ABSTRACT
In this study, we not only optimized and improved the synthesis process of levobupivacaine hydrochloride (21) but also conducted a comprehensive exploration of critical industrial-scale production details, and a novel high-performance liquid chromatography (HPLC) analysis method was developed. Starting with the readily available and cost-effective (R,S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (28) as the initial material and utilizing l-(-)-dibenzoyl tartaric acid (29) for chiral separation, and then through substitution and a salting reaction, levobupivacaine hydrochloride (21) was obtained with high purity (chemical purity of 99.90% and enantiomeric excess (ee) values of 99.30%). The total yield of the three steps was 45%. Structures of intermediates and the final product were confirmed using nuclear magnetic resonance (NMR) (1H NMR, 13C NMR), mass spectrometry (MS), and elemental analysis. The crystal structure of the final product was determined through differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray diffraction (XRD). Furthermore, we evaluated the risk of the substitution reaction using a reaction calorimeter and accelerating rate calorimetry (ARC). This process offers the advantages of simple operation, greenness, safety, controllable quality, and cost-effectiveness. It provides reliable technical support for the industrial-scale production of levobupivacaine hydrochloride (21), which is of significant importance in meeting clinical demands. Pilot-scale production has already been successfully completed by China National Medicines Guorui Pharmaceutical Co., Ltd., with a production scale of 20 kg.
ABSTRACT
BACKGROUND AND AIMS: The use of regional anesthesia for laparoscopic cholecystectomy has been reserved for patients who are at high-risk under general anesthesia (GA). The aim of this study was to assess whether thoracic combined spinal epidural (CSE) anesthesia is a feasible option for American Society of Anesthesiologists (ASA) physical status I and II patients undergoing elective laparoscopic cholecystectomy. MATERIAL AND METHODS: Thirty ASA physical status I and II patients undergoing elective laparoscopic cholecystectomy received thoracic CSE anesthesia at T9-T10 or T10-T11 interspinous space using the midline approach. Two ml of isobaric levobupivacaine 0.5% with 25 µg of fentanyl was given intrathecally. RESULTS: Surgery was conducted successfully in all except one patient. Thoracic CSE was performed at T9-T10 interspace in 25 patients and T10-T11 interspace in five patients. Paresthesia occurred in two patients (6.6%) transiently on Whitacre needle insertion that disappeared spontaneously. Dural puncture on epidural needle insertion occurred in one patient, and intrathecal placement of epidural catheter occurred in one. Ten patients (33%) complained of shoulder pain. Conversion to GA was done in one patient due to severe shoulder pain and anxiety. Hypotension occurred in 11 patients (36%) and all responded to single dose of mephenteramine 6 mg and fluid bolus. Bradycardia occurred in six patients (20%) which was managed in all with a single dose of atropine. CONCLUSION: Thoracic CSE anesthesia can be used effectively for ASA I and II patients undergoing laparoscopic cholecystectomy with significant postoperative benefits.
ABSTRACT
Local anesthetics, which are widely known to be neuronal voltage-gated Na(+) channel blockers, also affect a variety of other ion channels, N-methyl-d-asparate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-izoxazolepropionic acid (AMPA) receptors. Glutamate, which is released from presynaptic fibers, activates extracellular signal-regulated kinase (ERK) through NMDA and AMPA receptors in spinal dorsal horn neurons. ERK plays a key role in central sensitization, which contributes to the chronicity of pain. We investigated the effects of four representative local anesthetics, lidocaine, tetracaine, levobupivacaine, and ropivacaine on ERK phosphorylation induced by capsaicin, which releases glutamate from presynaptic neurons, NMDA, AMPA, or ionomycin, a calcium ionophore, in dorsal neurons. We observed capsaicin-induced phosphorylation of ERK, which was suppressed by lidocaine, tetracaine, or ropivacaine, but not by levobupivacaine. NMDA-induced phosphorylation of ERK was suppressed by lidocaine, tetracaine, or levobupivacaine, but not by ropivacaine. AMPA-induced phosphorylation of ERK was suppressed by lidocaine or tetracaine, but not by levobupivacaine or ropivacaine. Finally, ionomycin-induced ERK phosphorylation was suppressed by lidocaine, tetracaine, or ropivacaine, but not by levobupivacaine. Our results suggest that local anesthetics contribute to the prevention of the incidence of persistent postsurgical pain with varying intensities and through different mechanisms of action.