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      The safety of liposome bupivacaine following various routes of administration in animals

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          This report presents results from four preclinical studies evaluating safety and pharmacokinetics (PKs) of liposome bupivacaine following intravascular (intravenous [IV], intra-arterial [IA]), epidural, and intrathecal administration in dogs.


          Intravascular administration was initially tested in a pilot study to determine maximum tolerated doses, and then in an expanded study of systemic adverse effects and PKs. An epidural study compared properties of liposome bupivacaine alone and in combination with lidocaine/epinephrine vs bupivacaine HCl. Another study assessed effects after intrathecal administration.


          In the initial intravascular studies, maximum doses at which no meaningful adverse events were observed with liposome bupivacaine were higher than for bupivacaine HCl (4.5 mg/kg IV vs 0.75 mg/kg IV, and 1.5 mg/kg IA vs 0.1 mg/kg IA, respectively). In the expanded intravascular study, there was no mortality or changes in pathology; adverse clinical signs included convulsions, lying on side, and decreased muscle tone (all were transient). In the epidural study, liposome bupivacaine was well tolerated at doses up to the highest dose tested (40 mg), with no evidence of spinal cord damage and with less motor blockade than bupivacaine HCl 15 mg. Intrathecal administration of liposome bupivacaine 40 mg was not associated with meaningful safety concerns and resulted in less motor blockade than bupivacaine HCl 15 mg. PK analyses showed that maximum plasma bupivacaine levels following administration of liposome bupivacaine (4.5 mg/kg IV and 40 mg epidural) were similar to maximum plasma bupivacaine levels following a threefold lower dose of bupivacaine HCl (1.5 mg/kg IV and 15 mg epidural).


          Liposome bupivacaine has a favorable safety profile compared with bupivacaine HCl when administered to dogs via intravascular, epidural, and intrathecal routes. This favorable safety profile is likely related to the liposome-bound nature of bupivacaine in the liposome bupivacaine formulation.

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          Most cited references 22

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          ASRA practice advisory on local anesthetic systemic toxicity.

          The American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity assimilates and summarizes current knowledge regarding the prevention, diagnosis, and treatment of this potentially fatal complication. It offers evidence-based and/or expert opinion-based recommendations for all physicians and advanced practitioners who routinely administer local anesthetics in potentially toxic doses. The advisory does not address issues related to local anesthetic-related neurotoxicity, allergy, or methemoglobinemia. Recommendations are based primarily on animal and human experimental trials, case series, and case reports. When objective evidence is lacking or incomplete, recommendations are supplemented by expert opinion from the Practice Advisory Panel plus input from other experts, medical specialty groups, and open forum. Specific recommendations are offered for the prevention, diagnosis, and treatment of local anesthetic systemic toxicity.
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            The role of the anesthesiologist in fast-track surgery: from multimodal analgesia to perioperative medical care.

            Improving perioperative efficiency and throughput has become increasingly important in the modern practice of anesthesiology. Fast-track surgery represents a multidisciplinary approach to improving perioperative efficiency by facilitating recovery after both minor (i.e., outpatient) and major (inpatient) surgery procedures. In this article we focus on the expanding role of the anesthesiologist in fast-track surgery. A multidisciplinary group of clinical investigators met at McGill University in the Fall of 2005 to discuss current anesthetic and surgical practices directed at improving the postoperative recovery process. A subgroup of the attendees at this conference was assigned the task of reviewing the peer-reviewed literature on this topic as it related to the role of the anesthesiologist as a perioperative physician. Anesthesiologists as perioperative physicians play a key role in fast-track surgery through their choice of preoperative medication, anesthetics and techniques, use of prophylactic drugs to minimize side effects (e.g., pain, nausea and vomiting, dizziness), as well as the administration of adjunctive drugs to maintain major organ system function during and after surgery. The decisions of the anesthesiologist as a key perioperative physician are of critical importance to the surgical care team in developing a successful fast-track surgery program.
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              Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

              To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                30 October 2015
                : 8
                : 781-789
                [1 ]Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical School, Dallas, TX, USA
                [2 ]Pacira Pharmaceuticals, Inc., Parsippany, NJ, USA
                Author notes
                Correspondence: Girish P Joshi, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-9068, USA, Tel +1 214 590 7259, Fax +1 214 590 6945, Email Girish.Joshi@ 123456UTSouthwestern.edu
                © 2015 Joshi et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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