Pharmacodynamics and Pharmacokinetics of HSK3486, a Novel 2,6-Disubstituted Phenol Derivative as a General Anesthetic

Liao, Juan; Li, Meiting; Huang, Ching-Hui; Yu, Yaya; Chen, Yashu; Gan, Jiaqi; Xiao, Jie; Xiang, Guilin; Ding, Xizhi; Jiang, Rong; Yang, Mengchang

doi:10.3389/fphar.2022.830791

Cited by 33 publications

(46 citation statements)

References 28 publications

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“…However, propofol has unavoidable limitations, such as a narrow therapeutic index, injection pain, circulation and respiratory depression, and infusion syndrome ( Hughes et al, 2021 ). The active ingredient of ciprofol is similar to propofol, but it has single R-configured diastereoisomers ( Liao et al, 2022 ). The innovation of this drug lies in the cyclopropyl group, which not only increases the steric effect but also introduces stereoselective effects over their anesthetic properties ( Li et al, 2021 ; Hu et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial

Zhu

Wang

et al. 2022

Front. Pharmacol.

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Objective: Ciprofol is a novel 2,6-disubstituted phenol derivative that has improved pharmacokinetic and pharmacodynamic properties compared with propofol. This study was conducted to compare the efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil for patients undergoing fiberoptic bronchoscopy.Methods: Overall, 92 patients undergoing fiberoptic bronchoscopy were included in this prospective, randomized, double-blind, non-inferiority trial and were equally divided into two groups (n = 46 each). Fentanyl (50 μg) was given 2 min before the intravenous infusion of 0.3 mg/kg of ciprofol or 1.2 mg/kg of propofol over a time period of 30 s. During anesthesia maintenance, 0.05–0.2 μg/kg/min of remifentanil combined with one-third to one-fourth of the initial dose of ciprofol or propofol was repeated at 2-min intervals, as required, to maintain a Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scale score <3. The primary outcome was the successful rate of fiberoptic bronchoscopy. Secondary outcomes included demographic characteristics, time metrics, hemodynamics, coughing severity, intubating conditions, lowest oxygen saturation, utilization of study drug doses, number of remedies (lidocaine and vasoactive drugs) used, satisfaction scores of both patients and the endoscopist, occurrence of intraoperative awareness, patients’ willing to repeat fiberoptic bronchoscopy, and occurrence and severity of adverse events.Results: The successful completion rate of fiberoptic bronchoscopy was 91.30% (42 of 46; 95% confidence interval [CI]: 82.80%–99.80%) in the ciprofol-remifentanil group and 89.13% (41 of 46; 95% CI: 79.80%–98.50%) in the propofol-remifentanil group. Though the clinically acceptable intubating condition was improved in the ciprofol-remifentanil group, this difference has no clinical statistical difference (p > 0.05). No significant differences were noted between the two groups with respect to time metrics, consumption of fentanyl and remifentanil, or number of remedies (lidocaine and vasoactive drugs). Patients’ willingness to repeat fiberoptic bronchoscopy and the satisfaction of both patients and endoscopist were significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group (p < 0.05). Compared with patients in the propofol-remifentanil group, patients in the ciprofol-remifentanil group had more stable hemodynamics. The lowest oxygen saturation was significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group (p < 0.05). The numbers of patients who experienced pain on injection in the ciprofol-remifentanil group was significantly lower than the number in the propofol-remifentanil group (p < 0.01). Severity of coughing, clinically acceptable severity of coughing, incidence of intraoperative awareness, and other adverse events were all similar between the two groups (p > 0.05). Only four patients experienced grade 2 adverse events (severe hypotension in one patient in the ciprofol-remifentanil group and three patients in the propofol-remifentanil group; p > 0.05); they were treated with noradrenaline.Conclusion: Ciprofol-remifentanil was non-inferior to propofol-remifentanil with regard to successful sedation for flexible bronchoscopy, when used with pre-intravenous administration of 50 μg of fentanyl. At the same time, patients’ willingness to repeat flexible bronchoscopy and the satisfactions were all significantly improved.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial

Zhu

Wang

et al. 2022

Front. Pharmacol.

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“…Thus, similar to propofol, extensive metabolic clearance to inactive metabolites by UDP-glucuronosyltransferases (UGTs) and CYP enzymes in the liver was considered the major contributor to total body clearance of HSK3486. In vitro studies imply that CYP2B6 is the major CYP enzyme that mediates HSK3486 metabolism [ 2 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…The major circulating metabolite of HSK3486, M4 (79.3%), is a nonhypnotic and non-toxic glucuronidation product that is excreted through urine. Previous in vitro studies imply CYP2B6 is the major CYP enzyme that mediates HSK3486 metabolism [ 2 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment

Yue

Liu

et al. 2022

Annals of Medicine

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Background The primary objective of this study was to investigate if hepatic impairment alters the safety, pharma c okinetics, and pharmacodynamics of HSK3486. Research design and methods This was a clinical trial of HSK3486 in subjects with normal hepatic function ( n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min. Results In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS). Conclusions Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment. Trial registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596). Key Message HSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects. There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function. HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

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“…Like propofol, ciprofol is a positive allosteric modulator and direct agonist of the GABA A receptor. Competitive binding assays and whole-cell patch-clamp experiments demonstrated that ciprofol could trigger chloride influx by competitive binding to butylbicyclophosphorothionate and t-butylbicycloorthobenzoate targets in the chloride channels of GABA A receptors [ 19 ]. The influx of chloride can cause hyperpolarization of nerve cell membranes by increasing the intracellular chloride concentration and further activating GABAergic neurons to achieve central nerve inhibition, producing sedative and anesthetic effects.…”

Section: Structural Features and Mechanismsmentioning

confidence: 99%

Ciprofol: A Novel Alternative to Propofol in Clinical Intravenous Anesthesia?

Liu

et al. 2023

BioMed Research International

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Ciprofol is a novel compound that was independently developed in China. According to the Chinese product instructions approved by the China National Medical Products Administration and the information of official website, indications for ciprofol include sedation and anesthesia during the surgical/procedure of nontracheal intubation, induction and maintenance of general anesthesia, and sedation during intensive care. Ciprofol is a short-acting intravenous sedative based on the structural modification of propofol. Ciprofol has high efficacy, good selectivity, and fewer adverse reactions, indicating good clinical application potential. A series of clinical studies have been conducted to evaluate the sedative effect of ciprofol in various procedures and settings, including gastroscopy and colonoscopy, fiber-optic bronchoscopy, general anesthesia in elective surgeries, and mechanical ventilation in intensive care units. This review summarizes the chemical structure, pharmacodynamics, and pharmacokinetic properties of ciprofol. We also assessed the efficacy and safety of ciprofol by synthesizing the relevant clinical trial data.

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Pharmacodynamics and Pharmacokinetics of HSK3486, a Novel 2,6-Disubstituted Phenol Derivative as a General Anesthetic

Cited by 33 publications

References 28 publications

Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial

Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment

Ciprofol: A Novel Alternative to Propofol in Clinical Intravenous Anesthesia?

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