 patients reported wheezing during the treatment period. Additional RYN treatment can significantly reduce the occurrence of wheezing symptoms. The course of the amikacin pandemic was significantly shortened compared to the previously reported viral turn-to-negative time (11.43 days) and hospitalization time (12.97 days). Studies of the present invention show that SARS-CoV-2 has a negative transfer time of 8 (5-10) days and a hospitalization time of 9 (7-11) days.

Claims

1. Application of Reyanning in preparing medicine for treating children or teenagers SARS-CoV-2 asymptomatic or mild infection is provided.

2. Use of the yanning according to claim 1 for the preparation of a medicament for the treatment of asymptomatic or minor infections of SARS-CoV-2 in children or adolescents, characterized in that: application of Thermoyanning in preparing medicine for changing Ct value of SARS-CoV-2ORF1ab or N gene.

3. Use of a thermic effect according to claim 2 for the preparation of a medicament for the treatment of asymptomatic or minor infection of SARS-CoV-2 in children or adolescents, characterized in that: the Reyanning is prepared from water extracts of dandelion, giant knotweed, herba patriniae and barbed skullcap herb, wherein the weight ratio of the dandelion to the giant knotweed to the herba patriniae to the barbed skullcap herb is 1-3:1.

4. Use of a thermic effect according to claim 3 for the manufacture of a medicament for the treatment of asymptomatic or minor infection of SARS-CoV-2 in children or adolescents, characterized in that: the Reyanning is prepared by the following preparation method: decocting the above four materials with water twice for 2 hr for 1 hr, filtering, concentrating the filtrate under reduced pressure to appropriate amount, mixing the concentrated solutions, centrifuging, filtering, adding steviosin 1.5g and ethylparaben 0.5g, heating to boil, and making into 1000 ml.

5. The use of the yanning according to claim 4 for the preparation of a medicament for the treatment of asymptomatic or minor infections of SARS-CoV-2 in children or adolescents, characterized in that: the dosage of the antipyretic is as follows: under 3 years old, 5ml each time, three times daily; 4-6 years old, 10ml each time, three times per day; 7-14 years old, 15ml each time, three times daily; 15-17 years old, 20ml each time, 4 times daily.