Ciprofol

Ciprofol (also known as cipepofol, or HSK3486)[1] is a novel 2,6-disubstituted phenol derivative that is used for the intravenous induction of general anesthesia.[2][3] A short-acting and highly selective γ-aminobutyric acid agonist,[4] ciprofol is 4–6 times more potent than other phenol derivatives such as propofol or fospropofol.[5]

Ciprofol
INN: Cipepofol
Clinical data
Other names(R)-2-(1-cyclopropylethyl)-6-isopropylphenol
Pharmacokinetic data
MetabolismLiver glucuronidation
ExcretionKidney
Identifiers
  • 2-[(1R)-1-cyclopropylethyl]-6-isopropylphenol
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC14H20O
Molar mass204.313 g·mol−1
3D model (JSmol)
  • CC(C1=CC=CC([C@@H](C2CC2)C)=C1O)C
  • InChI=1S/C14H20O/c1-9(2)12-5-4-6-13(14(12)15)10(3)11-7-8-11/h4-6,9-11,15H,7-8H2,1-3H3/t10-/m1/s1 checkY
  • Key:BMEARIQHWSVDBS-SNVBAGLBSA-N checkY

As of 2023, it is still an investigational drug.[6] Manufactured by Haisco Pharmaceutical Group of Chengdu, Sichuan, China, ciprofol has undergone phase I and II trials in Australia and China.[6][7][8] In these early studies, ciprofol appears to be comparable in efficacy to propofol and is associated with fewer adverse events.[3][5][9][10][11][12][13][14][15][16]

Physical properties

Ciprofol is an optically active 2,6-disubstituted alkylphenol with a cyclopropylethyl group incorporated at the second carbon atom. This cyclopropyl group increases the steric effects and introduces stereoselective effects over its anesthetic properties. These properties appear to increase the anesthetic potency of ciprofol, when compared with propofol.[7]

Medical use

Ciprofol is used for the intravenous induction of general anesthesia.[2][3] As of 2023, it is still an investigational drug. Thus far, it has been found to be efficacious as a general anesthetic in patients undergoing gynecological surgery[5][9] and kidney transplantation,[17] as well as for endoscopic procedures such as bronchoscopy,[13][18] esophagogastroduodenoscopy and colonoscopy.[19][20]

Ciprofol has also been used for sedation of critically ill patients undergoing mechanical ventilation in the intensive care unit,[21] as well as for the treatment of agitation and delirium in that patient population.[22] When combined with mild therapeutic hypothermia, ciprofol may also be useful as a cerebral protective agent in the setting of cerebral ischemia-reperfusion injury.[23]

Experimental use

In experimental models of isoproterenol-induced myocardial infarction (using mice as subjects), ciprofol appears to protect the heart against oxidative damage, inflammation and apoptosis of cardiac muscle cells.[24]

Side effects

When compared with propofol, side effects such as pain on injection[13] and respiratory depression appear to be less common with ciprofol.[14]

Pharmacology

Pharmacokinetics

Compared to propofol, ciprofol exhibits stronger binding to the GABAA receptor and elicits a greater enhancement of GABAA receptor-mediated neurotransmission.[25]

It is not necessary to adjust the dose in people with mild or moderate renal impairment,[26] or in those with mild or moderate hepatic impairment.[27] In elderly people, a slightly lower dose (0.3 mg/kg) appears to be similar in efficacy to the higher doses administered to younger people but is associated with fewer adverse effects.[28][29]

Pharmacodynamics

Ciprofol exhibits pharmacodynamic properties similar to those of propofol, including both rapid onset and rapid offset. Ciprofol appears to have similar effects upon the respiratory and cardiovascular systems as those propofol.[5] At doses of 0.4 mg/kg to 0.5 mg/kg, ciprofol induces equivalent sedation/anesthesia and has an incidence of adverse events similar to that of propofol 2.0 mg/kg.[15][16]

Biodegradation and toxicity

Ciprofol is characterized by a rapid onset of action, and predictable absorption, distribution, metabolism, excretion processes. The compound undergoes glucuronidation in the liver, followed by excretion by the kidneys.[30]

References
  1. "Cipepofol (Synonyms: Ciprofol; HSK3486)". MedChemExpress. Monmouth Junction, New Jersey: MedChemExpress LLC. 2023. Retrieved 11 May 2023.
  2. Wang X, Wang X, Liu J, Zuo YX, Zhu QM, Wei XC, et al. (March 2022). "Effects of ciprofol for the induction of general anesthesia in patients scheduled for elective surgery compared to propofol: a phase 3, multicenter, randomized, double-blind, comparative study". European Review for Medical and Pharmacological Sciences. 26 (5): 1607–1617. PMID 35302207.
  3. Zeng Y, Wang DX, Lin ZM, Liu J, Wei XC, Deng J, et al. (February 2022). "Efficacy and safety of HSK3486 for the induction and maintenance of general anesthesia in elective surgical patients: a multicenter, randomized, open-label, propofol-controlled phase 2 clinical trial". European Review for Medical and Pharmacological Sciences. 26 (4): 1114–1124. PMID 35253166.
  4. Liao J, Li M, Huang C, Yu Y, Chen Y, Gan J, et al. (2022). "Pharmacodynamics and Pharmacokinetics of HSK3486, a Novel 2,6-Disubstituted Phenol Derivative as a General Anesthetic". Frontiers in Pharmacology. 13: 830791. doi:10.3389/fphar.2022.830791. PMC 8851058. PMID 35185584.
  5. Chen BZ, Yin XY, Jiang LH, Liu JH, Shi YY, Yuan BY (August 2022). "The efficacy and safety of ciprofol use for the induction of general anesthesia in patients undergoing gynecological surgery: a prospective randomized controlled study". BMC Anesthesiology. 22 (1): 245. doi:10.1186/s12871-022-01782-7. PMC 9347095. PMID 35922771.
  6. Lu M, Liu J, Wu X, Zhang Z (2023). "Ciprofol: A Novel Alternative to Propofol in Clinical Intravenous Anesthesia?". BioMed Research International. 2023: 7443226. doi:10.1155/2023/7443226. PMC 9879693. PMID 36714027.
  7. Qin L, Ren L, Wan S, Liu G, Luo X, Liu Z, et al. (May 2017). "Design, Synthesis, and Evaluation of Novel 2,6-Disubstituted Phenol Derivatives as General Anesthetics". Journal of Medicinal Chemistry. 60 (9): 3606–3617. doi:10.1021/acs.jmedchem.7b00254. PMID 28430430.
  8. Nair A, Seelam S (2022). "Ciprofol- a game changing intravenous anesthetic or another experimental drug!". Saudi Journal of Anaesthesia. 16 (2): 258–259. doi:10.4103/sja.sja_898_21. PMC 9009555. PMID 35431734.
  9. Man Y, Xiao H, Zhu T, Ji F (March 2023). "Study on the effectiveness and safety of ciprofol in anesthesia in gynecological day surgery: a randomized double-blind controlled study". BMC Anesthesiology. 23 (1): 92. doi:10.1186/s12871-023-02051-x. PMC 10039513. PMID 36964501.
  10. Chen X, Guo P, Yang L, Liu Z, Yu D (2022). "Comparison and Clinical Value of Ciprofol and Propofol in Intraoperative Adverse Reactions, Operation, Resuscitation, and Satisfaction of Patients under Painless Gastroenteroscopy Anesthesia". Contrast Media & Molecular Imaging. 2022: 9541060. doi:10.1155/2022/9541060. PMC 9314164. PMID 35935320.
  11. Zhong J, Zhang J, Fan Y, Zhu M, Zhao X, Zuo Z, et al. (May 2023). "Efficacy and safety of Ciprofol for procedural sedation and anesthesia in non-operating room settings". Journal of Clinical Anesthesia. 85: 111047. doi:10.1016/j.jclinane.2022.111047. PMID 36599219. S2CID 255468218.
  12. Liang P, Dai M, Wang X, Wang D, Yang M, Lin X, et al. (June 2023). "Efficacy and safety of ciprofol vs. propofol for the induction and maintenance of general anaesthesia: A multicentre, single-blind, randomised, parallel-group, phase 3 clinical trial". European Journal of Anaesthesiology. 40 (6): 399–406. doi:10.1097/EJA.0000000000001799. PMC 10155686. PMID 36647565.
  13. Luo Z, Tu H, Zhang X, Wang X, Ouyang W, Wei X, et al. (March 2022). "Efficacy and Safety of HSK3486 for Anesthesia/Sedation in Patients Undergoing Fiberoptic Bronchoscopy: A Multicenter, Double-Blind, Propofol-Controlled, Randomized, Phase 3 Study". CNS Drugs. 36 (3): 301–313. doi:10.1007/s40263-021-00890-1. PMC 8927014. PMID 35157236.
  14. Hu C, Ou X, Teng Y, Shu S, Wang Y, Zhu X, et al. (November 2021). "Sedation Effects Produced by a Ciprofol Initial Infusion or Bolus Dose Followed by Continuous Maintenance Infusion in Healthy Subjects: A Phase 1 Trial". Advances in Therapy. 38 (11): 5484–5500. doi:10.1007/s12325-021-01914-4. PMC 8523013. PMID 34559359.
  15. Teng Y, Ou M, Wang X, Zhang W, Liu X, Liang Y, et al. (September 2021). "Efficacy and safety of ciprofol for the sedation/anesthesia in patients undergoing colonoscopy: Phase IIa and IIb multi-center clinical trials". European Journal of Pharmaceutical Sciences. 164: 105904. doi:10.1016/j.ejps.2021.105904. PMID 34116176.
  16. Zhu Q, Luo Z, Wang X, Wang D, Li J, Wei X, et al. (April 2023). "Efficacy and safety of ciprofol versus propofol for the induction of anesthesia in adult patients: a multicenter phase 2a clinical trial". International Journal of Clinical Pharmacy. 45 (2): 473–482. doi:10.1007/s11096-022-01529-x. PMC 10147789. PMID 36680620.
  17. Qin K, Qin WY, Ming SP, Ma XF, Du XK (July 2022). "Effect of ciprofol on induction and maintenance of general anesthesia in patients undergoing kidney transplantation". European Review for Medical and Pharmacological Sciences. 26 (14): 5063–5071. PMID 35916802.
  18. Wu B, Zhu W, Wang Q, Ren C, Wang L, Xie G (2022). "Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial". Frontiers in Pharmacology. 13: 1091579. doi:10.3389/fphar.2022.1091579. PMC 9812563. PMID 36618929.
  19. Li J, Wang X, Liu J, Wang X, Li X, Wang Y, et al. (August 2022). "Comparison of ciprofol (HSK3486) versus propofol for the induction of deep sedation during gastroscopy and colonoscopy procedures: A multi-centre, non-inferiority, randomized, controlled phase 3 clinical trial". Basic & Clinical Pharmacology & Toxicology. 131 (2): 138–148. doi:10.1111/bcpt.13761. PMC 9543620. PMID 35653554.
  20. Long YQ, Feng CD, Ding YY, Feng XM, Liu H, Ji FH, Peng K (2022). "Esketamine as an Adjuvant to Ciprofol or Propofol Sedation for Same-Day Bidirectional Endoscopy: Protocol for a Randomized, Double-Blind, Controlled Trial With Factorial Design". Frontiers in Pharmacology. 13: 821691. doi:10.3389/fphar.2022.821691. PMC 8975265. PMID 35370640.
  21. Liu Y, Yu X, Zhu D, Zeng J, Lin Q, Zang B, et al. (May 2022). "Safety and efficacy of ciprofol vs. propofol for sedation in intensive care unit patients with mechanical ventilation: a multi-center, open label, randomized, phase 2 trial". Chinese Medical Journal. 135 (9): 1043–1051. doi:10.1097/CM9.0000000000001912. PMC 9276409. PMID 34924506.
  22. Liu GL, Wu GZ, Ge D, Zhou HJ, Cui S, Gao K, et al. (2023). "Efficacy and safety of ciprofol for agitation and delirium in the ICU: A multicenter, single-blind, 3-arm parallel randomized controlled trial study protocol". Frontiers in Medicine. 9: 1024762. doi:10.3389/fmed.2022.1024762. PMC 9868613. PMID 36698817.
  23. Wang YC, Wu MJ, Zhou SL, Li ZH (January 2023). "Protective effects of combined treatment with ciprofol and mild therapeutic hypothermia during cerebral ischemia-reperfusion injury". World Journal of Clinical Cases. 11 (3): 487–492. doi:10.12998/wjcc.v11.i3.487. PMC 9923870. PMID 36793629.
  24. Yang Y, Xia Z, Xu C, Zhai C, Yu X, Li S (2022). "Ciprofol attenuates the isoproterenol-induced oxidative damage, inflammatory response and cardiomyocyte apoptosis". Frontiers in Pharmacology. 13: 1037151. doi:10.3389/fphar.2022.1037151. PMC 9723392. PMID 36483733.
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  27. Hu Y, Li X, Liu J, Chen H, Zheng W, Zhang H, et al. (December 2022). "Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment". Annals of Medicine. 54 (1): 2769–2780. doi:10.1080/07853890.2022.2129433. PMC 9559057. PMID 36217101.
  28. Li X, Yang D, Li Q, Wang H, Wang M, Yan P, et al. (2021). "Safety, Pharmacokinetics, and Pharmacodynamics of a Single Bolus of the γ-aminobutyric Acid (GABA) Receptor Potentiator HSK3486 in Healthy Chinese Elderly and Non-elderly". Frontiers in Pharmacology. 12: 735700. doi:10.3389/fphar.2021.735700. PMC 8430033. PMID 34512361.
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Further reading
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