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      The Safety of EXPAREL ® (Bupivacaine Liposome Injectable Suspension) Administered by Peripheral Nerve Block in Rabbits and Dogs

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          Abstract

          A sustained-release DepoFoam injection formulation of bupivacaine (EXPAREL, 15 mg/mL) is currently being investigated for postsurgical analgesia via peripheral nerve block (PNB). Single-dose toxicology studies of EXPAREL (9, 18, and 30 mg/kg), bupivacaine solution (Bsol, 9 mg/kg), and saline injected around the brachial plexus nerve bundle were performed in rabbits and dogs. The endpoints included clinical pathology, pharmacokinetics, and histopathology evaluation on Day 3 and Day 15 (2/sex/group/period). EXPAREL resulted in a nearly 4-fold lower C max versus Bsol at the same dose. EXPAREL was well tolerated at doses up to 30 mg/kg. The only EXPAREL-related effect seen was minimal to mild granulomatous inflammation of adipose tissue around nerve roots (8 of 24 rabbits and 7 of 24 dogs) in the brachial plexus sites. The results indicate that EXPAREL was well tolerated in these models and did not produce nerve damage after PNB in rabbits and dogs.

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          Perineural administration of dexmedetomidine in combination with bupivacaine enhances sensory and motor blockade in sciatic nerve block without inducing neurotoxicity in rat.

          Mary A Norat, M M Palmisano, John M Palmisano … (2008)
          The current study was designed to test the hypothesis that high-dose dexmedetomidine added to local anesthetic would increase the duration of sensory and motor blockade in a rat model of sciatic nerve blockade without causing nerve damage. Thirty-one adult Sprague-Dawley rats received bilateral sciatic nerve blocks with either 0.2 ml bupivacaine, 0.5%, and 0.5% bupivacaine plus 0.005% dexmedetomidine in the contralateral extremity, or 0.2 ml dexmedetomidine, 0.005%, and normal saline in the contralateral extremity. Sensory and motor function were assessed by a blinded investigator every 30 min until the return of normal sensory and motor function. Sciatic nerves were harvested at either 24 h or 14 days after injection and analyzed for perineural inflammation and nerve damage. High-dose dexmedetomidine added to bupivacaine significantly enhanced the duration of sensory and motor blockade. Dexmedetomidine alone did not cause significant motor or sensory block. All of the nerves analyzed had normal axons and myelin at 24 h and 14 days. Bupivacaine plus dexmedetomidine showed less perineural inflammation at 24 h than the bupivacaine group when compared with the saline control. The finding that high-dose dexmedetomidine can safely improve the duration of bupivacaine-induced antinociception after sciatic nerve blockade in rats is an essential first step encouraging future studies in humans. The dose of dexmedetomidine used in this study may exceed the sedative safety threshold in humans and could cause prolonged motor blockade; therefore, future work with clinically relevant doses is necessary.
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            Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers.

            S Blomberg, N Edvardsson, M E Beckman … (1997)
            We have compared the incidence of CNS symptoms and changes in echocardiography and electrophysiology during i.v. infusions of ropivacaine, bupivacaine and placebo. Acute tolerance of i.v. infusion of 10 mg min-1 was studied in a crossover, randomized, double-blind study in 12 volunteers previously acquainted with the CNS effects of lignocaine. The maximum tolerated dose for CNS symptoms was higher after ropivacaine in nine of 12 subjects and higher after bupivacaine in three subjects. The 95% confidence limits for the difference in mean dose between ropivacaine and bupivacaine were -30 and 7 mg. The maximum tolerated unbound arterial plasma concentration was twice as high after ropivacaine (P < 0.001). Muscular twitching occurred more frequently after bupivacaine (P < 0.05). The time to disappearance of all symptoms was shorter after ropivacaine (P < 0.05). A threshold for CNS toxicity was apparent at a mean free plasma concentration of approximately 0.6 mg litre-1 for ropivacaine and 0.3 mg litre-1 for bupivacaine. Bupivacaine increased QRS width during sinus rhythm compared with placebo (P < 0.001) and ropivacaine (P < 0.01). Bupivacaine reduced both left ventricular systolic and diastolic function compared with placebo (P < 0.05 and P < 0.01, respectively), while ropivacaine reduced only systolic function (P < 0.01).
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              Acute and nonacute complications associated with interscalene block and shoulder surgery: a prospective study.

              A Borgeat, G Ekatodramis, Christopher C. Benz … (2001)
              The incidence, etiology, and evolution of complications after interscalene brachial plexus block (ISB) are not well-known. The authors prospectively monitored 521 patients for complications during the first 9 months after ISB. A total of 521 adults scheduled for elective shoulder surgery performed with an ISB were included in this prospective study. The ISB procedure was standardized for all patients Acute complications were recorded. Patients were observed daily (for 10 days) for paresthesias, dysesthesias, pain not related to surgery, and muscular weakness and were evaluated at 1, 3, 6, and 9 months after surgery. Persistence of paresthesias dysesthesias, pain not related to surgery, or muscular weakness was investigated at 1 or 3 months by means of electroneuromyography. Final evaluation was performed at 9 months. A total of 520 patients completed the study; one was excluded after surgical axillary nerve damage. Two hundred thirty-four patients had an interscalene catheter. Acute complications consisted of one pneumothorax (0.2%) and one episode of central nervous system toxicity (incoherent speech; 0.2%). A 10 days, 74 patients (14%) were symptomatic, and none had muscular weakness. At 1 month, 41 patients (7.9%) had symptoms, and none had muscular weakness. Thirty patients under went electroneuromyography; sulcus ulnaris syndrome (n = 8) carpal tunnel syndrome (n = 2), and complex regional pain syndrome (n = 1) were diagnosed. At 3 months 20 patient (3.9%) were symptomatic, and none had muscular weakness All underwent electroneuromyography; carpal tunnel syndrome (n = 2), complex regional pain syndrome (n = 4), plexus neuropathy (n = 1), and plexus damage (n = 1) were diagnosed. At 6 months, 5 patients (0.9%) were symptomatic. At 9 months 1 patient (0.2%) had persistence of dysesthesia. Interscalene brachial plexus block performed with a standardized technical approach, material, and drugs is associated with an incidence of short- and severe long-term complications of 0.4%. In case of persistent paresthesia, dysesthesia, or pain not related to surgery after ISB, sulcus ulnaris syndrome, carpal tunnel syndrome, or complex regional pain syndrome should be excluded since specific treatment may be required.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Drug Deliv
                Journal ID (publisher-id): JDD
                Title: Journal of Drug Delivery
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2090-3014
                ISSN (Electronic): 2090-3022
                Publication date (Print): 2012
                Publication date (Electronic): 17 January 2012
                Volume: 2012
                Electronic Location Identifier: 962101
                Affiliations
                1Clinical Research and Drug Safety Assessment, Pacira Pharmaceuticals, Inc., 10450 Science Center Drive, San Diego, CA 92121, USA
                2MPI Research Laboratories, North Main Street, Mattawan, MI 49071, USA
                Author notes
                *Brigitte M. Richard: brigitter@ 123456pacira.com

                Academic Editor: Guru V. Betageri

                Article
                DOI: 10.1155/2012/962101
                PMC ID: 3270427
                PubMed ID: 22363842
                SO-VID: c190151f-c82b-4c63-b78d-0d2a2e0978c6
                Copyright © Copyright © 2012 Brigitte M. Richard et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 20 July 2011
                Date accepted : 4 October 2011
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Pharmaceutical chemistry
                Data availability:
                ScienceOpen disciplines: Pharmaceutical chemistry

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