Use of ciprofol injection for surgical general anesthesia induction and maintenance in pediatric patient

Abstract

The present invention relates to use of a ciprofol injection for anesthesia and / or sedation in a pediatric patient and particularly to use of the ciprofol injection for general anesthesia induction and maintenance in the pediatric patient.

Description

Use of piroxifen injection in pediatric patients for induction and maintenance of general anesthesia during surgery. Technical Field

[0001] This invention relates to the use of picophenol injection in anesthesia and / or sedation of pediatric patients, and more specifically to the use of picophenol injection in the induction and maintenance of general anesthesia in pediatric patients. Background Technology

[0002] Anesthesia plays a crucial role in surgical procedures, providing essential protection for the operation. General anesthesia is a complex state involving multiple factors such as sedation, analgesia, muscle relaxation, and stress inhibition. General anesthesia includes induction, maintenance, and recovery. Induction refers to the patient's transition from a conscious state to an anesthetic state suitable for surgical procedures. Maintenance refers to the period from the completion of induction until the end of surgery, its main task being to maintain the depth of anesthesia at a certain level, meeting the needs of the surgery while preserving the patient's stable physiological functions. Sevoflurane and propofol are currently commonly used drugs for induction and maintenance of general anesthesia. Sevoflurane has the advantages of rapid induction and fewer side effects, but it can easily contaminate the operating room environment and induce laryngospasm. Propofol has now become the most commonly used intravenous anesthetic, but its traditional single induction dose can cause drastic hemodynamic fluctuations during loading, leading to a significant drop in blood pressure. This drop in blood pressure can be more pronounced in elderly patients, reaching 15%–40%. Furthermore, the induction dose of propofol can increase the incidence of respiratory depression, which is also a concern. In addition, injection pain is one of the common adverse reactions of propofol. When propofol is injected, patients may experience pain, which can increase their tension and anxiety, thereby directly or indirectly interfering with the stability of anesthesia induction.

[0003] For children, local anesthesia needs to be administered while the child is awake, but almost all children are unable to cooperate with local anesthesia. Therefore, general anesthesia is the most commonly used anesthetic method in clinical practice for infants and children. However, the safety of general anesthesia remains a significant concern for both the child's family and doctors.

[0004] Currently, there are a number of problems with pediatric sedative anesthetics, such as injection pain, respiratory depression, postoperative agitation / delirium, and postoperative nausea and vomiting, which cannot fully meet clinical needs. Propofol, as one of the commonly used intravenous anesthetics, also faces complex clinical problems that urgently need to be addressed. Furthermore, the types of sedative anesthetics commonly used in pediatric patients are limited in clinical practice, and most drug instructions lack standardized pediatric drug use information. Moreover, in December 2016, the U.S. Food and Drug Administration (FDA) issued a safety warning regarding the use of general anesthesia in children (under 3 years old) and pregnant women. The FDA raised concerns about the potential impact of repeated or prolonged use of general anesthesia and sedatives on brain development in children (under 3 years old) or pregnant women (third trimester) during surgery or procedures. In human studies, the neurotoxic effects of anesthetic drugs remain unclear. According to a meta-analysis of thirteen studies, children approaching 3 years of age have a slightly increased risk of neurodevelopmental disorders (Zhang et al., 2015). Another Bayesian meta-analysis also showed that there is a slight risk of neurotoxicity in children receiving anesthesia early in life (DiMaggio et al., 2012).

[0005] Cyclopofol is a compound with a chemical structure similar to propofol. It is a single diastereomer with two R-type chiral centers. Cyclopofol exhibits rapid onset and stable, rapid pharmacodynamic characteristics. Compared to propofol, cyclopofol has higher selectivity for its target and higher in vitro and in vivo activity, with a potency 4 to 5 times that of propofol. Cyclopofol has been approved for the induction and maintenance of anesthesia in adult surgery, sedation and anesthesia in non-intubated surgeries / procedures, and sedation in adult intensive care units. For anesthesia induction, the approved adult dose is 0.4 mg / kg, with a booster dose of 0.2 mg / kg. During the maintenance phase, the approved adult dose is 0.8 mg / kg / hr, with a dosing rate ranging from 0.4 to 2.4 mg / kg / hr. Multiple randomized controlled clinical trials in adults have demonstrated that cyclopofol provides good sedation and anesthesia in non-intubated surgeries / procedures, and is also suitable for the induction and maintenance of general anesthesia, showing good tolerability in target patients. Therefore, cyclopropionol can be widely used in the above-mentioned surgeries and procedures, as well as for the sedation needs of patients requiring mechanical ventilation in intensive care unit settings.

[0006] Therefore, there is a need for safer and more effective anesthesia and sedation for pediatric patients, such as methods for induction and maintenance of general anesthesia during surgery. Summary of the Invention

[0007] The inventors of this invention have found that propofol injection is effective and safe for anesthesia and / or sedation, especially for general anesthesia induction and maintenance, in pediatric patients aged ≥2 years and <18 years. Moreover, the side effects of propofol injection during general anesthesia induction and maintenance are significantly lower than those of the positive control propofol in cases of hypotension and / or bradycardia requiring drug intervention.

[0008] The present invention provides a method for anesthetizing and / or sedating pediatric patients, the method comprising administering an effective dose of cyclopropofol to the pediatric patient, wherein the dose of cyclopropofol is about 15 to about 35% higher per kilogram of body weight than that of an adult patient.

[0009] In some implementations, the method is applicable to the induction and maintenance of general anesthesia, sedation and anesthesia in non-endotracheal intubation surgeries / procedures, and sedation during mechanical ventilation in intensive care.

[0010] In some embodiments, the pediatric patient is under about 18 years of age. In some embodiments, the pediatric patient is about 0 to about 17 years of age. In some embodiments, the pediatric patient is about 12 to about 17 years of age. In some embodiments, the pediatric patient is about 6 to about 11 years of age. In some embodiments, the pediatric patient is about 2 to about 5 years of age.

[0011] In some embodiments, the pediatric patient will undergo elective surgery induction general anesthesia, with general anesthesia induced during the induction phase. In some embodiments, the pediatric patient will undergo elective surgery involving endotracheal intubation.

[0012] In some embodiments, during the induction of general anesthesia, the initial dose of propofol is about 0.40 to about 1.00 mg / kg or about 0.70 ± about 0.30 mg / kg; optionally, after the initial dose, a booster dose of propofol is about one-third to about one-half of the initial dose, up to two or three times.

[0013] In some implementations, during the induction of general anesthesia, for pediatric patients aged approximately 12 to approximately 17 years, the initial dose of picoplanin is approximately 0.30 to approximately 0.90 mg / kg or approximately 0.60 ± approximately 0.30 mg / kg, optionally followed by a booster dose of approximately one-third to approximately one-half of the initial dose, up to two or three times; for pediatric patients aged approximately 6 to approximately 11 years, the initial dose of picoplanin is approximately 0.45 to approximately 0.95 mg / kg or approximately 0. For patients aged approximately 2 to approximately 5 years, the initial dose of picoplanin is approximately 0.70 ± about 0.25 mg / kg, and optionally, after the first dose, the additional dose of picoplanin is about 1 / 3 to about 1 / 2 of the initial dose, up to 2 or 3 times; or for pediatric patients aged approximately 2 to approximately 5 years, the initial dose of picoplanin is about 0.40 to about 1.00 mg / kg or about 0.70 ± about 0.30 mg / kg, and optionally, after the first dose, the additional dose of picoplanin is about 1 / 3 to about 1 / 2 of the initial dose, up to 2 or 3 times.

[0014] In some implementations, during the induction of general anesthesia, for pediatric patients aged approximately 12 to approximately 17 years, the initial dose of propofol is approximately 0.5 mg / kg, with a booster dose of approximately 0.25 mg / kg; for pediatric patients aged approximately 2 to approximately 11 years, the initial dose of propofol is approximately 0.6 mg / kg, with a booster dose of approximately 0.3 mg / kg.

[0015] In some implementations, prior to the induction of general anesthesia, for pediatric patients aged approximately 12 to approximately 17 years, the initial dose of picoplanin is approximately 0.5 mg / kg, with a booster dose of approximately 0.25 mg / kg; for pediatric patients aged approximately 2 to approximately 11 years, the initial dose of picoplanin is approximately 0.6 mg / kg, with a booster dose of approximately 0.3 mg / kg.

[0016] In some implementations, during maintenance of general anesthesia, the initial dose of cyclopropofol is approximately 1.00-2.5 mg / kg / hr, or 1.8 or 2.0 mg / kg / hr.

[0017] In some implementations, during maintenance of general anesthesia, for pediatric patients aged approximately 12 to approximately 17 years, the initial dose of cyclopofol is 1.5–2.5 mg / kg / hr, or 1.8 or 2.0 mg / kg / hr, with a dosing rate ranging from approximately 0.5 to approximately 3 mg / kg / hr; for pediatric patients aged approximately 2 to approximately 11 years, the initial dose of cyclopofol is approximately 1.2–1.8 mg / kg / hr, with a dosing rate ranging from approximately 0.6 to approximately 4 mg / kg / hr.

[0018] In some implementations, propofol can be administered via single dose, multiple doses, continuous administration, or infusion.

[0019] In some implementations, cyclopropofol is administered via slow intravenous injection, with the injection lasting approximately 25 to 35 seconds during the surgical induction phase.

[0020] In some embodiments, the method further includes administering an effective dose of a first anesthetic drug to the pediatric patient prior to the induction phase, the first anesthetic drug being selected from sedatives / anesthetics, analgesics, and muscle relaxants. In some embodiments, the first anesthetic drug is administered prior to induction at a dose of about 0.35 to about 2 mcg / kg or about 25 to about 200 mcg / kg of the patient. In some embodiments, the first anesthetic drug is a sedative / anesthetic drug, including but not limited to midazolam, sevoflurane, dexmedetomidine, and esketamine; the analgesic includes but is not limited to fentanyl derivatives, oxycodone, and nalbuphine, and may be selected from fentanyl derivatives (such as fentanyl, remifentanil, sufentanil, alfentanil), oxycodone, nalbuphine, morphine, meperidine, dexmedetomidine, buprofenol, hydrocodone, nefopam, or a pharmaceutically acceptable salt of any of the above; the muscle relaxant includes but is not limited to rocuronium bromide and cisatracurium bromide, and may be selected from rocuronium bromide, cisatracurium bromide, vecuronium bromide, rocuronium bromide, pancuronium bromide, pipecuronium bromide, mivacuronium bromide, succinylcholine, or a pharmaceutically acceptable salt of any of the above. In some embodiments, the first anesthetic drug is selected from fentanyl, midazolam, sufentanil, ketamine, thiopental sodium, sodium hydroxybutyrate, etomidate, diazepam, flunitrazepam, clonazepam, flunitrazepam, lorazepam, metoprolol, buprofen, chlorpromazine, barbituric acid, phenobarbital, pentobarbital, amobarbital, serbabarbital, or thiopental sodium, or a pharmaceutical salt of any of the above.

[0021] In some embodiments, the method further includes administering an effective dose of a second anesthetic drug to the pediatric patient during the maintenance phase. In some embodiments, the second anesthetic drug is used to maintain general anesthesia after endotracheal intubation.

[0022] In some embodiments, the second anesthetic drug used during the maintenance phase is an inhaled anesthetic. In some embodiments, the second anesthetic drug used during the maintenance phase is sevoflurane, isoflurane, enflurane, desflurane, halothane, anesthetic ether, methoxyflurane, or nitrous oxide. In some embodiments, the second anesthetic drug used during the maintenance phase is propofol or sodium fosfopropofol. In some embodiments, the second anesthetic drug used during the maintenance phase is cyclopropofol.

[0023] In some embodiments, the method further includes administering an anesthetic adjuvant selected from anticholinergics, muscle relaxants, antiemetics, local anesthetics, or analgesics during the pre-induction and / or maintenance phases. In some embodiments, the dosage of the anesthetic adjuvant is selected from about 0.01 mg / kg to about 15.0 mg / kg, about 0.01 mg / kg to about 10.0 mg / kg, about 0.01 mg / kg to about 5.0 mg / kg, about 0.01 mg / kg to about 2.0 mg / kg, or about 0.01 mg / kg to about 1.0 mg / kg. In some implementations, the anticholinergic drug is selected from atropine or scopolamine or a pharmaceutically acceptable salt of any of the above; the muscle relaxant is selected from vecuronium bromide, rocuronium bromide, pancuronium bromide, pipecuronium bromide, mivacuronium bromide, succinylcholine or cisatracurium bromide or a pharmaceutically acceptable salt of any of the above; the antiemetic is selected from topisetron, palonosetron, granisetron, dolasetron, scopolamine, fluperidone or metoclopramide or a pharmaceutically acceptable salt of any of the above; the local anesthetic is selected from lidocaine, ropivacaine, bupivacaine, levobupivacaine, articaine or deslorine or a pharmaceutically acceptable salt of any of the above; and the analgesic is selected from fentanyl, remifentanil, sufentanil, alfentanil, morphine, meperidine, dexmedetomidine, buprofenol, hydrocodone or nefopam or a pharmaceutically acceptable salt of any of the above. Attached Figure Description

[0024] Figure 1 is a roadmap for the implementation of clinical research of this invention. Detailed Implementation

[0025] The term "about" refers to ±5% to ±10% of the stated number or value.

[0026] Ciprofol, namely 2-[(1R)-[1-cyclopropylethyl]]-6-isopropylphenol, is a structural analog of propofol, wherein the introduction of an R-chiral center and a cyclopropyl group improves its pharmacological and physicochemical properties. The ciprofol of this invention also includes its pharmaceutically acceptable salts.

[0027] This invention is based on the evaluation of a retrospective study on the efficacy and safety of propofol injection for the induction and maintenance of general anesthesia in pediatric patients.

[0028] Clinical research

[0029] I. Research Plan

[0030] (I) Research Design Methods

[0031] 1. Research Center

[0032] Hunan Children's Hospital

[0033] 2. Research Objectives

[0034] The primary objective of this study was to compare the efficacy of propofol and cyclopropofol in induction and maintenance of general anesthesia in pediatric surgical patients; the secondary objective was to compare the safety of propofol and cyclopropofol in induction and maintenance of general anesthesia in pediatric surgical patients.

[0035] 3. Selection of the study population

[0036] a) Selection Criteria

[0037] 1) Age < 18 years old, gender not limited;

[0038] 2) Pediatric patients who require endotracheal intubation or laryngeal mask airway for general anesthesia and mechanical ventilation to complete surgery;

[0039] 3) Pediatric patients who received cephalexin or propofol during induction and / or maintenance of general anesthesia (induction of general anesthesia is defined as the time from the first intravenous injection of cephalexin or propofol to the first completion of endotracheal intubation / laryngostomy mask; maintenance of general anesthesia is defined as the time from the completion of endotracheal intubation / laryngostomy mask to the completion of the surgery);

[0040] 4) As of March 31, 2023.

[0041] b) Exclusion criteria: Data should be excluded from the study if it meets any of the following criteria:

[0042] 1) Children undergoing emergency surgery or requiring emergency treatment during surgery;

[0043] 2) Children undergoing diagnostic examinations such as gastroscopy, colonoscopy, and bronchoscopy;

[0044] 3) If the time or record of endotracheal intubation or laryngeal mask placement is missing, it is impossible to determine whether induction was successful and the data will be excluded from the final analysis.

[0045] 4) If the records of the surgery completion time or anesthesia completion time are missing, it cannot be determined whether the anesthesia was maintained and the procedure will be excluded from the final analysis.

[0046] 4. Treatment plan or measures (exposure factors)

[0047] a) Treatment cohort

[0048] Cyclopofol injection: Cyclopofol is used during the induction and maintenance of general anesthesia.

[0049] The initial dosage, cumulative dosage, additional dosage, and number of additional dosages of propofol were analyzed.

[0050] b) Control queue

[0051] Propofol injection: Propofol is used during the induction and maintenance of general anesthesia.

[0052] The initial dosage, cumulative dosage, additional dosage, and number of additional dosages of propofol were analyzed.

[0053] 5. Combined medication

[0054] Collection and analysis of combined medications: Analysis of other sedatives / anesthetics, analgesics, and muscle relaxants used from the start of operation to the end of anesthesia (collecting drug names, dosages, and administration times). Specific classifications of combined medications are as follows:

[0055] a) Sedatives / anesthetics: mainly including midazolam, sevoflurane, dexmedetomidine, esketamine, etc.;

[0056] b) Analgesics: mainly including fentanyl derivatives, oxycodone, nalbuphine, etc.;

[0057] c) Muscle relaxants: mainly including rocuronium bromide and cisatracurium.

[0058] 6. Research Results (Outcome Variables)

[0059] a) Effective endpoint during general anesthesia induction

[0060] 1) Calculate the two-sided 95% confidence intervals for the success rate of anesthesia induction and the difference between the rates in the cyclopropofol and propofol groups, respectively. The success rate of anesthesia induction is the proportion of subjects who are successfully anesthetized. Successful anesthesia induction is defined as a single successful endotracheal intubation or laryngeal mask airway insertion (excluding cases where multiple endotracheal intubations are required due to anatomical factors).

[0061] 2) Duration of anesthesia induction: The time from the end of the first intravenous injection of propofol or cyclophosphamide to the first endotracheal intubation / laryngosmal mask airway placement was descriptively analyzed according to the treatment group. The Log-Rank test was used to compare the differences between treatment groups for each efficacy index. Kaplan-Meier curves for each efficacy index of different treatment groups were plotted and the median duration and 95% confidence interval were provided.

[0062] b) Effective endpoint during maintenance of general anesthesia

[0063] 1) Calculate the two-sided 95% confidence intervals for the anesthesia maintenance success rate and the difference between the rates in the cyclopropofol and propofol groups. The anesthesia maintenance success rate is the proportion of subjects whose anesthesia was maintained. Anesthesia maintenance success is defined as the absence of intraoperative awakening (clinical signs of intraoperative awakening assessed by the investigator, such as lacrimation and sweating), the absence of unexpected limb movements, and the absence of the need for resuscitation with other anesthetic drugs.

[0064] 2) Assessment of depth of anesthesia: The bispectral index (BIS) of the brain was used to assess the BIS level from the time of successful anesthesia induction to the end of the operation (if BIS monitoring was available).

[0065] 3) Duration of spontaneous respiration recovery: The time from the discontinuation of anesthetic drugs at the end of surgery to the recovery of spontaneous respiration was analyzed using descriptive statistics for each group and comparisons were made between groups.

[0066] 4) Duration from the end of the operation to the removal of the endotracheal tube or laryngeal mask: The duration from the end of the operation to the removal of the endotracheal tube or laryngeal mask was descriptively summarized and analyzed for each group, and inter-group comparisons were made.

[0067] c) Analysis of combined medication use

[0068] 1) The proportion of other sedatives / anesthetics, analgesics, and muscle relaxants used in combination during anesthesia induction was analyzed. Descriptive statistics were performed based on the types of other sedatives / anesthetics, analgesics, and muscle relaxants and the treatment group. Chi-square test or Fisher's exact test was used for intergroup comparisons, and p-values ​​were provided.

[0069] 2) The proportion of other sedatives / anesthetics, analgesics, and muscle relaxants used in combination during anesthesia maintenance was analyzed using descriptive statistics based on the types of other sedatives / anesthetics, analgesics, and muscle relaxants and the treatment group. Intergroup comparisons were performed using the chi-square test or Fisher's exact test, and p-values ​​were provided.

[0070] d) Safety endpoint

[0071] 1) The proportion of vital signs (systolic blood pressure, diastolic blood pressure, heart rate) and blood oxygen saturation that changed from baseline by <15%, 15-30%, and >30% from the first intravenous injection of cephalexin or propofol to 5 minutes after the end of anesthesia;

[0072] 2) The proportion of events requiring pharmacological intervention for decreased blood pressure and / or bradycardia during the period from the first intravenous injection of cefprozil or propofol to 5 minutes after the end of anesthesia.

[0073] Hypotension during anesthesia is defined as a decrease in blood pressure exceeding 20% ​​of baseline, accompanied by administration of phenylephrine or dopamine to improve blood pressure. Bradycardia is defined as a heart rate <100 beats / min in infants under 1 year old, <80 beats / min in children aged 1–6 years, and <60 beats / min in children over 6 years old, accompanied by administration of atropine, beta-agonists (isoproterenol, dopamine, dobutamine, epinephrine), or other medications to improve bradycardia.

[0074] 1) Laboratory tests: Blood biochemistry test results (if possible, collect data from the date of surgery to 7 days after surgery).

[0075] 2) Adverse events (AEs) and serious adverse events (SAEs).

[0076] a) Adverse Events: Adverse events (AEs) refer to all adverse medical events that occur to a subject during a clinical trial. They may manifest as symptoms, signs, illnesses, or abnormal laboratory test values, but are not necessarily causally related to the investigational drug. Therefore, adverse events can be any unfavorable, unexpected signs, symptoms, or illnesses (new occurrences or exacerbations of existing conditions).

[0077] b) Adverse events occurring after a subject uses the investigational drug are defined as treatment-emergent adverse events (TEAEs). Note: Investigational drug refers to the investigational drug (propofol or control drug) used in the clinical trial.

[0078] c) AE does not include:

[0079] i. During administration of anesthetic drugs, a decrease in BIS, drowsiness, lethargy, or even loss of consciousness may occur (but if the degree exceeds clinical expectations, adverse events (AEs) should also be recorded).

[0080] ii. Pre-existing abnormalities and / or diseases prior to signing the ICF (except for cases where the severity of the abnormality and / or disease worsened as assessed by the investigator after administration);

[0081] iii. Elective medical examinations or surgeries planned prior to signing the ICF;

[0082] iv. Overdose of the investigational drug or concomitant medication without causing any symptoms or signs;

[0083] v. A chronic disease newly diagnosed during or after surgery;

[0084] vi. Discomfort caused by surgical procedures (e.g., coughing, tearing, body movement, throat discomfort, oral mucosal bleeding, or postoperative pain caused by surgery, as determined by the investigator; however, if the relevance to the procedure is unclear or exceeds the expected clinical manifestations, it is still recorded as an adverse event).

[0085] d) Serious adverse events: refers to any adverse event that meets any of the following criteria:

[0086] i. leading to death;

[0087] ii. Life-threatening (“Life-threatening” means that the subject is in immediate danger of death when the event occurs, rather than an event that, hypothetically, could lead to death if the situation were more serious);

[0088] iii. Leading to hospitalization or prolonging hospitalization;

[0089] iv. Leading to permanent or severe disability or loss of function;

[0090] v. to cause congenital abnormalities or birth defects;

[0091] vi. Important medical event.

[0092] 3) Injection pain: During the induction of general anesthesia, the researcher will observe the child's condition from the start of administration of the experimental drug until the child loses consciousness and score the degree of injection pain.

[0093] (II) Research Design Methods

[0094] 1. Research Center

[0095] Eight hospitals (multi-center) including Shanghai Children's Medical Center affiliated with Shanghai Jiao Tong University School of Medicine

[0096] 2. Research Objectives

[0097] The primary objective was to confirm the efficacy of picoplanin injection for general anesthesia in pediatric patients aged 2–17 years; the secondary objective was to evaluate the safety of picoplanin injection for general anesthesia in pediatric patients aged 2–17 years; and the exploratory objective was to evaluate the occurrence of awakening agitation after picoplanin injection for general anesthesia in pediatric patients aged 2–17 years.

[0098] 3. Selection of the study population

[0099] a) Inclusion criteria (all of the following criteria must be met)

[0100] 1) Age ≥ 2 years and < 18 years, gender not limited;

[0101] 2) Elective surgeries requiring mechanical ventilation via endotracheal intubation and general anesthesia, with an estimated anesthesia time of approximately 30–120 minutes;

[0102] 3) Intravenous anesthesia is suitable for both induction and maintenance of general anesthesia;

[0103] 4) The ASA classification is Level I-II;

[0104] 5) Before any trial-related activities begin, the patient’s guardian or at least one of the patient’s and both parents’ guardians must sign an informed consent form.

[0105] b) Exclusion criteria (meeting any one of the following criteria will result in exclusion):

[0106] 1) The type of surgery is emergency surgery or requires emergency resuscitation during the operation, or the investigator determines that a blood transfusion may be necessary;

[0107] 2) Those with contraindications to general anesthesia or a history of anesthetic accidents;

[0108] 3) Individuals with known or suspected hypersensitivity to the excipients in propofol injection, excipients in cyclopropofol injection (soybean oil, glycerin, triglycerides, egg yolk lecithin, sodium oleate, and sodium hydroxide), benzodiazepines, opioids, rocuronium bromide, atropine, or their active ingredients; or individuals with contraindications to propofol injection.

[0109] 4) Those with a history or evidence of increased sedation / anesthesia risk collected within 3 months prior to screening / during the screening period, and deemed unsuitable for participation by the investigator:

[0110] • Cardiovascular diseases: severe congenital heart disease (such as tetralogy of Fallot), severe arrhythmia (such as tachycardia / bradycardia requiring drug treatment, third-degree atrioventricular block), severe heart failure, etc.

[0111] • Respiratory diseases: respiratory insufficiency, history of bronchospasm / asthma requiring treatment within 1 month prior to screening, or acute upper respiratory tract infection with obvious symptoms such as fever, wheezing or expectorating cough within 1 week prior to screening;

[0112] • Cranial and cerebrovascular diseases: history of traumatic brain injury, seizures, epilepsy, intracranial hypertension, cerebral aneurysm, or cerebrovascular accident; or a known history of mental disorders, such as epileptic seizures, schizophrenia, mania, long-term use of psychotropic drugs, or cognitive impairment.

[0113] • Gastrointestinal diseases: gastrointestinal retention, active bleeding, and conditions that may lead to reflux and aspiration;

[0114] • Uncontrolled history of clinically significant diseases of the liver, kidneys, hematologic system, nervous system, or metabolic system;

[0115] • Individuals who have had a severe infection or major surgery within the four weeks prior to screening;

[0116] • History of malignant hyperthermia or family history of such illness.

[0117] 5) Any of the following respiratory management risks existed within / at the week prior to screening:

[0118] • Asthma attack, wheezing;

[0119] • Individuals with a history of failed endotracheal intubation;

[0120] Researchers assessed that there was a risk of difficulty breathing through the mask or difficulty in intubation.

[0121] 6) Individuals who have participated in any drug clinical trials within the month prior to screening;

[0122] 7) Those whose laboratory test indicators meet the following standards during the screening period and are confirmed by retesting:

[0123] • Alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) ≥ 3.0 × upper limit of normal (ULN);

[0124] • Total bilirubin ≥ 3.0 × ULN;

[0125] • Serum creatinine ≥ 2.5 × ULN.

[0126] 8) Women of childbearing age (i.e., postmenopausal) who do not wish to use contraception throughout the trial period;

[0127] 9) Pediatric patients requiring special care or supervision by courts / social welfare institutions;

[0128] 10) Subjects who, in the researchers' opinion, have any other factors that would preclude them from participating in this trial.

[0129] 4. Treatment Plan

[0130] Anesthesia induction: Cyclopofol or propofol will be administered. Cyclopofol or propofol will be administered via intravenous bolus. After successful induction (MOAA / S≤1), sufentanil or fentanyl and rocuronium will be administered via intravenous bolus. After the muscle relaxant takes effect, endotracheal intubation will be performed and the intubation time will be recorded.

[0131] Maintenance anesthesia: After endotracheal intubation, maintenance medication was initiated. The picoplanin group received picoplanin maintenance medication, followed by the analgesic remifentanil.

[0132] Researchers may administer sufentanil or fentanyl intravenously before, during, and at the end of the surgery, depending on the circumstances.

[0133] During the procedure, researchers may administer additional rocuronium bromide as needed.

[0134] 5. Research Indicators

[0135] a) Primary therapeutic endpoint:

[0136] 1) Anesthesia success rate: the proportion of subjects who are successfully induced and maintained by anesthesia.

[0137] • Definition of “successful induction of anesthesia”: During the induction of anesthesia, the subject achieves successful induction (i.e., MOAA / S≤1) within 5 minutes after the administration of the investigational drug, and no remedial measures are taken, and endotracheal intubation is completed.

[0138] • Definition of “successful maintenance of anesthesia”: no intraoperative awakening, no unexpected limb movement and no remedial action.

[0139] • Definition of “rescue”: If the induction or maintenance of anesthesia fails to achieve the above-mentioned goals, other methods shall be used to remedy the situation.

[0140] Note: If a subject received remedial treatment during anesthesia induction, there is no need to continue with the maintenance phase of general anesthesia.

[0141] b) Secondary therapeutic endpoints:

[0142] 1) Anesthesia induction success rate: the proportion of subjects who are successfully induced to receive anesthesia;

[0143] 2) Anesthesia maintenance success rate: the proportion of subjects whose anesthesia is successfully maintained;

[0144] 3) Duration of successful anesthesia induction: the time from the end of the first administration of the investigational drug to the first MOAA / S≤1;

[0145] 4) Postoperative general anesthesia satisfaction evaluation: The general anesthesia satisfaction rating scale (Table 1) was used for evaluation;

[0146] Table 1. Survey of researchers' overall satisfaction with anesthetic drugs after general anesthesia.

[0147] 5) Information on the use of investigational and recovery drugs (including the number of times and dosage of drugs used).

[0148] c) Safety endpoint:

[0149] 1) Adverse events (AEs) and serious adverse events (SAEs);

[0150] 2) Vital signs;

[0151] 3) Electrocardiogram (ECGs);

[0152] 4) Laboratory tests, etc.;

[0153] 5) Injection pain. The Ambesh 4-point scale was used to score injection pain. During the induction of general anesthesia, the researcher observed the child's condition from the start of administration of the experimental drug until the child lost consciousness, and scored the degree of injection pain according to the above criteria.

[0154] d) Exploratory endpoint:

[0155] 1) Incidence and severity of agitation during the recovery period: The PAED scoring scale was used to evaluate the incidence and severity of agitation in the subjects.

[0156] (III) Research Design Methods

[0157] 1. Research Center

[0158] Hunan Children's Hospital

[0159] 2. Research Objectives

[0160] The purpose of this study was to preliminarily evaluate the efficacy and safety of cyclopropofol for sedation / anesthesia during intraoperative bronchoscopy in pediatric patients.

[0161] 3. Selection of the study population

[0162] a) Selection Criteria

[0163] 1) Age ≥ 2 years and < 18 years, gender not limited;

[0164] 2) Children who have undergone diagnosis and / or treatment via laryngeal mask airway fiberoptic bronchoscopy;

[0165] 3) The ASA classification is Level I-II;

[0166] 4) Before any trial-related activities begin, the patient’s guardian or at least one of the patient’s and both parents’ guardians must sign an informed consent form.

[0167] c) Exclusion criteria (meeting any one of the following criteria will result in exclusion):

[0168] 1) Those with contraindications to deep sedation / general anesthesia or a history of sedation / anesthesia accidents;

[0169] 2) Individuals with known allergies to eggs, soy products, opioids and their antidotes, propofol, etc.; or those with contraindications to propofol, opioids and their antidotes.

[0170] 3) Patients who have undergone endotracheal intubation and / or mechanical ventilation prior to bronchoscopy;

[0171] 4) Patients who are expected to require bronchoalveolar lavage during bronchoscopy;

[0172] 5) Those with a history or evidence of increased sedation / anesthesia risk collected within 3 months prior to screening / during the screening period, and deemed unsuitable for participation by the investigator:

[0173] • Cardiovascular diseases: severe congenital heart disease (such as tetralogy of Fallot), severe arrhythmia (such as tachycardia / bradycardia requiring drug treatment, third-degree atrioventricular block), severe heart failure, etc.

[0174] • Respiratory diseases: respiratory insufficiency, history of bronchospasm / asthma requiring treatment within 1 month prior to screening, or acute upper respiratory tract infection with obvious symptoms such as fever, wheezing or expectorating cough within 1 week prior to screening;

[0175] • Cranial and cerebrovascular diseases: history of traumatic brain injury, seizures, epilepsy, intracranial hypertension, cerebral aneurysm, or cerebrovascular accident; or a known history of mental disorders, such as epileptic seizures, schizophrenia, mania, long-term use of psychotropic drugs, or cognitive impairment.

[0176] • Gastrointestinal diseases: gastrointestinal retention, active bleeding, and conditions that may lead to reflux and aspiration;

[0177] • Uncontrolled history of clinically significant diseases of the liver, kidneys, hematologic system, nervous system, or metabolic system;

[0178] • Individuals who have had a severe infection or major surgery within the four weeks prior to screening;

[0179] • History of malignant hyperthermia or family history of such illness.

[0180] 6) Any of the following respiratory management risks existed within / at the week prior to screening:

[0181] • Asthma attack, wheezing;

[0182] • Individuals with a history of failed endotracheal intubation;

[0183] Researchers assessed that there was a risk of difficulty breathing through the mask or difficulty in intubation.

[0184] 7) Individuals who have participated in any drug clinical trials within the month prior to screening;

[0185] 8) Those whose laboratory test indicators meet the following standards during the screening period and are confirmed by retesting:

[0186] • Alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) ≥ 3.0 × upper limit of normal (ULN);

[0187] • Total bilirubin ≥ 3.0 × ULN;

[0188] • Serum creatinine ≥ 2.5 × ULN.

[0189] 9) Women of childbearing age (i.e., postmenopausal) who do not wish to use contraception throughout the trial period;

[0190] 10) Pediatric patients requiring special care or supervision by courts / social welfare institutions;

[0191] 11) Subjects who, in the researchers' opinion, have any other factors that would preclude them from participating in this trial.

[0192] 4. Treatment methods

[0193] Anesthesia induction period: Cyclopofol is initially administered via intravenous bolus. After successful induction (MOAA / S ≤ 1), a laryngeal mask airway and bronchoscope can be inserted. If MOAA / S is still > 1 2 minutes after the initial administration, additional cyclopofol should be administered, with an interval of at least 2 minutes between administrations.

[0194] Maintenance of anesthesia: from insertion to removal of the bronchoscope. During this period, the researchers will decide whether to administer additional cephalexin based on the child's performance, such as signs of weakening anesthesia, such as body movement, swallowing, eye opening, and coughing. Except when administering the study drug via laryngeal mask airway or bronchoscope, the study drug will be administered at least 2 minutes apart.

[0195] Researchers may administer sufentanil or fentanyl, or other sedatives or anesthetics other than those commonly used in clinical practice, via intravenous bolus injection, depending on the situation.

[0196] 5. Research Indicators

[0197] a) Efficacy indicators

[0198] 1) Success rate of bronchoscopy. Successful treatment requires meeting both of the following conditions: ① bronchoscopy is completed; ② no alternative sedation / anesthesia drugs are used, i.e., the number of times the study drug is administered within any 15 minutes from the first administration of the study drug to the completion of the bronchoscopy is ≤5.

[0199] 2) Duration of successful sedation / anesthesia induction: the time from the first administration of the study drug to the first Modified Investigator Awareness / Sedation Score (MOAA / S) ≤ 1;

[0200] 3) Duration of full consciousness: The time from the removal of the bronchoscope or the last administration of the study drug to the first occurrence of MOAA / S=5 in three consecutive MOAA / S=5;

[0201] 4) Duration of absence from the bronchoscope: the time from the removal of the bronchoscope or the last administration of the study drug to the first occurrence of three consecutive Aldrete scores ≥9.

[0202] 5) Investigate the use of drugs and alternative drugs;

[0203] 6) Sedation / anesthesia satisfaction, including satisfaction ratings from subjects, anesthesiologists, and bronchoscopists.

[0204] b) Efficacy indicators

[0205] 1) Adverse events, sedation-related adverse events, and serious adverse events;

[0206] 2) Vital signs, 12-ECG, physical examination and laboratory tests.

[0207] II. Drug administration process

[0208] The day of surgery is defined as D1. The following procedures / evaluations will be performed:

[0209] 1) Pre-anesthesia preparation

[0210] In accordance with standard procedures, we collect relevant information about pediatric patients and monitor their vital signs.

[0211] 2) Anesthesia induction and maintenance drug administration regimens

[0212] Anesthesia induction period:

[0213] The time at which the first administration of propofol injection or control (propofol injection) begins is recorded as 0 min. Propofol is administered intravenously via bolus injection at the predetermined starting dose. The MOAA / S score is evaluated every 30 s ± 10 s after the initial administration of propofol injection until MOAA / S ≤ 1. The criteria for booster dosing are as follows: The MOAA / S score is evaluated every 30 s ± 10 s after the initial administration of propofol injection. If MOAA / S > 1 after two consecutive evaluations, an additional 0.2 mg / kg is administered within 10 s after the second evaluation. Thereafter, booster dosing is administered at intervals of at least N2 MOAA / S evaluations until MOAA / S < 1, meeting the criteria for endotracheal intubation.

[0214] After successful induction (MOAA / S<1), administer an intravenous bolus of a muscle relaxant, such as sufentanil 0.2–0.4 mg / kg or fentanyl 2–4 mg / kg, or rocuronium 0.6 mg / kg. Once the muscle relaxant has taken effect, perform endotracheal intubation and record the intubation time.

[0215] Maintenance of anesthesia:

[0216] After endotracheal intubation, maintenance administration of cephalexin injection or control was initiated. The initial maintenance dose (rate) of cephalexin or control was 0.8 mg / kg / h, while other sedatives such as remifentanil were administered concurrently at 0.2-2 mg / kg / min. Maintenance dose adjustments were made as follows: the investigator adjusted the maintenance dose rate of cephalexin or administered additional doses based on the subject's anesthetic response to achieve the target depth of general anesthesia (no awakening, no limb movement, and no drug intervention during surgery until the end of the procedure).

[0217] During anesthesia induction and maintenance, observe and record the following indicators:

[0218] - Injection pain score

[0219] -MOAA / S rating

[0220] -BIS Monitoring

[0221] - Monitoring of vital signs (RR, SBP / DBP, HR, T, SpO2)

[0222] -3 or 5-lead ECG

[0223] -Number of intubations and duration

[0224] -Use of test drugs (propofol or propofol) during the induction and maintenance phases

[0225] -Use of propofol as a rescue agent during the induction and maintenance phases

[0226] - Adverse events

[0227] - Combined medication

[0228] - Surgical Name

[0229] -Surgery start and end times (surgery start time is counted from the start of skin incision, and surgery end time is counted from the completion of the last skin suture; investigational drugs are discontinued at the end of the surgery).

[0230] - Removal method: The tube was removed while the patient was under deep sedation, and the removal time and conditions were recorded.

[0231] During the postoperative observation period (D1-D2), the following indicators were observed and recorded:

[0232] -Time of entry into PACU, method and time of extubation, and time of eye opening.

[0233] - Improved Aldrete rating

[0234] - Postoperative anesthesia satisfaction evaluation (see Table 1)

[0235] -PAED rating

[0236] - Vital signs (SBP / DBP, HR, RR, SpO2)

[0237] -Laboratory tests

[0238] - Adverse events

[0239] - Combined medication

[0240] During the follow-up period (D2-D3), observe and record the following indicators:

[0241] - Vital signs (SBP / DBP, HR, RR, T, SpO2)

[0242] -12-ECG

[0243] -Laboratory tests

[0244] - Adverse events

[0245] - Combined medication

[0246] All adverse events (AEs) will be observed and recorded throughout the trial period [from the start of administration of the investigational drug to the end of the follow-up period (D2-3), and appropriate treatment and management will be provided as necessary. All AEs occurring during the study period will be followed up until they are cured, deemed clinically insignificant, become well-characterized chronic symptoms, return to baseline levels, or the patient refuses to follow up, or the patient is lost to follow-up.

[0247] III. Research Results

[0248] 1. Research Results—Hunan Children's Hospital

[0249] 1.1 Baseline characteristics of general anesthesia induction

[0250] As of July 31, 2022, among the pediatric patients at Hunan Children's Hospital who received cyclopofol injection (hereinafter referred to as cyclopofol) or propofol injection (hereinafter referred to as propofol) during general anesthesia induction for surgery, a total of 22,795 patients ultimately met the inclusion and exclusion criteria and the data governance plan, with 8,987 patients in the cyclopofol group and 13,808 patients in the propofol group.

[0251] In the propofol group and the propofol-positive control group, the demographic and other baseline characteristics of the two pediatric populations were comparable.

[0252] Demographic characteristics and age distribution: In the 2–5 year age group, the propofol group and the propofol group accounted for 59.5% and 55.7% respectively, with mean ages of 3.5±1.12 years and 3.4±1.09 years respectively; in the 6–11 year age group, the propofol group and the propofol group accounted for 34.5% and 37.7% respectively, with mean ages of 7.9±1.69 years and 8.0±1.64 years respectively; in the 12–17 year age group, the propofol group and the propofol group accounted for 5.9% and 6.6% respectively, with mean ages of 13.0±1.19 years and 13.2±1.32 years respectively, showing a balanced distribution.

[0253] Other baseline characteristics: According to the ASA classification, based on the severity percentages: for grades I-II, the cyclopropofol group and the propofol group accounted for 97.8% and 98.1%, respectively; for grades III-IV, the cyclopropofol group and the propofol group accounted for 2.1% and 1.9%, respectively; the distribution ratios of the two groups were balanced. Based on the surgical grade analysis, for grades I-II, the cyclopropofol group and the propofol group accounted for 15.6% and 17.2%, respectively; for grades III-IV, the cyclopropofol group and the propofol group accounted for 84.4% and 82.8%, respectively; the distribution ratios of the two groups were balanced. Specifically, for surgical grade IV, the cyclopropofol group accounted for 10.4% (935 / 8987) and the propofol group accounted for 13.9% (1915 / 13808), with the two groups having similar proportions.

[0254] 1.2 Maintaining baseline characteristics under general anesthesia

[0255] As of March 31, 2023, among the pediatric patients at Hunan Children's Hospital who used propofol or cyclopropofol during maintenance of general anesthesia for surgery, a total of 4,346 patients ultimately met the inclusion and exclusion criteria and the data governance plan, with 2,345 patients in the cyclopropofol group and 2,001 patients in the propofol group.

[0256] In the propofol group and the propofol-positive control group, the demographic and other baseline characteristics of the two pediatric populations were comparable.

[0257] Demographic characteristics and age distribution: In the 2–5 year age group, the propofol group and the propofol group accounted for 57.8% and 45.1% respectively, with mean ages of 3.5±1.12 years and 3.5±1.12 years respectively; in the 6–11 year age group, the propofol group and the propofol group accounted for 35.6% and 43.5% respectively, with mean ages of 7.9±1.63 years and 8.1±1.66 years respectively; in the 12–17 year age group, the propofol group and the propofol group accounted for 6.6% and 11.3% respectively, with mean ages of 13.0±1.14 years and 13.2±1.27 years respectively, showing a relatively balanced distribution.

[0258] Other baseline characteristics: According to the ASA classification, based on the proportion of severity: for grades I-II, the cyclopropofol group and the propofol group accounted for 93.2% and 94.1%, respectively; for grades III-IV, the cyclopropofol group and the propofol group accounted for 6.9% and 5.8%, respectively; the distribution ratio of the two groups was balanced.

[0259] According to the analysis of surgical grades, for grades I and II, the cyclopropofol group and the propofol group accounted for 10.4% and 9.0%, respectively; for grades III and IV, the cyclopropofol group and the propofol group accounted for 89.6% and 91.0%, respectively, with the two groups having a balanced distribution.

[0260] 1.3 Exposure Analysis

[0261] Based on data from all pediatric populations, the mean dosage during anesthesia induction was 0.699 ± 0.3017 mg / kg for 8987 pediatric patients in the propofol group and 2.554 ± 1.0237 mg / kg for 13808 pediatric patients. Stratified statistical analysis of the mean dosage during general anesthesia induction in pediatric populations by age group revealed the following mean dosages for propofol: 0.726 ± 0.331 mg / kg for preschool children aged 2–5 years, 0.670 ± 0.243 mg / kg for school-aged children aged 6–11 years, and 0.593 ± 0.2589 mg / kg for adolescents aged 12–17 years.

[0262] Based on data from all pediatric populations, the mean dose per unit body weight during maintenance anesthesia was 0.871 ± 0.966 mg / kg / h in the propofol group (2343 cases, 2 missing) and 3.198 ± 2.113 mg / kg / h in the propofol group (1999 cases, 2 missing). Stratified statistical analysis of the mean dose per unit body weight during maintenance anesthesia in pediatric populations of different age groups revealed the following hourly doses per unit body weight for propofol maintenance: 0.934 ± 1.140 mg / kg / h for preschool children aged 2–5 years, 0.804 ± 0.666 mg / kg / h for school-aged children aged 6–11 years, and 0.672 ± 0.526 mg / kg / h for adolescents aged 12–17 years.

[0263] 1.4 Analysis of Efficacy Results (Based on the Efficacy Analysis Set)

[0264] General anesthesia induction

[0265] 1) Anesthesia induction success rate: In the efficacy analysis set, the anesthesia induction success rate of both the propofol group and the propofol group was 100%.

[0266] 2) Duration of anesthesia induction: In the efficacy analysis, the average duration of anesthesia induction in the propofol group and the propofol group were 3.195±1.3050 minutes and 3.021±1.4657 minutes, respectively, which were comparable between the two groups.

[0267] General anesthesia maintenance

[0268] Anesthesia maintenance success rate was based on the original database and efficacy analysis set. The anesthesia induction success rate was 100% in both the propofol and propofol groups.

[0269] - No clinical signs of awakening occurred during the maintenance of anesthesia—such as tearing or sweating; no unexpected limb movements occurred; no other anesthetic drugs were used for resuscitation; and all data sets in the database, including excluded cases, were recorded as the end of the surgery.

[0270] - According to communication with the researchers, no anesthesia failure events occurred during the clinical trial.

[0271] 1.5 Analysis of concomitant medication (based on all study populations)

[0272] The combined medications (other than propofol or cyclopropofol) used during the induction and maintenance of general anesthesia were analyzed as a whole. The data were collected for both groups from the time they entered the operating room until the end of anesthesia, during which at least one combined medication (including the combined use of other sedatives / anesthetics, analgesics, and muscle relaxants) was used. The types and proportions of combined medications were comparable between the two groups.

[0273] 1.6 Security Result Analysis (Based on Security Set):

[0274] 1) Changes in vital signs (systolic blood pressure, diastolic blood pressure, heart rate) and blood oxygen saturation

[0275] During the induction of general anesthesia, the changes in vital signs (systolic blood pressure, diastolic blood pressure, heart rate) and blood oxygen saturation from baseline were analyzed. The proportions of changes in <15%, 15%–30%, and >30% were comparable between the propofol and propofol groups.

[0276] During the maintenance of general anesthesia, the changes in vital signs (systolic blood pressure, diastolic blood pressure, heart rate) and blood oxygen saturation varied for each subject due to the different duration of surgery. The vital signs (systolic blood pressure, diastolic blood pressure, heart rate) and blood oxygen saturation were monitored and analyzed from the start of infusion of cephalexin or propofol to 60 minutes after administration. The trends of change were relatively consistent between the two groups. Due to the lack of baseline data, no analysis of the changes compared to the baseline was performed.

[0277] - Events requiring medication intervention due to decreased blood pressure and / or bradycardia.

[0278] ■ Events requiring drug intervention during general anesthesia induction: decreased blood pressure and / or bradycardia. 0 cases in the propofol group and 5 cases in the propofol group.

[0279] ■ The incidence of events requiring drug intervention due to hypotension / bradycardia during maintenance of general anesthesia was 4.4% in the propofol group and 7.7% in the propofol group.

[0280] 1.7 Conclusion:

[0281] Povidone injection has good efficacy and safety for induction and maintenance of general anesthesia in pediatric patients aged ≥2 years and <18 years. The dosage of povidone for pediatric patients aged ≥2 years and <18 years is as follows:

[0282] 1) The average dose range for induction of general anesthesia was 0.699±0.3017 mg / kg. The average loading dose per unit body weight of cyclopropofol in pediatric populations of different age groups was as follows: 0.726±0.331 mg / kg for preschool children aged 2–5 years, 0.670±0.243 mg / kg for school-aged children aged 6–11 years, and 0.593±0.2589 mg / kg for adolescents aged 12–17 years.

[0283] 2) The average dosing rate for maintenance anesthesia was 0.871±0.966 mg / kg / h. The hourly dose per unit body weight for maintenance in pediatric populations of different age groups was as follows: 0.934±1.140 mg / kg / h for preschool children aged 2–5 years, 0.804±0.666 mg / kg / h for school children aged 6–11 years, and 0.672±0.526 mg / kg / h for adolescents aged 12–17 years.

[0284] 2. Study Results (Multicenter Clinical Trial) – Anesthesia Induction and Maintenance Dosing Regimens

[0285] 2.1 Baseline characteristics of the anesthesia induction and maintenance populations

[0286] As of April 7, 2024, among the 155 subjects enrolled in FAS, 14 (17.9%) were female and 64 (82.1%) were male in the propofol group, while 18 (23.4%) were female and 59 (76.6%) were male in the propofol group. The gender ratio was basically consistent across the three cohorts in both groups. Han Chinese comprised 71 (91.0%) subjects in the propofol group and 76 (98.7%) subjects in the propofol group, with the ethnic composition being basically consistent across the three cohorts in both groups.

[0287] Demographic characteristics: The mean age in the propofol group was 8.6 years, and in the propofol group it was 8.8 years. The youngest age in both groups was 2 years, and the oldest was 17 years. The age distribution of both groups was basically consistent across the three cohorts. The mean height in the propofol group was 134.92 cm, and in the propofol group it was 135.98 cm. The mean weight in the propofol group was 35.222 kg, and in the propofol group it was 35.347 kg. The mean BMI in the propofol group was 17.96 kg / m². 2 The propofol group had a concentration of 17.70 kg / m³. 2 The two groups had basically the same height, weight and BMI across the three cohorts.

[0288] Other baseline characteristics: Based on the FAS, among the 78 subjects in the propofol group, 11 (14.1%) had a history of allergy, 20 (25.6%) had a history of surgery, and 22 (28.2%) had a history of anesthesia. 56 (71.8%) had an ASA grade I, and the remaining 22 (28.2%) had a grade II. All subjects had no history of clinical research, and their airway assessments were all non-high-risk. Based on the FAS, among the 77 subjects in the propofol group, 6 (7.8%) had a history of allergy, 13 (16.9%) had a history of surgery, and 23 (29.9%) had a history of anesthesia. 52 (67.5%) had an ASA grade I, and the remaining 25 (32.5%) had a grade II. All subjects had no history of clinical research, and their airway assessments were all non-high-risk.

[0289] 2.2 Validity Results

[0290] 2.2.1 Anesthesia success rate results

[0291] Based on FAS, the anesthesia success rates in the propofol and propofol groups were 98.7% and 100%, respectively. The difference in anesthesia success rates between the two groups (propofol group - propofol group) was -1.28%, with a 95% confidence interval of (-6.91%, 3.59%). The lower limit of this interval is greater than the pre-set non-inferiority margin of -8%, indicating that the anesthesia success rate in the propofol group was not inferior to that in the propofol group. Based on PPS, the anesthesia success rates in both the propofol and propofol groups were 100%, and the difference in success rates between the two groups (propofol group - propofol group) was 0.00%. Sensitivity analysis using the CMH chi-square test yielded conclusions consistent with the main analysis.

[0292] Based on FAS, in cohort 2 of the propofol group, one subject (3.8%) experienced anesthesia failure, while the remaining subjects were successfully anesthetized. The difference in anesthesia success rate between the propofol and propofol groups in cohort 2 was -3.85%. All subjects in cohorts 1 and 3 achieved successful anesthesia, with a difference in success rate of 0.00%. Based on PPS, the difference in anesthesia success rate between the propofol and propofol groups in all cohorts (propofol group - propofol group) was 0.00%.

[0293] Based on FAS, the success rate of anesthesia induction was 100% in both the propofol and propofol groups, and the difference in success rate between the two groups (propofol group - propofol group) was 0.00%. Therefore, it cannot be concluded that there is a difference in the success rate of anesthesia induction between the two groups.

[0294] Analysis of PPS yielded conclusions consistent with those of FAS.

[0295] Based on FAS, the anesthesia maintenance success rates in the propofol and propofol groups were 98.7% and 100%, respectively, with a difference in success rate between the two groups (propofol group - propofol group) of -1.28% and a 95% confidence interval of (-6.91%, 3.59%). There was no statistically significant difference in anesthesia maintenance success rates between the two groups. Based on PPS, the anesthesia maintenance success rates in both the propofol and propofol groups were 100%, with a difference in success rate between the two groups (propofol group - propofol group) of 0.00%.

[0296] 2.2.2 Results of successful anesthesia induction

[0297] Based on FAS, the median time to successful anesthesia induction was 0.50 min in both the propofol and propofol groups. Using a stratified Cox proportional hazards model with age cohorts as the stratification, the hazard ratio (propofol / propofol) was 0.96, with a corresponding 95% confidence interval of (0.70, 1.33). There was no statistically significant difference in the time to successful anesthesia induction between the two groups.

[0298] Analysis of PPS yielded conclusions consistent with those of FAS.

[0299] 2.2.3 Postoperative general anesthesia satisfaction results

[0300] Based on the FAS (Features, Analyses, and Analyses), the mean total scores for postoperative general anesthesia satisfaction in the propofol and propofol groups were 13.0 and 12.4, respectively. The total score for postoperative general anesthesia satisfaction in the propofol group was significantly higher than that in the propofol group. In all three cohorts, the total score for postoperative general anesthesia satisfaction in the propofol group was significantly higher than that in the propofol group, with a statistically significant difference in cohort 1.

[0301] Analysis of PPS yielded conclusions consistent with those of FAS.

[0302] 2.2.4 Results of anesthesia induction dosage

[0303] Based on the FAS (Features, Analyses, and Analyses), during the anesthesia induction period, the mean total induction dose in the propofol and cyclopropofol groups were 0.80 mg / kg and 3.38 mg / kg, respectively. In cohorts 1, 2, and 3 of the cyclopropofol group, the doses were 0.93, 0.83, and 0.63 mg / kg, respectively, while in cohorts 1, 2, and 3 of the propofol group, the doses were 3.62, 3.28, and 3.24 mg / kg, respectively. With increasing age, the total induction dose in both the cyclopropofol and propofol groups decreased to varying degrees.

[0304] Based on the FAS (Features, Analyses, and Analyses), during the anesthesia induction period, the mean initial induction doses in the propofol and cyclopofol groups were 0.77 and 3.18 mg / kg, respectively. In the cyclopofol groups, cohorts 1, 2, and 3 had doses of 0.89, 0.81, and 0.61 mg / kg, respectively, while in the propofol groups, cohorts 1, 2, and 3 had doses of 3.16, 3.22, and 3.17 mg / kg, respectively. The initial induction doses in cohorts 1 and 2 of the cyclopofol group were essentially the same, and higher than those in cohort 3. The initial induction doses in the three propofol groups were essentially the same.

[0305] Based on the FAS (Fluid Anesthesia System), during the anesthesia induction period, 10.3% and 14.3% of subjects in the propofol and propofol groups, respectively, received additional study drug (ADD). The ADD rates for cohorts 1, 2, and 3 in the propofol group were 15.4%, 7.7%, and 7.7%, respectively, while those in cohorts 1, 2, and 3 in the propofol group were 26.9%, 7.7%, and 8.0%, respectively. The proportion of subjects receiving ADD in the propofol group was numerically lower than that in the propofol group, and the incidence rate in cohort 1 was higher than in the other two cohorts in both groups.

[0306] 2.2.5 Results of Anesthesia Maintenance Dosage

[0307] Based on the FAS (Fluid Anesthesia System), during the maintenance anesthesia period, the mean total duration of drug use in the propofol and propofol groups was 66.8 and 63.1 minutes, respectively, which were essentially consistent between the two groups and among the cohorts. The mean initial doses in the propofol and propofol groups were 1.424 and 9.649 mg / kg / h, respectively. The doses in cohorts 1, 2, and 3 of the propofol group were 1.437, 1.389, and 1.446 mg / kg / h, respectively, while those in cohorts 1, 2, and 3 of the propofol group were 9.846, 9.808, and 9.280 mg / kg / h, respectively. The mean highest doses in the propofol and propofol groups were 1.905 and 12.087 mg / kg / h, respectively. For cohorts 1, 2, and 3 of the propofol group, the mean doses were 2.277, 1.758, and 1.681 mg / kg / h, respectively, while for cohorts 1, 2, and 3 of the propofol group, the mean doses were 13.336, 12.346, and 10.520 mg / kg / h, respectively. The mean maintenance doses in the propofol and propofol groups were 1.834 and 11.547 mg / kg / h, respectively. For cohorts 1, 2, and 3 of the propofol group, the mean doses were 2.169, 1.713, and 1.619 mg / kg / h, respectively, while for cohorts 1, 2, and 3 of the propofol group, the mean doses were 13.088, 11.845, and 9.634 mg / kg / h, respectively. With increasing age, both the highest dose and the mean maintenance dose decreased to varying degrees in both the propofol and propofol groups.

[0308] Based on the FAS (Features, Analyses, and Analyses), during the maintenance anesthesia period, 83.3% and 76.6% of subjects in the propofol and propofol groups, respectively, adjusted their dosing rate. The rates for cohorts 1, 2, and 3 in the propofol group were 96.2%, 76.9%, and 76.9%, respectively, while those in cohorts 1, 2, and 3 in the propofol group were 80.8%, 80.8%, and 68.0%, respectively. The proportion of subjects adjusting their dosing rate was numerically higher in the propofol group than in the propofol group, and the proportion in cohort 1 was higher than in cohort 3 in both groups.

[0309] In the picocyclopofol and propofol groups, 15.4% and 20.8% of subjects, respectively, received a single intravenous booster. The rates for cohorts 1, 2, and 3 in the picocyclopofol group were 30.8%, 11.5%, and 3.8%, respectively, while those in cohorts 1, 2, and 3 in the propofol group were 34.6%, 15.4%, and 12.0%, respectively. The proportion of subjects receiving a booster of the study drug was numerically lower in the picocyclopofol group than in the propofol group, and the rate in cohort 1 was higher than in the other two cohorts in both groups.

[0310] 2.3 Security Results

[0311] The overall safety profile of both the propofol and propofol groups was good.

[0312] During the study, the incidence of treatment-associated adverse events (TEAEs) in the propofol and propofol groups was 67.9% and 81.8%, respectively, and the incidence of adverse drug reactions (ADRs) was 48.7% and 77.9%, respectively. Except for one case of a possible non-study-related adverse event (SAE) in the propofol group (S07039) in cohort 1, all other TEAEs were grade 1 or 2 in severity. No TEAEs leading to dose adjustment of the study drug, withdrawal from the trial, or death occurred. The incidence of TEAEs and ADRs in the propofol group was significantly lower than that in the propofol group.

[0313] The types of TEAEs in the propofol and propofol groups were basically the same. TEAEs with a total incidence ≥5.0% in either group [total incidence % in the propofol group (cohorts 1, 2, 3) vs. total incidence % in the propofol group (cohorts 1, 2, 3)] included: hypotension [17.9 (0, 34.6, 19.2) vs. 20.8 (23.1, 26.9, 12.0)], hypertension [12.8 (15.4, 7.7, 15.4) vs. 3.9 (3.8, 7.7, 0)], bradycardia [25.6 (42.3, 19.2, 15.4) vs. 27.3 (42.3, 30.8, 8.0)], and injection site pain [12.8 (19.2, 11.5, 7.7) vs. 12.8 (19.2, 11.5, 7.7) vs. 12.0 (12.8 ... 68.8 (76.9, 73.1, 56.0)], fever [10.3 (11.5, 15.4, 3.8) vs 3.9 (0, 7.7, 4.0)], urine ketones detected [7.7 (15.4, 3.8, 3.8) vs 10.4 (15.4, 3.8, 12.0)], elevated white blood cell count [5.1 (0, 3.8, 11.5) vs 7.8 (7.7, 3.8, 12.0)], wound complications [0 (0, 0, 0) vs 5.2 (3.8, 0, 12.0)], hematuria [0 (0, 0, 0) vs 5.2 (3.8, 3.8, 8.0)].

[0314] The types of ADRs in the propofol and propofol groups were basically the same. ADRs with an overall incidence of ≥5.0% in either group [overall incidence % in the propofol group (cohorts 1, 2, 3) vs. overall incidence % in the propofol group (cohorts 1, 2, 3)] included: bradycardia [25.6 (42.3, 19.2, 15.4) vs. 26.0 (42.3, 26.9, 8.0)], hypotension [17.9 (0, 34.6, 19.2) vs. 20.8 (23.1, 26.9, 12.0)], and injection site pain [12.8 (19.2, 11.5, 7.7) vs. 68.8 (76.9, 73.1, 56.0)].

[0315] 2.4 Results of Exploratory Indicators

[0316] Based on the FAS, a total of 3 patients in this study had a PAED score ≥12, 1 in the propofol group (1.3%) and 2 in the propofol group (2.6%), all of whom were in cohort 1. The mean PAED scores in the propofol group and the propofol group were 1.8 and 2.1, respectively, with no statistically significant difference.

[0317] 2.5 Conclusion

[0318] In children aged 2–11 years and 12–17 years, anesthesia induction with cephalexin at 0.8 ± 0.2 mg / kg and 0.6 ± 0.2 mg / kg, respectively, followed by maintenance anesthesia at an initial dose of 1.4 ± 0.4 mg / kg / h, showed a non-inferior success rate compared to propofol (induction at 2.5–4 mg / kg, maintenance at an initial dose of 9–15 mg / kg / h). Cephalexin also demonstrated rapid anesthesia induction, a lower proportion of subjects requiring additional study drugs during induction and maintenance, and a higher overall postoperative satisfaction score for general anesthesia compared to propofol. Overall, cephalexin showed good safety, with a significantly lower incidence of adverse reactions compared to propofol, particularly hypotension and injection pain.

[0319] In summary, the efficacy and safety of cephalexin injection for induction and maintenance of general anesthesia in elective surgeries in pediatric patients aged 2-17 years are well-established, supporting its use as a novel anesthetic for general anesthesia in pediatric patients.

[0320] The results of the study indicate that cyclopropofol has good efficacy and safety in sedation / anesthesia for intraoperative bronchoscopy in pediatric patients.

Claims

1. A method for anesthetizing and / or sedating a pediatric patient, the method comprising administering an effective dose of cyclopropofol to the pediatric patient, wherein the dose of cyclopropofol is about 15 to about 35% higher per kilogram of body weight than that of an adult patient.

2. The method of claim 1, wherein the method is applicable to the induction and maintenance of general anesthesia, sedation and anesthesia in non-endotracheal intubation surgery / procedures, and sedation during mechanical ventilation in intensive care.

3. The method of claim 2, wherein the method is applicable to the induction and maintenance of general anesthesia; The pediatric patient is less than about 18 years old; or the pediatric patient is about 0 to about 17 years old; or the pediatric patient is about 12 to about 17 years old; or the pediatric patient is about 6 to about 11 years old; or the pediatric patient is about 2 to about 5 years old.

4. The method of claim 3, wherein during the induction of general anesthesia, the initial dose of propofol is about 0.40 to about 1.00 mg / kg or about 0.70 ± about 0.30 mg / kg; optionally, after the initial dose, an additional dose of propofol is about 1 / 3 to about 1 / 2 of the initial dose, and the additional dose is administered up to 2 or 3 times.

5. The method of claim 3, wherein during the induction of general anesthesia, for pediatric patients aged approximately 12 to approximately 17 years, the initial dose of picoplanin is approximately 0.30 to approximately 0.90 mg / kg or approximately 0.60 ± approximately 0.30 mg / kg, optionally followed by a booster dose of picoplanin of approximately one-third to approximately one-half of the initial dose, up to two or three times; for pediatric patients aged approximately 6 to approximately 11 years, the initial dose of picoplanin is approximately 0.45 to approximately 0.95 mg / kg. The initial dose of propofol is approximately 0.40 to about 1.00 mg / kg or about 0.70 ± about 0.25 mg / kg. Optionally, after the first dose, the additional dose of propofol is about 1 / 3 to about 1 / 2 of the initial dose, with up to 2 or 3 additional doses. Alternatively, for pediatric patients aged about 2 to about 5 years, the initial dose of propofol is approximately 0.40 to about 1.00 mg / kg or about 0.70 ± about 0.30 mg / kg. Optionally, after the first dose, the additional dose of propofol is about 1 / 3 to about 1 / 2 of the initial dose, with up to 2 or 3 additional doses.

6. The method of claim 3, wherein during the induction of general anesthesia, for pediatric patients aged approximately 12 to approximately 17 years, the initial dose of propofol is approximately 0.5 mg / kg, and the booster dose is approximately 0.25 mg / kg; or for pediatric patients aged approximately 2 to approximately 11 years, the initial dose of propofol is approximately 0.6 mg / kg, and the booster dose is approximately 0.3 mg / kg.

7. The method of claim 3, wherein during maintenance of general anesthesia, the initial dose of cyclopropofol is about 1.0-2.5 mg / kg / hr, or 1.8 or 2.0 mg / kg / hr.

8. The method of claim 3, wherein during maintenance of general anesthesia, for pediatric patients aged 12-17 years, the initial dose of cyclopropofol is 1 mg / kg / hr, and the administration rate ranges from about 0.5 to about 3 mg / kg / hr; for pediatric patients aged 2-11 years, the initial dose of cyclopropofol is about 1.2 mg / kg / hr, and the administration rate ranges from about 0.6 to about 4 mg / kg / hr.

9. The method of claim 3, wherein the method further comprises administering an effective dose of a first anesthetic drug to the pediatric patient prior to the induction phase, the first anesthetic drug being selected from sedatives / anesthetics, analgesics, and muscle relaxants.

10. The method of claim 9, wherein the first anesthetic drug is administered prior to induction at a dose of about 0.35 to about 2 mcg / kg or about 25 to about 200 mcg / patient.

11. The method of claim 9, wherein the first anesthetic drug is a sedative / anesthetic drug selected from fentanyl, midazolam, sevoflurane, dexmedetomidine, esketamine, sufentanil, ketamine, thiopental sodium, sodium oxybutyrate, etomidate, diazepam, flunitrazepam, clonazepam, flunitrazepam, lorazepam, metoprolol, buprofen, chlorpromazine, barbituric acid, phenobarbital, pentobarbital, amobarbital, and thiamethoxam. Barbabite, thiopental sodium, or any of the above-mentioned pharmaceutical salts; the analgesic is selected from fentanyl derivatives, oxycodone, nalbuphine, morphine, meperidine, dexmedetomidine, buprofenol, hydrocodone, nefopam, or any of the above-mentioned pharmaceutically acceptable salts; the muscle relaxant is selected from rocuronium bromide, cisatracurium bromide, vecuronium bromide, rocuronium bromide, pancuronium bromide, pipecuronium bromide, mivacuronium bromide, succinylcholine, or any of the above-mentioned pharmaceutically acceptable salts.

12. The method of claim 3, wherein the method further comprises administering an effective dose of a second anesthetic drug to the pediatric patient during the maintenance phase.

13. The method of claim 12, wherein the second anesthetic drug used during the maintenance phase is an inhaled anesthetic.

14. The method of claim 12, wherein the second anesthetic drug used during the maintenance phase is selected from sevoflurane, isoflurane, enflurane, desflurane, halothane, anesthetic ether, methoxyflurane, nitrous oxide, propofol, sodium fosfopropoxyphenate, or cyclopropofol.

15. The method of claim 12, wherein the method further comprises administering an anesthetic adjuvant selected from anticholinergics, muscle relaxants, antiemetics, local anesthetics, or analgesics during the pre-induction and / or maintenance phases.

16. The method of claim 15, wherein the dosage of the anesthetic adjuvant is selected from about 0.01 mg / kg to about 15.0 mg / kg, about 0.01 mg / kg to about 10.0 mg / kg, about 0.01 mg / kg to about 5.0 mg / kg, about 0.01 mg / kg to about 2.0 mg / kg, or about 0.01 mg / kg to about 1.0 mg / kg.

17. The method of claim 15, wherein the anticholinergic drug is selected from atropine or scopolamine or a pharmaceutically acceptable salt of any of the above; the muscle relaxant is selected from vecuronium bromide, rocuronium bromide, pancuronium bromide, pipecuronium bromide, mivacuronium bromide, succinylcholine or cisatracurium bromide or a pharmaceutically acceptable salt of any of the above; and the antiemetic is selected from topisetron, palonosetron, granisetron, dolasetron, and scopolamine. The following are acceptable salts of the following drugs: fluperidone or metoclopramide; local anesthetics are selected from lidocaine, ropivacaine, bupivacaine, levobupivacaine, articaine, or deslorine, or pharmaceutically acceptable salts of any of the above; analgesics are selected from fentanyl, remifentanil, sufentanil, alfentanil, morphine, pethidine, dexmedetomidine, buprofenol, hydrocodone, or nefopam, or pharmaceutically acceptable salts of any of the above.

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