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Lucke-Wold B, Karamian A. Effect of esketamine on reducing postpartum pain and depression. World J Clin Cases 2025; 13:100422. [PMID: 40051793 PMCID: PMC11612688 DOI: 10.12998/wjcc.v13.i7.100422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 11/04/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024] Open
Abstract
In this editorial, we comment on a recent article by Chen et al, that addressed the effect of intraoperative injection of esketamine on postoperative analgesia and postoperative rehabilitation after cesarean section. Poor management of post-cesarean pain is associated with decreased maternal care for the baby, longer hospitalization, and higher risk of developing postpartum depression. Esketamine is a more potent S-enantiomer of ketamine which has shown promising analgesic and antidepressant properties for managing post-cesarean pain and depression in clinical studies. However, due to its potential adverse effects on the neurological and hemodynamic status of patients, it is recommended that its usage in low doses should be limited to cesarean candidates experiencing unbearable pain. Before any recommendation for routine perioperative use of esketamine, more standardized clinical trials are needed to strengthen our existing knowledge of its effectiveness in reducing postpartum pain and depression.
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Affiliation(s)
- Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, United States
| | - Armin Karamian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 198396-9411, Tehrān, Iran
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Fouad A, El-Sayed DH, Salman BE, Bakr HH, Adel SE, Alzarak TM, Mahmoud A. Macrocyclic Antibiotics as Effective Chiral Selectors in Liquid Chromatography for Enantiomeric Separation of Pharmaceutical Compounds: A Review. Crit Rev Anal Chem 2023; 54:3095-3113. [PMID: 37342891 DOI: 10.1080/10408347.2023.2224442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/23/2023]
Abstract
Chiral separation techniques play a crucial role in the pharmaceutical industry, where the enantiomeric purity of drugs can have a significant impact on their efficacy and safety. Macrocyclic antibiotics are highly effective chiral selectors used in various chiral separation techniques, including LC, HPLC, SMB, and TLC, offering reproducible results and a wide range of applications. However, developing robust and efficient immobilization mechanisms for these chiral selectors remains a challenge. This review article focuses on various immobilization approaches, such as immobilization, coating, encapsulation, and photosynthesis, that have been applied to immobilize macrocyclic antibiotics on their support. Commercially available macrocyclic antibiotics for conventional liquid chromatography include Vancomycin, Norvancomycin, Eremomycin, Teicoplanin, Ristocetin A, Rifamycin, Avoparcin, Bacitracin, and others. In addition, capillary (nano) liquid chromatography has also been used in chiral separation utilizing Vancomycin, Polymyxin B, Daptomycin, and Colistin Sulfate. Macrocyclic antibiotic-based CSPs have been extensively applied due to their reproducible results, ease of use, and broad range of applications, capable of separating a large number of racemates.
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Affiliation(s)
- Ali Fouad
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | | | | | - Hanan H Bakr
- Faculty of Science, Tanta University, Tanta, Egypt
| | - Shahd E Adel
- Faculty of Science, Tanta University, Tanta, Egypt
| | | | - Abdelrahman Mahmoud
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
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Schäfer C, Baranov DG. Chiral Polaritonics: Analytical Solutions, Intuition, and Use. J Phys Chem Lett 2023; 14:3777-3784. [PMID: 37052302 PMCID: PMC10123817 DOI: 10.1021/acs.jpclett.3c00286] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 03/22/2023] [Indexed: 06/19/2023]
Abstract
Preferential selection of a given enantiomer over its chiral counterpart has become increasingly relevant in the advent of the next era of medical drug design. In parallel, cavity quantum electrodynamics has grown into a solid framework to control energy transfer and chemical reactivity, the latter requiring strong coupling. In this work, we derive an analytical solution to a system of many chiral emitters interacting with a chiral cavity similar to the widely used Tavis-Cummings and Hopfield models of quantum optics. We are able to estimate the discriminating strength of chiral polaritonics, discuss possible future development directions and exciting applications such as elucidating homochirality, and deliver much needed intuition to foster the newly flourishing field of chiral polaritonics.
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Affiliation(s)
- Christian Schäfer
- MC2
Department, Chalmers University of Technology, 41258 Gothenburg, Sweden
| | - Denis G. Baranov
- Center
for Photonics and 2D Materials, Moscow Institute
of Physics and Technology, Dolgoprudny 141700, Russia
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Xu LL, Wang C, Deng CM, Dai SB, Zhou Q, Peng YB, Shou HY, Han YQ, Yu J, Liu CH, Xia F, Zhang SQ, Wang DX, Chen XZ. Efficacy and Safety of Esketamine for Supplemental Analgesia During Elective Cesarean Delivery: A Randomized Clinical Trial. JAMA Netw Open 2023; 6:e239321. [PMID: 37083664 PMCID: PMC10122167 DOI: 10.1001/jamanetworkopen.2023.9321] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 03/03/2023] [Indexed: 04/22/2023] Open
Abstract
Importance Epidural anesthesia is a primary choice for cesarean delivery, but supplemental analgesics are often required to relieve pain during uterine traction. Objective To investigate the sedative and analgesic effects of intravenous esketamine administered before childbirth via cesarean delivery with the patient under epidural anesthesia. Design, Setting, and Participants This multicenter, double-blind randomized clinical trial assessed 903 women 18 years or older who had full-term single pregnancy and were scheduled for elective cesarean delivery with epidural anesthesia in 5 medical centers in China from September 18, 2021, to September 20, 2022. Intervention Patients were randomized to receive intravenous injection of 0.25 mg/kg of esketamine or placebo before incision. Main Outcomes and Measures The coprimary outcomes included scores on the numeric rating scale of pain (an 11-point scale, with 0 indicating no pain and 10 indicating the worst pain; a difference of ≥1.65 points was clinically meaningful) and Ramsay Sedation Scale (a 6-point scale, with 1 indicating restlessness and 6 indicating deep sleep without response; a difference of ≥2 points was clinically meaningful) immediately after fetal delivery. Secondary outcomes included neonatal Apgar score assessed at 1 and 5 minutes after birth. Results A total of 600 women (mean [SD] age, 30.7 [4.3] years) were enrolled and randomized; all were included in the intention-to-treat analysis. Immediately after fetal delivery, the score on the numeric rating scale of pain was lower with esketamine (median [IQR], 0 [0-1]) than with placebo (median [IQR], 0 [0-2]; median difference, 0; 95% CI, 0-0; P = .001), but the difference was not clinically important. The Ramsay Sedation Scale scores were higher (sedation deeper) with esketamine (median [IQR], 4 [3-4]) than with placebo (median [IQR], 2 [2-2]; median difference, 2; 95% CI, 2-2; P < .001). The neonatal Apgar scores did not differ between the 2 groups at 1 minute (median difference, 0; 95% CI, 0-0; P = .98) and at 5 minutes (median difference, 0; 95% CI, 0-0; P = .27). Transient neurologic or mental symptoms were more common in patients given esketamine (97.7% [293 of 300]) than in those given placebo (4.7% [14 of 300]; P < .001). Conclusions and Relevance For women undergoing cesarean delivery under epidural anesthesia, a subanesthetic dose of esketamine administered before incision produced transient analgesia and sedation but did not induce significant neonatal depression. Mental symptoms and nystagmus were common but transient. Indications and the optimal dose of esketamine in this patient population need further clarification, but study should be limited to those who require supplemental analgesia. Trial Registration ClinicalTrials.gov Identifier: NCT04548973.
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Affiliation(s)
- Li-Li Xu
- Department of Anesthesia, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Chun Wang
- Department of Anesthesia, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Chun-Mei Deng
- Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing, China
| | - Shao-Bing Dai
- Department of Anesthesia, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Qun Zhou
- Department of Anesthesiology, Jiangxi Maternal and Child Health Hospital, Jiangxi Province, China
| | - Yong-Bao Peng
- Department of Anesthesiology, Jiangxi Maternal and Child Health Hospital, Jiangxi Province, China
| | - Hong-Yan Shou
- Department of Anesthesiology, Hangzhou Women's Hospital, Zhejiang, China
| | - Yin-Qiu Han
- Department of Anesthesiology, Hangzhou Women's Hospital, Zhejiang, China
| | - Jing Yu
- Department of Anesthesiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Chao-Hui Liu
- Department of Anesthesiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Feng Xia
- Department of Anesthesiology, Jiaxing Maternity and Child Health Care Hospital, Jiaxing, Zhejiang Province, China
| | - Su-Qin Zhang
- Department of Anesthesiology, Jiaxing Maternity and Child Health Care Hospital, Jiaxing, Zhejiang Province, China
| | - Dong-Xin Wang
- Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing, China
| | - Xin-Zhong Chen
- Department of Anesthesia, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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Zhang T, Yue Z, Yu L, Li S, Xie Y, Wei J, Wu M, Liu H, Tan H. S-ketamine promotes postoperative recovery of gastrointestinal function and reduces postoperative pain in gynecological abdominal surgery patients: a randomized controlled trial. BMC Surg 2023; 23:74. [PMID: 36997940 PMCID: PMC10061816 DOI: 10.1186/s12893-023-01973-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 03/27/2023] [Indexed: 04/01/2023] Open
Abstract
BACKGROUND This prospective randomized controlled study was designed to evaluate the effect of S-ketamine with sufentanil given intraoperatively and postoperatively on recovery of gastrointestinal (GI) function and postoperative pain in gynecological patients undergoing open abdomen surgery. METHODS One hundred gynecological patients undergoing open abdomen surgery were randomized into an S-ketamine group (group S) or placebo group (0.9% saline; group C). Anesthesia was maintained with S-ketamine, sevoflurane, and remifentanil-propofol target-controlled infusion in group S and with sevoflurane and remifentanil-propofol target-controlled infusion in group C. All patients were connected to patient-controlled intravenous analgesia (PCIA) pump at the end of the surgery with sufentanil, ketorolac tromethamine, and tropisetron in group C and additional S-ketamine in group S. The primary outcome was the time of first postoperative flatus, and the secondary outcome was postoperative pain score of patients. Postoperative sufentanil consumption within the first postoperative 24 h and adverse events such as nausea and vomiting were recorded. RESULTS The time of first postoperative flatus in group S was significantly shorter (mean ± SD, 50.3 ± 13.5 h) than that in group C (mean ± SD, 56.5 ± 14.3 h, p = 0.042). The patient's visual analog scale (VAS) pain score 24 h after surgery at rest was significantly lower in group S than in group C (p = 0.032). There were no differences in sufentanil consumption within the first postoperative 24 h, postoperative complications related to PCIA between the two groups. CONCLUSIONS S-ketamine accelerated postoperative GI recovery and reduced 24 h postoperative pain in patients undergoing open gynecological surgery. TRIAL REGISTRATION ChiCTR2200055180. Registered on 02/01/2022. It is a secondary analysis of the same trial.
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Affiliation(s)
- Tianzhuo Zhang
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Haidian District, #52 Fucheng Street, Beijing, 100142, China
| | - Zhijie Yue
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Haidian District, #52 Fucheng Street, Beijing, 100142, China
| | - Ling Yu
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Haidian District, #52 Fucheng Street, Beijing, 100142, China
| | - Shuo Li
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Haidian District, #52 Fucheng Street, Beijing, 100142, China
| | - Yining Xie
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Haidian District, #52 Fucheng Street, Beijing, 100142, China
| | - Jin Wei
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Haidian District, #52 Fucheng Street, Beijing, 100142, China
| | - Mengge Wu
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Haidian District, #52 Fucheng Street, Beijing, 100142, China
| | - Honglei Liu
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Haidian District, #52 Fucheng Street, Beijing, 100142, China
| | - Hongyu Tan
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Haidian District, #52 Fucheng Street, Beijing, 100142, China.
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Chen Y, Ru F, Ye Q, Wu X, Hu X, Zhang Y, Wu Y. Effect of S-ketamine administered at the end of anesthesia on emergence delirium in preschool children undergoing tonsillectomy and/or adenoidectomy. Front Pharmacol 2023; 14:1044558. [PMID: 36874017 PMCID: PMC9981794 DOI: 10.3389/fphar.2023.1044558] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 02/09/2023] [Indexed: 02/19/2023] Open
Abstract
Background: S-ketamine (the S-isomer of ketamine) is twice as potent as the racemic mixture of this agent and carries fewer side effects when administered to humans. Information regarding the use of S-ketamine for the prevention of emergence delirium (ED) is limited. Thus, we evaluated the effect of S-ketamine administered at the end of anesthesia on ED in preschool children undergoing tonsillectomy and/or adenoidectomy. Methods: We investigated 108 children aged 3-7 years, who were scheduled for elective tonsillectomy and/or adenoidectomy under general anesthesia. They were randomly assigned to receive either S-ketamine 0.2 mg/kg or an equal volume of normal saline at the end of anesthesia. The primary outcome was the highest score on the pediatric anesthesia ED (PAED) scale during the first 30 min post-surgery. The secondary outcomes included the incidence of ED (defined as a score of ≥ 3 on Aono scale), pain score, time to extubation, and incidences of adverse events. Multivariate analyses were also performed using logistic regression to evaluate the independent factors predictive of ED. Results: The median (interquartile range) PAED score of the S-ketamine group (0 [0, 3]) was significantly lower than that in the control group (1 [0, 7]) (estimate median difference = 0, 95% confidence interval -2 to 0, p = 0.040). Significantly fewer patients in the S-ketamine group had an Aono scale score ≥ 3 (4 [7%] vs. 12 [22%], p = 0.030). Patients in the S-ketamine group also had a lower median pain score than did control subjects (4 [4, 6] vs. 6 [5, 8], p = 0.002). The time to extubation and incidences of adverse events were comparable between the two groups. However, multivariate analyses indicated that except S-ketamine use, pain scores, age and duration of anesthesia were independent factors predictive of ED. Conclusion: S-ketamine (0.2 mg/kg) administered at the end of anesthesia effectively reduced the incidence and severity of ED in preschool children undergoing tonsillectomy and/or adenoidectomy without prolonging the time to extubation or increasing adverse events. However, S-ketamine use was not an independent factor predictive of ED.
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Affiliation(s)
- Yang Chen
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Anesthesiology, Anhui Medical University, Hefei, China
| | - Feixiang Ru
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Anesthesiology, Anhui Medical University, Hefei, China
| | - Qiuping Ye
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xinzhe Wu
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xianwen Hu
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ye Zhang
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yun Wu
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
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Dhurjad P, Dhalaram CS, Ali N, Kumari N, Sonti R. Metal-organic frameworks in chiral separation of pharmaceuticals. Chirality 2022; 34:1419-1436. [PMID: 35924487 DOI: 10.1002/chir.23499] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 12/18/2022]
Abstract
Stereoselective chiral molecules are responsible for specific biological functions in nature. At present, more than half of the prescribed drugs are chiral. Living organisms display divergent pharmacological responses to the enantiomers, leading to altered toxicity, pharmacokinetics, and pharmacodynamics. Thus, chiral analysis, separation, and extraction are crucial for ensuring enantiomeric purity to develop safe and effective medication. In recent times, metal-organic frameworks (MOFs) with appealing structures are gaining importance because of their fascinating properties as a sorbent and stationary phase. MOFs are crystalline porous solid materials built by interconnecting metal ions or clusters and organic linkers. This review explores the advancements in MOFs for the isolation and separation of chiral active pharmaceutical drugs.
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Affiliation(s)
- Pooja Dhurjad
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Choudhary Sampat Dhalaram
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Nazish Ali
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Nikita Kumari
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Rajesh Sonti
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
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Zhang F, Ding J, Luo M, Luo H, Sun X, Fang X, Chen L, Tao J, Zhu Z. Effects of subanesthesia dose S-ketamine induction on postoperative psychiatric complications after gynecological surgery. IBRAIN 2022; 8:165-175. [PMID: 37786893 PMCID: PMC10529021 DOI: 10.1002/ibra.12039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/03/2022] [Accepted: 04/24/2022] [Indexed: 10/04/2023]
Abstract
Ketamine may become an important drug for multimodal analgesia regime again because of its strong analgesic effects and retaining the advantage of spontaneous breathing. The present study was designed to explore the influences of different dosages of S-ketamine anesthesia induction regimes on psychiatric complications and postoperative prognosis in patients undergoing gynecological operations. In this prospective, triple-blinded, randomized, controlled study, patients undergoing elective gynecological surgery were randomized to one of three treatment groups: low-dose S-ketamine (LDSK) group (a 0.3 mg/kg bolus for anesthesia induction), minimal-dose S-ketamine (MDSK) group (a 0.2 mg/kg bolus for anesthesia induction), and placebo (CON) group (a saline bolus for anesthesia induction). The main outcome measures were as follows: intraoperative vital signs, extubation time, anesthesia recovery time and postanesthesia care unit (PACU) stay duration, incidence of psychiatric complications, Ramsay sedation scale (RSS) 1, 2, 24, and 48 h, postoperatively, and overall prognosis. One hundred and eighty female participants were finally included in this study from April 2021 to December 2021. Significant differences were not observed in age, height, weight, American Society of Anesthesiologists physical status classification, or history of mental illness between the groups. No statistically significant differences were discovered with regard to intraoperative vital signs, extubation time and PACU stay duration, incidence of psychiatric complications, and RSS scores at 1, 2, 24, and 48 h postoperatively in the three groups. However, the visual analog scale (VAS) scores of the CON group at 10 min after extubation and at the time point leaving PACU were much higher than that of the LDSK and MDSK groups. The VAS scores at 48 h after surgery in the MDSK group were also lower than that of the CON group and the CON group had received more analgesic drug treatment in the surgical wards consequently. Postoperative nausea and vomiting (PONV) occurrence at 24 and 48 h, postoperatively, increased sharply in the CON group than in the other two experimental groups, which led to an increase in the use of postoperative antiemetic drugs in this group. According to the postoperative satisfaction survey, patients in the CON group had lower medical satisfaction. Our data demonstrate that a small dosage of S-ketamine anesthesia induction can reduce postoperative pain and the incidence of PONV without increasing hemodynamic fluctuations or psychiatric complications.
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Affiliation(s)
- Fan Zhang
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Jun Ding
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Man Luo
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Hao‐Hua Luo
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Xiao‐Lin Sun
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Xu Fang
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Lei Chen
- Department of AnesthesiologyQian Xi Nan People's HospitalQianxinanGuizhouChina
| | - Jun Tao
- Department of AnesthesiologyTongren Municipal People's HospitalTongrenGuizhouChina
| | - Zhao‐Qiong Zhu
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
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Wang X, Lin C, Lan L, Liu J. Perioperative intravenous S-ketamine for acute postoperative pain in adults: A systematic review and meta-analysis. J Clin Anesth 2020; 68:110071. [PMID: 33007645 DOI: 10.1016/j.jclinane.2020.110071] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 08/16/2020] [Accepted: 09/20/2020] [Indexed: 01/08/2023]
Abstract
STUDY OBJECTIVE To evaluate the effectiveness and safety of S-ketamine for pain relief and analgesic consumption in surgical patients. DESIGN Systematic review and meta-analysis of randomized controlled trials (RCTs). SETTING Perioperative setting. PATIENTS A total of 905 adult patients undergoing surgery using general anesthesia: 504 patients in the S-ketamine group and 401 patients in the placebo group. INTERVENTION Intravenous S-ketamine as an adjuvant to general anesthesia compared with placebo. MEASUREMENTS The primary outcomes were resting and movement pain scores (VAS/NRS 0-10) and morphine consumption within 4, 12, 24 and 48 h after surgery. The secondary outcomes included postoperative complications such as nausea, vomiting, and psychotomimetic adverse events. We used the guidelines of the Recommendation Assessment, Development, and Evaluation (GRADE) system to evaluate the level of certainty for the main results. MAIN RESULTS A total of 12 studies were included. The types of surgery included abdominal surgery, thoracotomy, gynecologic surgery, arthroscopic anterior cruciate ligament repair, cardiac surgery, laparoscopic cholecystectomy, lumbar spinal fusion surgery, radical prostatectomy, and hemorrhoidectomy. There were significant improvements in resting pain scores at 4, 12 and 24 h with S-ketamine versus placebo [4 h: standardized mean difference (SMD) -1.11; 95% confidence interval (CI): -1.53, -0.68, p < 0.00001; GRADE = moderate; 12 h: SMD -0.88; 95%CI: -1.42, -0.34, p = 0.001; GRADE = moderate; 24 h: SMD -0.39; 95%CI: -0.73, -0.06, p = 0.02; GRADE = moderate]. The incidence of pain scores at 48 h showed no statistical difference between the two groups (SMD -0.27; 95%CI: -1.12, 0.58, p = 0.53, GRADE = moderate). The movement pain scores were not significantly different between the two groups at each time point (4 h: SMD -0.34; 95%CI: -0.73, 0.05, p = 0.09, GRADE = moderate; 12 h: SMD -0.42; 95%CI: -1.46, 0.63, p = 0.44, GRADE = low; 24 h: SMD -0.58; 95%CI: -1.25, 0.09, p = 0.09, GRADE = moderate; 48 h: SMD -0.49; 95%CI: -1.11, 0.14, p = 0.13, GRADE = low). At 4 and 12 h after surgery, the consumption of morphine was significantly reduced in the S-ketamine group (4 h: SMD -0.98; 95%CI: -1.37, -0.06, p < 0.00001, GRADE = moderate; 12 h: SMD -1.36; 95%CI: -2.26, -0.46, p = 0.003, GRADE = low). There were no significant differences in morphine use at 24 and 48 h between the two groups (24 h: SMD -0.70; 95%CI: -1.42, 0.02, p = 0.06, GRADE = low; 48 h: SMD -0.79; 95%CI: -2.26, 1.03, p = 0.39, GRADE = low). The risk for nausea [relative risk (RR) = 1.04; 95%CI: 0.83, 1.30, p = 0.73], vomiting (RR = 1.07; 95%CI: 0.84, 1.38, p = 0.57), and psychotomimetic adverse events (RR = 1.57; 95%CI: 0.82, 2.99, p = 0.17) showed no significant increase in the S-ketamine group. CONCLUSIONS Intravenous S-ketamine as an adjunct to general anesthesia is effective for assisting analgesia and decreases the intensity of pain and opioid requirements in a short period of time after surgery, but it may increase the psychotomimetic adverse event rate. Overall, the level of certainty is moderate to low.
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Affiliation(s)
- Xuemei Wang
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Cheng Lin
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Lifang Lan
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Jingchen Liu
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
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Mwamwitwa KW, Kaibere RM, Fimbo AM, Sabitii W, Ntinginya NE, Mmbaga BT, Shewiyo DH, Shearer MC, Smith AD, Kaale EA. A retrospective cross-sectional study to determine chirality status of registered medicines in Tanzania. Sci Rep 2020; 10:17834. [PMID: 33082444 PMCID: PMC7575591 DOI: 10.1038/s41598-020-74932-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/08/2020] [Indexed: 11/25/2022] Open
Abstract
Medicines with a stereogenic center (asymmetric carbon) are mainly present as racemates with a mixture of equal amounts of enantiomers. One enantiomer may be active while the other inactive, alternatively one may produce side-effects and even toxicity. However, there is lack of information on the chirality status (either racemates, single active enantiomer or achiral) of medicines circulated on the market particularly in African countries. We established the chirality status of registered medicines in Tanzania by conducting a retrospective cross-sectional study. Registration data for the past 15 years from 2003 to 2018 were extracted from TMDA-IMIS database to Microsoft excel for review and analysis. A total of 3,573 human medicines had valid registration. Out of which 2,150 (60%) were chiral and 1,423 (40%) achiral. Out of the chiral medicines, 1,591 (74%) and 559 (26%) were racemates and single active enantiomers, respectively. The proportion of racemates within chiral medicines was considerably higher than single enantiomer medicines. The use of racemates may cause harm to the public and may contribute to antimicrobial resistance due to potential existence of inactive and toxic enantiomers. In order to protect public health, regulatory bodies need to strengthen control of chiral medicines by conducting analysis of enantiomeric impurity.
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Affiliation(s)
- Kissa W Mwamwitwa
- Pharm R&D Lab and Department of Medicinal Chemistry, School of Pharmacy, Muhimbili University of Health and Allied Sciences, P. O. Box 65545, Dar es Salaam, Tanzania.
- Tanzania Medicines and Medical Devices Authority, P. O. Box 77150, Dar es Salaam, Tanzania.
| | - Raphael M Kaibere
- Pharm R&D Lab and Department of Medicinal Chemistry, School of Pharmacy, Muhimbili University of Health and Allied Sciences, P. O. Box 65545, Dar es Salaam, Tanzania
| | - Adam M Fimbo
- Tanzania Medicines and Medical Devices Authority, P. O. Box 77150, Dar es Salaam, Tanzania
| | - Wilber Sabitii
- School of Medicine, University of St, Andrews, Fife, KY16 9TF, Scotland, UK
| | - Nyanda E Ntinginya
- National Institute of Medical Research - Mbeya Medical Research Centre, P. O. Box 2410, Mbeya, Tanzania
| | - Blandina T Mmbaga
- Kilimanjaro Clinical Research Institute, P. O. Box 2236, Moshi, Kilimanjaro, Tanzania
- Kilimanjaro Christian Medical University College, P. O. Box 3010, Moshi, Kilimanjaro, Tanzania
| | - Danstan H Shewiyo
- Tanzania Medicines and Medical Devices Authority, P. O. Box 77150, Dar es Salaam, Tanzania
| | - Morven C Shearer
- School of Medicine, University of St, Andrews, Fife, KY16 9TF, Scotland, UK
| | - Andrew D Smith
- School of Chemistry, University of St, Andrews, Fife, KY16 9TF, Scotland, UK
| | - Eliangiringa A Kaale
- Pharm R&D Lab and Department of Medicinal Chemistry, School of Pharmacy, Muhimbili University of Health and Allied Sciences, P. O. Box 65545, Dar es Salaam, Tanzania
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11
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Čižmáriková R, Čižmárik J, Valentová J, Habala L, Markuliak M. Chiral Aspects of Local Anesthetics. Molecules 2020; 25:E2738. [PMID: 32545678 PMCID: PMC7355888 DOI: 10.3390/molecules25122738] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 05/29/2020] [Accepted: 06/09/2020] [Indexed: 01/04/2023] Open
Abstract
Thanks to the progress made in chemical technology (particularly in the methodologies of stereoselective syntheses and analyses) along with regulatory measures, the number of new chiral drugs registered in the form of pure enantiomers has increased over the past decade. In addition, the pharmacological and pharmacokinetic properties of the individual enantiomers of already-introduced racemic drugs are being re-examined. The use of the pure enantiomer of a drug that has been used to date in the form of a racemate is called a "chiral switch". A re-examination of the properties of the pure enantiomers of racemates has taken place for local anesthetics, which represent a group of drugs which have long been used. Differences in (R) and (S)-enantiomers were found in terms of pharmacodynamic and pharmacokinetic activity as well as in toxicity. Levobupivacaine and robivacaine were introduced into practice as pure (S)-(-)-enantiomers, exhibiting more favorable properties than their (R)-(+)-stereoisomers or racemates. This overview focuses on the influence of chirality on the pharmacological and toxicological activity of local anesthetics as well as on individual HPLC and capillary electrophoresis (CE) methods used for enantioseparation and the pharmacokinetic study of individual local anesthetics with a chiral center.
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Affiliation(s)
- Ružena Čižmáriková
- Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (R.Č.); (J.V.); (M.M.)
| | - Jozef Čižmárik
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia;
| | - Jindra Valentová
- Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (R.Č.); (J.V.); (M.M.)
| | - Ladislav Habala
- Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (R.Č.); (J.V.); (M.M.)
| | - Mário Markuliak
- Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (R.Č.); (J.V.); (M.M.)
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12
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Basic pharmacology of local anaesthetics. BJA Educ 2019; 20:34-41. [PMID: 33456928 DOI: 10.1016/j.bjae.2019.10.002] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/10/2019] [Accepted: 10/18/2019] [Indexed: 12/16/2022] Open
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13
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Tijanic M, Buric N. A randomized anesthethic potency comparison between ropivacaine and bupivacaine on the perioperative regional anesthesia in lower third molar surgery. J Craniomaxillofac Surg 2019; 47:1652-1660. [DOI: 10.1016/j.jcms.2019.07.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/08/2019] [Accepted: 07/14/2019] [Indexed: 11/16/2022] Open
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14
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Gohari SJ, Javidan A, Moghimi A, Taghizadeh MJ, Iman M. Novel enantioselective synthesis of (S)-ketamine using chiral auxiliary and precursor Mannich base. CAN J CHEM 2019. [DOI: 10.1139/cjc-2017-0731] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Ketamine has been extensively used as an anesthetic drug. Chiral auxiliaries such as tert-butanesulfinamide (TBSA) can be used for the asymmetric synthesis of (S)-ketamine. Condensation of TBSA with ketones provides tert-butanesulfinylimines in consistently high yields. The tert-butanesulfinyl group actuates the imine for nucleophilic addition, is a potent chiral directing group, and after nucleophilic addition is easily dissociated by intervention with acid solution. To prepare 2-(N-piperidinomethyl)-1-phenylcyclohexylamine (1), we started with the cyclohexanone and using Mannich reaction achieved an aminoketone. Then, we made the sulfiniylamin (2) by the condensation of TBSA with aminoketone. By using salts such as Ti(OEt)4, we obtained N-tert-butanesulfinylketimine in 85% yield. Next, we provided a new chiral center (3) using Grignard reagent as nucleophile at −78 °C (80% yield). Finally, after many steps, the (S)-ketamine synthesized under ozonolysis conditions, with good yield and enantioselectivity (75% yield and 75% ee).
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Affiliation(s)
- Seyed Jamaladdin Gohari
- Department of Chemistry, Faculty of Science, Imam Hossein Comprehensive University, Tehran, Iran
| | - Abdollah Javidan
- Department of Medicine Chemistry, Faculty of Science, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran, and University of Eyvanekey, Eyvanekey, Iran
| | - Abolghasem Moghimi
- Department of Chemistry, Faculty of Science, Islamic Azad University, Tehran North Branch, Tehran, Iran
| | | | - Maryam Iman
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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15
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Chambers SA, DeSousa JM, Huseman ED, Townsend SD. The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production. ACS Chem Neurosci 2018; 9:2307-2330. [PMID: 29342356 PMCID: PMC6205722 DOI: 10.1021/acschemneuro.7b00528] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.
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Affiliation(s)
- Schuyler A. Chambers
- Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Nashville, Tennessee 37235, United States
| | - Jenna M. DeSousa
- Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Nashville, Tennessee 37235, United States
| | - Eric D. Huseman
- Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Nashville, Tennessee 37235, United States
| | - Steven D. Townsend
- Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Nashville, Tennessee 37235, United States
- Institute of Chemical Biology, Vanderbilt University, 896 Preston Research Building, Nashville, Tennessee 37232, United States
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16
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A novel strategy for the asymmetric synthesis of (S)-ketamine using (S)-tert-butanesulfinamide and 1,2-cyclohexanedione. JOURNAL OF THE IRANIAN CHEMICAL SOCIETY 2018. [DOI: 10.1007/s13738-018-1404-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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17
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Alata I, Pérez-Mellor A, Ben Nasr F, Scuderi D, Steinmetz V, Gobert F, Jaïdane NE, Zehnacker-Rentien A. Does the Residues Chirality Modify the Conformation of a Cyclo-Dipeptide? Vibrational Spectroscopy of Protonated Cyclo-diphenylalanine in the Gas Phase. J Phys Chem A 2017; 121:7130-7138. [DOI: 10.1021/acs.jpca.7b06159] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Ivan Alata
- Institut
des Sciences Moléculaires d’Orsay, CNRS, Univ. Paris-Sud, Université Paris-Saclay, F-91405 Orsay, France
| | - Ariel Pérez-Mellor
- Institut
des Sciences Moléculaires d’Orsay, CNRS, Univ. Paris-Sud, Université Paris-Saclay, F-91405 Orsay, France
| | - Feriel Ben Nasr
- Institut
des Sciences Moléculaires d’Orsay, CNRS, Univ. Paris-Sud, Université Paris-Saclay, F-91405 Orsay, France
- Laboratoire
de Spectroscopie Atomique Moléculaire et Applications, Université de Tunis El Manar, Tunis 1060, Tunisia
| | - Debora Scuderi
- Laboratoire
de Chimie Physique, CNRS, UMR8000, Univ. Paris-Sud, Orsay F-91405, France
| | - Vincent Steinmetz
- Laboratoire
de Chimie Physique, CNRS, UMR8000, Univ. Paris-Sud, Orsay F-91405, France
| | - Fabrice Gobert
- Laboratoire
de Chimie Physique, CNRS, UMR8000, Univ. Paris-Sud, Orsay F-91405, France
| | - Nejm-Eddine Jaïdane
- Laboratoire
de Spectroscopie Atomique Moléculaire et Applications, Université de Tunis El Manar, Tunis 1060, Tunisia
| | - Anne Zehnacker-Rentien
- Institut
des Sciences Moléculaires d’Orsay, CNRS, Univ. Paris-Sud, Université Paris-Saclay, F-91405 Orsay, France
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18
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Tago T, Furumoto S, Okamura N, Harada R, Adachi H, Ishikawa Y, Yanai K, Iwata R, Kudo Y. Preclinical Evaluation of [(18)F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer. Mol Imaging Biol 2016; 18:258-66. [PMID: 26194011 DOI: 10.1007/s11307-015-0879-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE Noninvasive imaging of tau and amyloid-β pathologies would facilitate diagnosis of Alzheimer's disease (AD). Recently, we have developed [(18)F]THK-5105 for selective detection of tau pathology by positron emission tomography (PET). The purpose of this study was to clarify biological properties of optically pure [(18)F]THK-5105 enantiomers. PROCEDURES Binding for tau aggregates in AD brain section was evaluated by autoradiography (ARG). In vitro binding assays were performed to evaluate the binding properties of enantiomers for AD brain homogenates. The pharmacokinetics in the normal mouse brains was assessed by ex vivo biodistribution assay RESULTS The ARG of enantiomers showed the high accumulation of radioactivity corresponding to the distribution of tau deposits. In vitro binding assays revealed that (S)-[(18)F]THK-5105 has slower dissociation from tau than (R)-[(18)F]THK-5105. Biodistribution assays indicated that (S)-[(18)F]THK-5105 eliminated faster from the mouse brains and blood compared with (R)-[(18)F]THK-5105. CONCLUSION (S)-[(18)F]THK-5105 could be more suitable than (R)-enantiomer for a tau imaging agent.
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Affiliation(s)
- Tetsuro Tago
- Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan
- Department of Radiopharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Shozo Furumoto
- Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan.
- Department of Radiopharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
- Cyclotron and Radioisotope Center (CYRIC), Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan.
| | - Nobuyuki Okamura
- Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan
| | - Ryuichi Harada
- Division of Neuro-Imaging, Institute of Development, Aging and Cancer, Sendai, Japan
| | - Hajime Adachi
- Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan
- Department of Radiopharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Yoichi Ishikawa
- Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan
| | - Kazuhiko Yanai
- Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan
| | - Ren Iwata
- Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan
| | - Yukitsuka Kudo
- Division of Neuro-Imaging, Institute of Development, Aging and Cancer, Sendai, Japan
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19
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Münzner M, Dornberg G, Küster C, Enke D. Synthese von porösen Voll- und Core-Shell-Glaskugeln zur Trennung von chiralen Anästhetika. CHEM-ING-TECH 2016. [DOI: 10.1002/cite.201600053] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Bu W, Pereira LM, Eckenhoff RG, Yuki K. Stereoselectivity of isoflurane in adhesion molecule leukocyte function-associated antigen-1. PLoS One 2014; 9:e96649. [PMID: 24801074 PMCID: PMC4011845 DOI: 10.1371/journal.pone.0096649] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 04/09/2014] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Isoflurane in clinical use is a racemate of S- and R-isoflurane. Previous studies have demonstrated that the effects of S-isoflurane on relevant anesthetic targets might be modestly stronger (less than 2-fold) than R-isoflurane. The X-ray crystallographic structure of the immunological target, leukocyte function-associated antigen-1 (LFA-1) with racemic isoflurane suggested that only S-isoflurane bound specifically to this protein. If so, the use of specific isoflurane enantiomers may have advantage in the surgical settings where a wide range of inflammatory responses is expected to occur. Here, we have further tested the hypothesis that isoflurane enantioselectivity is apparent in solution binding and functional studies. METHODS First, binding of isoflurane enantiomers to LFA-1 was studied using 1-aminoanthracene (1-AMA) displacement assays. The binding site of each enantiomer on LFA-1 was studied using the docking program GLIDE. Functional studies employed the flow-cytometry based ICAM binding assay. RESULTS Both enantiomers decreased 1-AMA fluorescence signal (at 520 nm), indicating that both competed with 1-AMA and bound to the αL I domain. The docking simulation demonstrated that both enantiomers bound to the LFA-1 "lovastatin site." ICAM binding assays showed that S-isoflurane inhibited more potently than R-isoflurane, consistent with the result of 1-AMA competition assay. CONCLUSIONS In contrast with the x-ray crystallography, both enantiomers bound to and inhibited LFA-1. S-isoflurane showed slight preference over R-isoflurane.
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Affiliation(s)
- Weiming Bu
- Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Luis M. Pereira
- Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America
- Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Roderic G. Eckenhoff
- Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Koichi Yuki
- Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America
- Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts, United States of America
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21
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Interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol: mechanistic and clinical implications for anesthetic and cardiotoxic effects. Anesthesiol Res Pract 2013; 2013:297141. [PMID: 24174934 PMCID: PMC3794646 DOI: 10.1155/2013/297141] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 08/13/2013] [Accepted: 08/17/2013] [Indexed: 01/13/2023] Open
Abstract
Despite a long history in medical and dental application, the molecular mechanism and precise site of action are still arguable for local anesthetics. Their effects are considered to be induced by acting on functional proteins, on membrane lipids, or on both. Local anesthetics primarily interact with sodium channels embedded in cell membranes to reduce the excitability of nerve cells and cardiomyocytes or produce a malfunction of the cardiovascular system. However, the membrane protein-interacting theory cannot explain all of the pharmacological and toxicological features of local anesthetics. The administered drug molecules must diffuse through the lipid barriers of nerve sheaths and penetrate into or across the lipid bilayers of cell membranes to reach the acting site on transmembrane proteins. Amphiphilic local anesthetics interact hydrophobically and electrostatically with lipid bilayers and modify their physicochemical property, with the direct inhibition of membrane functions, and with the resultant alteration of the membrane lipid environments surrounding transmembrane proteins and the subsequent protein conformational change, leading to the inhibition of channel functions. We review recent studies on the interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol. Understanding the membrane interactivity of local anesthetics would provide novel insights into their anesthetic and cardiotoxic effects.
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Abstract
Many molecules can exist as right-handed and left-handed forms that are non-superimposable mirror images of each other. They are known as enantiomers or substances of opposite shape. Such compounds are also said to be chiral (Greek chiros meaning ‘hand’). Such chiral molecules are of great relevance to anaesthetic theory and practice. This review summarizes the basic concepts, pharmacokinetic and pharmacodynamic aspects of chirality, and some specific examples of their application in anaesthesia, along with recent advances to elucidate the anaesthetic mechanisms. Chirality is relevant to anaesthesia, simply because more than half of the synthetic agents used in anaesthesia practice are chiral drugs. Almost all these synthetic chiral drugs are administered as racemic mixture, rather than as single pure enantiomers. These mixtures are not drug formulations containing two or more therapeutic substances, but combination of isomeric substances, with the therapeutic activity residing mainly in one of the enantiomer. The other enantiomer can have undesirable properties, have different therapeutic activities or be pharmacologically inert. Specific examples of application of chirality in anaesthetic drugs include inhalational general anaesthetics (e.g. isoflurane), intravenous anaesthetics (e.g. etomidate, thiopentone), neuromuscular blocking agents (e.g. cisatracurium), local anaesthetics (e.g. ropivacaine and levobupivacaine) and other agents (e.g. levosimendan, dexmedetomidine, L-cysteine). In the recent advances, chirality study has not only helped new drug development as mentioned above, but has also contributed in a more profound way to the understanding of the mechanism of anaesthesia and anaesthetic drugs.
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Affiliation(s)
- Sukanya Mitra
- Departments of Anaesthesia and Intensive Care, Government Medical College and Hospital, Chandigarh, India
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Abstract
Halogen bonding is the electron density donation based weak interaction of halogens with Lewis bases. Its applicability for molecular recognition processes long remained unappreciated and has so far mostly been studied in silico and in solid state. As most physiological processes and chemical reactions take place in solution, investigations in solutions are of highest relevance for its use in the pharmaceutical and material scientific toolboxes. Following a short discussion of the phenomenon of halogen bonding, this tutorial review presents an overview of the methods hitherto applied for gaining an improved understanding of its behaviour in solutions and summarizes the gained knowledge in order to indicate the scope of the techniques and to facilitate exciting future developments.
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Affiliation(s)
- Máté Erdélyi
- Department of Chemistry and Molecular Biology, University of Gothenburg, Kemivägen 10, SE-41296 Gothenburg, Sweden.
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24
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How pharmacokinetic can help to choose the right local anesthetics during epidural infusion. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.eujps.2011.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Simon MJ, Veering BT. Factors affecting the pharmacokinetics and neural block characteristics after epidural administration of local anaesthetics. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.eujps.2010.09.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Abstract
Local anesthetics (LA) block propagation of impulses along nerve fibers by inactivation of voltage-gated sodium channels, which initiate action potentials (1). They act on the cytosolic side of phospholipid membranes. Two main chemical compounds are used, amino esters and amino amides. Amino esters are degraded by pseudocholinesterases in plasma. Amino amides are metabolized exclusively by the liver. Only amide LAs will be considered in this article.
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Affiliation(s)
- Jean-Xavier Mazoit
- Département d'Anesthésie-Réanimation, Hôpitaux Universitaires Paris-Sud, AP-HP, Le Kremlin-Bicětre, France.
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Martin-Jurado O, Bektas R, Fahrion A, Bettschart-Wolfensberger R, Hammer S. Comparison of the effects of racemic ketamine and S-ketamine for anesthesia in Rheem gazelles (Gazella subgutturosa marica) and Subgutturosa gazelles (Gazella subgutturosa subgutturosa). Am J Vet Res 2011; 72:1164-70. [DOI: 10.2460/ajvr.72.9.1164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Tsuchiya H, Ueno T, Mizogami M. Stereostructure-based differences in the interactions of cardiotoxic local anesthetics with cholesterol-containing biomimetic membranes. Bioorg Med Chem 2011; 19:3410-5. [PMID: 21550810 DOI: 10.1016/j.bmc.2011.04.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Revised: 04/12/2011] [Accepted: 04/13/2011] [Indexed: 01/09/2023]
Abstract
Amide-type pipecoloxylidide local anesthetics, bupivacaine, and ropivacaine, show cardiotoxic effects with the potency depending on stereostructures. Cardiotoxic drugs not only bind to cardiomyocyte membrane channels to block them but also modify the physicochemical property of membrane lipid bilayers in which channels are embedded. The opposite configurations allow enantiomers to be discriminated by their enantiospecific interactions with another chiral molecule in membranes. We compared the interactions of local anesthetic stereoisomers with biomimetic membranes consisting of chiral lipid components, the differences of which might be indicative of the drug design for reducing cardiotoxicity. Fluorescent probe-labeled biomimetic membranes were prepared with cardiolipin and cholesterol of varying compositions and different phospholipids. Local anesthetics were reacted with the membrane preparations at a cardiotoxically relevant concentration of 200 μM. The potencies to interact with biomimetic membranes and change their fluidity were compared by measuring fluorescence polarization. All local anesthetics acted on lipid bilayers to increase membrane fluidity. Chiral cardiolipin was ineffective in discriminating S(-)-enantiomers from their antipodes. On the other hand, cholesterol produced the enantiospecific membrane interactions of bupivacaine and ropivacaine with increasing its composition in membranes. In 40 mol% and more cholesterol-containing membranes, the membrane-interacting potency was S(-)-bupivacaine<racemic bupivacaine<R(+)-bupivacaine, and S(-)-ropivacaine<R(+)-ropivacaine. Ropivacaine (S(-)-enantiomer), levobupivacaine (S(-)-enantiomeric), and bupivacaine (racemic) interacted with biomimetic membranes in increasing order of intensity. The rank order of membrane interactivity agreed with that of known cardiotoxicity. The stereoselective membrane interactions determined by cholesterol with higher chirality appears to be associated with the stereoselective cardiotoxic effects of local anesthetics. The stereostructure and membrane interactivity relationship supports the clinical use and development of S(-)-enantiomers to decrease the adverse effects of pipecoloxylidide local anesthetics on the cardiovascular system.
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Affiliation(s)
- Hironori Tsuchiya
- Department of Dental Basic Education, Asahi University School of Dentistry, Mizuho, Gifu 501-0296, Japan.
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Optimizing the separation of gaseous enantiomers by simulated moving bed and pressure swing adsorption. ADSORPTION 2010. [DOI: 10.1007/s10450-010-9299-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Direct vasocontractile activities of bupivacaine enantiomers on the isolated rat thoracic aorta. Anesthesiol Res Pract 2010; 2010:820186. [PMID: 20981258 PMCID: PMC2964006 DOI: 10.1155/2010/820186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 09/23/2010] [Accepted: 10/06/2010] [Indexed: 11/19/2022] Open
Abstract
Background. In vitro studies with isolated arteries have shown direct vasoactivity of racemic bupivacaine. However, there is little information on the direct vasoactivities of bupivacaine enantiomers, S(−)- and R(+)-bupivacaine. Methods. We performed functional examinations using isolated intact thoracic aortic rings from male Wistar rats. Changes in ring tension produced by S(−)-, R(+)-, or racemic bupivacaine were measured in Krebs solution. Results. S(−)-bupivacaine produced the strongest contraction of the three agents. R(+)-bupivacaine showed limited vasoconstriction. The effects of racemic bupivacaine were located between these two.
Conclusion. Each bupivacaine enantiomer showed specific vasocontractile activity, which affects the activity of racemic bupivacaine.
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Kasprzyk-Hordern B. Pharmacologically active compounds in the environment and their chirality. Chem Soc Rev 2010; 39:4466-503. [PMID: 20852776 DOI: 10.1039/c000408c] [Citation(s) in RCA: 287] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Pharmacologically active compounds including both legally used pharmaceuticals and illicit drugs are potent environmental contaminants. Extensive research has been undertaken over the recent years to understand their environmental fate and toxicity. The one very important phenomenon that has been overlooked by environmental researchers studying the fate of pharmacologically active compounds in the environment is their chirality. Chiral drugs can exist in the form of enantiomers, which have similar physicochemical properties but differ in their biological properties such as distribution, metabolism and excretion, as these processes (due to stereospecific interactions of enantiomers with biological systems) usually favour one enantiomer over the other. Additionally, due to different pharmacological activity, enantiomers of chiral drugs can differ in toxicity. Furthermore, degradation of chiral drugs during wastewater treatment and in the environment can be stereoselective and can lead to chiral products of varied toxicity. The distribution of different enantiomers of the same chiral drug in the aquatic environment and biota can also be stereoselective. Biological processes can lead to stereoselective enrichment or depletion of the enantiomeric composition of chiral drugs. As a result the very same drug might reveal different activity and toxicity and this will depend on its origin and exposure to several factors governing its fate in the environment. In this critical review a discussion of the importance of chirality of pharmacologically active compounds in the environmental context is undertaken and suggestions for directions in further research are made. Several groups of chiral drugs of major environmental relevance are discussed and their pharmacological action and disposition in the body is also outlined as it is a key factor in developing a full understanding of their environmental occurrence, fate and toxicity. This review will be of interest to environmental scientists, especially those interested in issues associated with environmental contamination with pharmacologically active compounds and chiral pollutants. As the review will outline current state of knowledge on chiral drugs, it will be of value to anyone interested in the phenomenon of chirality, chiral drugs, their stereoselective disposition in the body and environmental fate (212 references).
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Affiliation(s)
- Barbara Kasprzyk-Hordern
- University of Huddersfield, Department of Chemical and Biological Sciences, School of Applied Sciences, Queensgate, Huddersfield HD1 3DH, UK.
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Yokoyama T, Yokoyama R, Nomura S, Matsumoto S, Fujiyama R, Kiyooka SI. Synthesis of (S)-Ketamine via [1,3]-Chirality Transfer of a Stereocenter Created by Enantioselective Aldol Reaction. BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN 2009. [DOI: 10.1246/bcsj.82.1528] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Udelsmann A, Silva WA, Moraes ACD, Dreyer E. Hemodynamic effects of ropivacaine and levobupivacaine intravenous injection in swines. Acta Cir Bras 2009; 24:296-302. [DOI: 10.1590/s0102-86502009000400009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2009] [Accepted: 04/18/2009] [Indexed: 11/22/2022] Open
Abstract
PURPOSE: To compare the hemodynamic effects following a toxic dose of either agent after intravenous injection in swines, as might accidentally occur during regional anesthesia in humans. METHODS: Large White pigs were anesthetized with thiopental, tracheal intubation was performed and mechanical ventilation was instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheterization. After a 30-minute resting period, the animals were randomly divided into two groups in a double-blinded fashion and received a bolus intravenous injection of 4 mg.kg-1 of either agent. Hemodynamic results were evaluated at rest and 1, 5, 10, 15, 20 and 30 minutes after intoxication. RESULTS: Hemodynamic repressions of acute intoxication with levobupivacaine were more important and more prolonged than those of ropivacaína. CONCLUSION: In pigs, levobupivacaine was shown to be more toxic than ropivacaine when the same large doses are injected intravenously.
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Yokoyama R, Matsumoto S, Nomura S, Higaki T, Yokoyama T, Kiyooka SI. Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring: first asymmetric synthesis of anesthetic (S)-ketamine with high selectivity. Tetrahedron 2009. [DOI: 10.1016/j.tet.2009.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Tsuchiya H, Mizogami M. Membrane interactivity of charged local anesthetic derivative and stereoselectivity in membrane interaction of local anesthetic enantiomers. Local Reg Anesth 2008; 1:1-9. [PMID: 22915858 PMCID: PMC3417937 DOI: 10.2147/lra.s3876] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
With respect to the membrane lipid theory as a molecular mechanism for local anesthetics, two critical subjects, the negligible effects of charged drugs when applied extracellularly and the stereoselective effects of enantiomers, were verified by paying particular attention to membrane components, phospholipids with the anionic property, and cholesterol with several chiral carbons. The membrane interactivities of structurally-different anesthetics were determined by their induced fluidity changes of liposomal membranes. Lidocaine (3.0 μmol/mL) fluidized phosphatidylcholine membranes, but not its quaternary derivative QX-314 (3.0 μmol/mL). Similarly to the mother molecule lidocaine, however, QX-314 fluidized phosphatidylserine-containing nerve cell model membranes and acidic phospholipids-constituting membranes depending on the acidity of membrane lipids. Positively charged local anesthetics are able to act on lipid bilayers by ion-pairing with anionic (acidic) phospholipids. Bupivacaine (0.75 mol/mL) and ropivacaine (0.75 and 1.0 μmol/mL) fluidized nerve cell model membranes with the potency being S(−)-enantiomer < racemate < R(+)-enantiomer (P < 0.01, vs antipode and racemate) and cardiac cell model membranes with the potency being S(−)-ropivacaine < S(−)-bupivacaine < R(+)-bupivacaine (P < 0.01). However, their membrane effects were not different when removing cholesterol from the model membranes. Stereoselectivity is producible by cholesterol which increases the chirality of lipid bilayers and enables to discriminate anesthetic enantiomers. The membrane lipid interaction should be reevaluated as the mode of action of local anesthetics.
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Affiliation(s)
- Hironori Tsuchiya
- Department of Dental Basic Education, Asahi University School of Dentistry, Mizuho, Gifu, Japan
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DUQUE JC, OLESKOVICZ N, GUIRRO ECBP, VALADO CAA, SOARES VE. Relative potency of ketamine and S(+)-ketamine in dogs. J Vet Pharmacol Ther 2008; 31:344-8. [DOI: 10.1111/j.1365-2885.2008.00965.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Pardey G, Grousson S, de Souza EP, Mottolese C, Dailler F, Duflo F. Levobupivacaine scalp nerve block in children. Paediatr Anaesth 2008; 18:271-2. [PMID: 18230073 DOI: 10.1111/j.1460-9592.2008.02416.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
Local anesthetics are used broadly to prevent or reverse acute pain and treat symptoms of chronic pain. This chapter, on the analgesic aspects of local anesthetics, reviews their broad actions that affect many different molecular targets and disrupt their functions in pain processing. Application of local anesthetics to peripheral nerve primarily results in the blockade of propagating action potentials, through their inhibition of voltage-gated sodium channels. Such inhibition results from drug binding at a site in the channel's inner pore, accessible from the cytoplasmic opening. Binding of drug molecules to these channels depends on their conformation, with the drugs generally having a higher affinity for the open and inactivated channel states that are induced by membrane depolarization. As a result, the effective potency of these drugs for blocking impulses increases during high-frequency repetitive firing and also under slow depolarization, such as occurs at a region of nerve injury, which is often the locus for generation of abnormal, pain-related ectopic impulses. At distal and central terminals the inhibition of voltage-gated calcium channels by local anesthetics will suppress neurogenic inflammation and the release of neurotransmitters. Actions on receptors that contribute to nociceptive transduction, such as TRPV1 and the bradykinin B2 receptor, provide an independent mode of analgesia. In the spinal cord, where local anesthetics are present during epidural or intrathecal anesthesia, inhibition of inotropic receptors, such as those for glutamate, by local anesthetics further interferes with neuronal transmission. Activation of spinal cord mitogen-activated protein (MAP) kinases, which are essential for the hyperalgesia following injury or incision and occur in both neurons and glia, is inhibited by spinal local anesthetics. Many G protein-coupled receptors are susceptible to local anesthetics, with particular sensitivity of those coupled via the Gq alpha-subunit. Local anesthetics are also infused intravenously to yield plasma concentrations far below those that block normal action potentials, yet that are frequently effective at reversing neuropathic pain. Thus, local anesthetics modify a variety of neuronal membrane channels and receptors, leading to what is probably a synergistic mixture of analgesic mechanisms to achieve effective clinical analgesia.
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Affiliation(s)
- F Yanagidate
- Pain Research Center, BWH/MRB611, 75 Francis Street, Boston, MA 02115-6110, USA
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Abstract
The use of levobupivacaine and of ropivacaine may increase the safety of regional anaesthesia. These pure enantiomers have similar pharmacokinetic properties as those of the racemic mixtures. However, they are less cardiotoxic than the racemic mixtures, especially at the high heart rate usually encountered in infants. We may then recommend the use of these agents in the paediatric patients.
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Affiliation(s)
- J-X Mazoit
- Département d'anesthésie et laboratoire d'anesthésie UPRES EA3540, faculté de médecine de Bicêtre, hôpital de Bicêtre 94276 Bicêtre, Le Kremlin-Bicêtre cedex, France.
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In Vitro Antagonism of Recombinant Ligand-Gated Ion-Channel Receptors by Stereospecific Enantiomers of Bupivacaine. Reg Anesth Pain Med 2006. [DOI: 10.1097/00115550-200601000-00005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Ibarra M CA, Ichihara Y, Hikita M, Yoshida K, Junji S, Maehara Y, Kikuchi H. Effect of bupivacaine enantiomers on Ca2+ release from sarcoplasmic reticulum in skeletal muscle. Eur J Pharmacol 2005; 512:77-83. [PMID: 15840391 DOI: 10.1016/j.ejphar.2005.01.053] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2005] [Revised: 01/26/2005] [Accepted: 01/31/2005] [Indexed: 10/25/2022]
Abstract
Local anesthetics affect intracellular Ca2+ movement in the myocyte. The use of isomers may help to reveal specific mechanisms of action, such as receptor mediation. In the present study, we used skinned fibers from mammalian skeletal muscle to test whether bupivacaine enantiomers had different effects on Ca2+ release and uptake by the sarcoplasmic reticulum, and on the Ca2+ sensitivity of the contractile system. Ca2+-induced Ca2+ release was enhanced by S-bupivacaine 1 approximately 3 mM, but inhibited by R-bupivacaine 3 mM, remaining unaffected at lower doses. These enantiomers inhibited Ca2+ uptake to different degrees, with R-bupivacaine having a stronger effect. Ca2+ sensitivity of the contractile system was equally enhanced by R- and S-bupivacaine. These findings might help to explain the myoplasmic Ca2+ elevation induced by bupivacaine. The observed stereoselectivity suggests effects on specific proteins, the ryanodine Ry1 receptor and the Ca2+-ATPase pump, rather than non-specific increase in Ca2+ permeability.
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Affiliation(s)
- Carlos A Ibarra M
- First Department of Anesthesiology, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo 143-0015, Japan
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Burmester MD, Schlüter KD, Daut J, Hanley PJ. Enantioselective Actions of Bupivacaine and Ropivacaine on Coronary Vascular Resistance at Cardiotoxic Concentrations. Anesth Analg 2005; 100:707-712. [PMID: 15728056 DOI: 10.1213/01.ane.0000146511.79069.01] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The main concern with the use of the long-acting local anesthetics bupivacaine and ropivacaine is inadvertent IV injection, which exposes the heart to toxic drug concentrations. We tested the hypothesis that these chiral anesthetics exert enantioselective actions on coronary vascular tone, the regulation of which does not involve voltage-gated Na(+) channels. Coronary perfusion pressure (CPP) was continuously measured in isolated hearts perfused via the aorta at a constant flow rate. This method provides a sensitive assay of coronary vascular resistance in the intact heart. In parallel experiments, we examined the effects of bupivacaine and ropivacaine on intracellular [Ca(2+)] in coronary endothelial cells. In addition, the effect of bupivacaine on mitochondrial membrane potential was assessed using isolated ventricular myocytes. Racemic bupivacaine and R(+)-bupivacaine produced similar dose-dependent decreases in CPP. However, S(-)-bupivacaine, S(-)-ropivacaine and R(+)-ropivacaine increased CPP. In contrast to adenosine triphosphate, neither racemic bupivacaine nor S(-)-ropivacaine changed endothelial intracellular [Ca(2+)], suggesting that these clinically used drugs do not modulate endothelial nitric oxide synthase. We also showed that the putative uncoupler bupivacaine did not depolarize mitochondria in intact ventricular myocytes. In conclusion, the long-acting local anesthetics have enantioselective actions on coronary resistance vessels. Racemic bupivacaine and R(+)-bupivacaine are coronary vasodilators, whereas S(-)-bupivacaine, S(-)-ropivacaine and, to a lesser extent, R(+)-ropivacaine all induce coronary vasoconstriction.
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Affiliation(s)
- Marko D Burmester
- Institut für Normale und Pathologische Physiologie, Universität Marburg, Marburg, Germany; Department of Physiology, Physiologisches Institut, Justus-Liebig-Universität, Giessen, Germany
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Kawata T, Homma M, Kakiuchi Y, Inomata S, Miyabe M, Kobayashi D, Morimoto Y, Kohda Y. Liquid Chromatographic Determination of Plasma Ropivacaine for Assessing Pharmacokinetics of the Viscous Preparation. Biol Pharm Bull 2005; 28:2271-3. [PMID: 16327164 DOI: 10.1248/bpb.28.2271] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We developed assay method for determination of plasma ropivacaine by using reversed-phase high performance liquid chromatography (HPLC) equipped with ordinary octadecylsilyl silica-gel (ODS) column. Plasma samples spiked with internal standard (bupivacaine) were treated by ethylacetate to extract ropivacaine and internal standard. The ropivacaine and internal standard separated on ODS column were detected by an ultra violet (UV) detector set at 215 nm. The mobile phase solvent consisted of acetonitrile, methanol and 0.05 M phosphate buffer adjusted to pH 4.0 (10 : 30 : 60, v/v) was pumped at a flow rate of 0.8 ml/min. The calibration curve of ropivacaine was linear at the concentration of 25-1,000 ng/ml (r=0.9998). The recoveries of ropivacaine from plasma were greater than 87.9% with the coefficient of variations (CVs) less than 6.1%. The CVs for intra- and inter-day assay of ropivacaine were 2.0-12.0% and 1.7-14.8%, respectively. This HPLC method was applied to determining plasma ropivacaine in two healthy subjects after receiving 0.5% ropivacaine viscous preparation, which was prepared in our hospital. Our preliminary pharmacokinetic data showed that ropivacaine viscous could be used safely based on the plasma ropivacaine concentrations (C(max): 89-125 ng/ml) for pain relief in oral mucosa.
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Affiliation(s)
- Takeshi Kawata
- Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Ten-nodai, Ibaraki 305-0295, Japan
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Abstract
Efforts to develop new hypnotic compounds continue, although several have recently failed in development. Propofol has been reformulated in various presentations with and without preservatives. Pharmacokinetic and pharmacodynamic differences exist between some of these preparations, and it is currently unclear whether any have substantial advantages over the original presentation. The use of target-controlled infusion (TCI) has been extended to include paediatric anaesthesia and sedation. Application of TCI to remifentanil is now licensed. Linking of electroencephalogram (EEG) monitoring to TCI for closed-loop anaesthesia remains a research tool, although commercial development may follow. The availability of stereoisomer ketamine and improved understanding of its pharmacology have increased non-anaesthetic use of ketamine as an adjunct analgesic. It may be useful in subhypnotic doses for postsurgical patients with pain refractory to morphine administration.
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Affiliation(s)
- J R Sneyd
- Peninsula Medical School, Portland Square, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK.
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Nagels W, Demeyere R, Van Hemelrijck J, Vandenbussche E, Gijbels K, Vandermeersch E. Evaluation of the neuroprotective effects of S(+)-ketamine during open-heart surgery. Anesth Analg 2004; 98:1595-1603. [PMID: 15155311 DOI: 10.1213/01.ane.0000117227.00820.0c] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
UNLABELLED We compared the effect of S(+)-ketamine to remifentanil, both in combination with propofol, on the neurocognitive outcome after open-heart surgery in 106 patients. A battery of neurocognitive tests was administered before surgery and 1 and 10 wk after surgery. Fourteen patients (25%) in the control group and 10 patients (20%) in the S(+)-ketamine group had 2 or more tests with a cognitive deficit (decline by at least one preoperative SD of that test in all patients) 10 wk after surgery (P = 0.54). Z-scores were calculated for all tests. No significantly better performance could be detected in the S(+)-ketamine group, except for the Trailmaking B test 10 wk after surgery. We conclude that S(+)-ketamine offers no greater neuroprotection compared with remifentanil during open-heart surgery. IMPLICATIONS N-methyl-D-aspartic acid receptors play an important role during ischemic brain injury. We could not demonstrate that S(+)-ketamine resulted in greater neuroprotective effects compared with remifentanil during cardiopulmonary bypass procedures when both were combined with propofol.
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Affiliation(s)
- W Nagels
- Departments of *Anesthesiology, †Neuropsychology, and ‡Laboratory Medicine, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium
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Blatt DH, Pryor WA, Mata JE, Rodriguez-Proteau R. Re-evaluation of the relative potency of synthetic and natural α-tocopherol: experimental and clinical observations. J Nutr Biochem 2004; 15:380-95. [PMID: 15219923 DOI: 10.1016/j.jnutbio.2003.12.011] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2003] [Revised: 10/20/2003] [Accepted: 12/20/2003] [Indexed: 10/26/2022]
Abstract
Nutritionists generally consider all-rac-alpha-tocopherol and RRR-alpha-tocopherol equivalent in vitamin E activity but disagree whether equivalency requires a dosage ratio of 1.36:1 or 2:1. In contrast, we hypothesize that all-rac- and RRR-alpha-tocopherols are not equivalent in any dosage ratio. Previous observations that all-rac- and RRR-alpha-tocopherols are distributed and eliminated via saturable and stereospecific pathways imply that their relative bioavailability varies with the saturation of these pathways and therefore varies with dosage. Indeed, previous studies observed that the relative bioavailability of all-rac- and RRR-alpha-tocopherols varies between tissues as well as with dose, time after dosing, and duration of dosing. This non-constant relative bioavailability predicts non-constant relative activity (i.e., non-parallel dose-concentration curves predict non-parallel dose-effect curves). Non-constant relative bioavailability suggests that a fixed dosage ratio of all-rac- and RRR-alpha-tocopherols cannot produce a fixed ratio of effects on all processes in all tissues at all times after all dosages. However, previous studies suggest that all-rac- and RRR-alpha-tocopherols have equivalent effects (parallel dose-effect curves) in vitamin E-deficient animals and non-vitamin E-deficient humans. We re-evaluate the data from these animal studies and find non-parallel dose-effect and concentration-effect curves. We discuss pharmacokinetic and pharmacodynamic reasons why previous studies in non-vitamin E-deficient humans did not find non-parallel dose-effect curves for all-rac- and RRR-alpha-tocopherols. We note that saturable elimination predicts that all-rac- and RRR-alpha-tocopherols might inhibit and/or induce elimination of other compounds (including 30-40% of prescription drugs) eliminated via the same saturable pathways, and stereospecific elimination predicts that all-rac- and RRR-alpha-tocopherol have non-parallel dose-effect curves for these interactions.
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Affiliation(s)
- David H Blatt
- Biodynamics Institute, Louisiana State University, Baton Rouge, LA 70803, USA.
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Levobupivacaine Versus Ropivacaine for Sciatic Nerve Block in the Rat. Reg Anesth Pain Med 2003. [DOI: 10.1097/00115550-200307000-00008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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