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      Pharmacokinetic Compatibility Study of Lidocaine with EXPAREL in Yucatan Miniature Pigs

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          Abstract

          We explored the potential for EXPAREL to interact with lidocaine. Sixty (60) male Yucatan Swine were randomized into 20 groups ( N = 3/group). EXPAREL (2 or 4 mg/kg) and/or lidocaine HCl solution 1% or 2% (with epinephrine 1 : 200,000) were injected subcutaneously along a 5 cm virtual incision line. The effects on the pharmacokinetics of bupivacaine and lidocaine were examined when 5, 10, 20, and 40 minutes had passed between administration of lidocaine and EXPAREL. Systemic exposure to lidocaine was increased (AUC 0−24 hr by 48%; C max by 1,640%) when lidocaine (4 mg/kg) was followed 5 minutes later by EXPAREL (4 mg/kg) compared to lidocaine administered alone. Plasma bupivacaine was increased (AUC 0−24 hr by 50–95%; C max by 67–1,000%) when lidocaine (4 mg/kg) was followed 5 or 10 minutes later by EXPAREL (4 mg/kg) compared to EXPAREL alone. While EXPAREL should not be admixed with lidocaine, this study shows that local administration of EXPAREL after at least 20 minutes following local administration of lidocaine did not increase the release of either drug.

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          Most cited references 19

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          The pig as a model for human wound healing.

          The medical literature describes numerous in vitro and in vivo wound-healing models. The selection of an animal model depends on a number of factors including availability, cost, ease of handling, investigator familiarity, and anatomical/functional similarity to humans. Small mammals are frequently used for wound healing studies, however, these mammals differ from humans in a number of anatomical and physiological ways. Anatomically and physiologically, pig skin is more similar to human skin. The many similarities between man and pig would lead one to believe that the pig should make an excellent animal model for human wound healing. The purpose of this paper is to review the existing literature for evidence of this supposition and determine how well the various models correlate to human wound healing. Studies of wound dressings, topical antimicrobials, and growth factors are examined. Over 180 articles were utilized for this comparative review. Our conclusion is that the porcine model is an excellent tool for the evaluation of therapeutic agents destined for use in human wounds.
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            A comparison of the pharmacodynamics and pharmacokinetics of bupivacaine, ropivacaine (with epinephrine) and their equal volume mixtures with lidocaine used for femoral and sciatic nerve blocks: a double-blind randomized study.

            Mixtures of lidocaine with a long-acting local anesthetic are commonly used for peripheral nerve block. Few data are available regarding the safety, efficacy, or pharmacokinetics of mixtures of local anesthetics. In the current study, we compared the effects of bupivacaine 0.5% or ropivacaine 0.75% alone or in a mixed solution of equal volumes of bupivacaine 0.5% and lidocaine 2% or ropivacaine 0.75% and lidocaine 2% for surgery after femoral-sciatic peripheral nerve block. The primary end point was onset time. In a double-blind, randomized study, 82 adults scheduled for lower limb surgery received a sciatic (20 mL) and femoral (20 mL) peripheral nerve block with 0.5% bupivacaine (200 mg), a mixture of 0.5% bupivacaine 20 mL (100 mg) with 2% lidocaine (400 mg), 0.75% ropivacaine (300 mg) or a mixture of 0.75% ropivacaine 20 mL (150 mg) with 2% lidocaine (400 mg). Each solution contained epinephrine 1:200,000. Times to perform blocks, onset times (end of injection to complete sensory and motor block), duration of sensory and motor block, and morphine consumption via IV patient-controlled analgesia were compared. Venous blood samples of 5 mL were collected for determination of drug concentration at 0, 5, 15, 30, 45, 60, and 90 min after placement of the block. Patient demographics and surgical times were similar for all four groups. Sciatic onset times (sensory and motor block) were reduced by combining lidocaine with the long-acting local anesthetic. The onset of bupivacaine-lidocaine was 16 +/- 9 min versus 28 +/- 12 min for bupivacaine alone. The onset of ropivacaine-lidocaine was 16 +/- 12 min versus 23 +/- 12 for ropivacaine alone. Sensory blocks were complete for all patients within 40 min for those receiving bupivacaine-lidocaine versus 60 min for those receiving bupivacaine alone and 30 min for those receiving ropivacaine-lidocaine versus 40 min for those receiving ropivacaine alone (P < 0.05). Duration of sensory and motor block was significantly shorter in mixture groups. There was no difference among groups for visual analog scale pain scores and morphine consumption during the 48 h postoperative period, except for bupivacaine alone (median: 9 mg) versus bupivacaine-lidocaine mixture (15 mg), P < 0.01. There was no difference in the incidence of adverse events among groups. Plasma concentrations of bupivacaine and ropivacaine were higher, and remained elevated longer, in patients who received only the long-acting local anesthetic compared to patients who received the mixture of long-acting local anesthetic with lidocaine (P < 0.01). Mixtures of long-acting local anesthetics with lidocaine induced faster onset blocks of decreased duration. Whether there is a safety benefit is unclear, as the benefit of a decreased concentration of long-acting local anesthetic may be offset by the presence of a significant plasma concentration of lidocaine.
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              Pharmacology of drugs formulated with DepoFoam: a sustained release drug delivery system for parenteral administration using multivesicular liposome technology.

              Lamellar liposome technology has been used for several decades to produce sustained-release drug formulations for parenteral administration. Multivesicular liposomes are structurally distinct from lamellar liposomes and consist of an aggregation of hundreds of water-filled polyhedral compartments separated by bi-layered lipid septa. The unique architecture of multivesicular liposomes allows encapsulating drug with greater efficiency, provides robust structural stability and ensures reliable, steady and prolonged drug release. The favourable characteristics of multivesicular liposomes have resulted in many drug formulations exploiting this technology, which is proprietary and referred to as DepoFoam. Currently, two formulations using multivesicular liposome technology are approved by the US FDA for clinical use, and many more formulations are at an experimental developmental stage. The first clinically available formulation contains the antineoplastic agent cytarabine (DepoCyt) for its intrathecal injection in the treatment of malignant lymphomatous meningitis. Intrathecal injection of DepoCyt reliably results in the sustained release of cytarabine and produces cytotoxic concentrations in cerebrospinal fluid (CSF) that are maintained for at least 2 weeks. Early efficacy data suggest that DepoCyt is fairly well tolerated, and its use allows reduced dosing frequency from twice a week to once every other week and may improve the outcome compared with frequent intrathecal injections of unencapsulated cytarabine. The second available formulation contains morphine (DepoDur) for its single epidural injection in the treatment of postoperative pain. While animal studies confirm that epidural injection of DepoDur results in the sustained release of morphine into CSF, the CSF pharmacokinetics have not been determined in humans. Clinical studies suggest that the use of DepoDur decreases the amount of systemically administered analgesics needed for adequate postoperative pain control. It may also provide superior pain control during the first 1-2 postoperative days compared with epidural administration of unencapsulated morphine or intravenous administration of an opioid. However, at this timepoint the overall clinical utility of DepoDur has yet to be defined and some safety concerns remain because of the unknown CSF pharmacokinetics of DepoDur in humans. The versatility of multivesicular liposome technology is reflected by the many agents including small inorganic and organic molecules and macromolecules including proteins that have successfully been encapsulated. Data concerning many experimental formulations containing antineoplastic, antibacterial and antiviral agents underscore the sustained, steady and reliable release of these compounds from multivesicular liposomes after injection by the intrathecal, subcutaneous, intramuscular, intraperitoneal and intraocular routes. Contingent on the specific formulation and manufacturing process, agents were released over a period of hours to weeks as reflected by a 2- to 400-fold increase in elimination half life. Published data further suggest that the encapsulation process preserves bioactivity of agents as delicate as proteins and supports the view that examined multivesicular liposomes were non-toxic at studied doses. The task ahead will be to examine whether the beneficial structural and pharmacokinetic properties of multivesicular liposome formulations will translate into improved clinical outcomes, either because of decreased drug toxicity or increased drug efficacy.
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                Author and article information

                Journal
                ISRN Pharm
                PHARMACEUTICS
                ISRN Pharmaceutics
                International Scholarly Research Network
                2090-6145
                2090-6153
                2011
                27 December 2011
                : 2011
                Affiliations
                1Clinical Research & Drug Safety Assessment, Pacira Pharmaceuticals Inc., San Diego, CA 92121, USA
                2Raleigh, NC 27613, USA
                3ABC Laboratories, Columbia, MO 65201, USA
                4Sinclair Research Center, LLC, Auxvasse, MO 65231, USA
                Author notes
                *Brigitte M. Richard: brigitter@ 123456pacira.com

                Academic Editors: G. M. El Maghraby, J. K. Lalla, M. Moneghini, A. I. Segall, A. Shahiwala, and J. Torrado

                Article
                10.5402/2011/582351
                3263713
                22389853
                Copyright © 2011 Brigitte M. Richard et al.

                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.

                Categories
                Research Article

                Pharmacology & Pharmaceutical medicine

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