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      Continuous wound infusion with chloroprocaine in a pig model of surgical lesion: drug absorption and effects on inflammatory response

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          Abstract

          Continuous wound infusion (CWI) may protect from inflammation, hyperalgesia and persistent pain. Current local anesthetics display suboptimal pharmacokinetic profile during CWI; chloroprocaine (CP) has ideal characteristics, but has never been tested for CWI. We performed an animal study to investigate the pharmacokinetic profile and anti-inflammatory effect of CP during CWI. A total of 14 piglets received an infusion catheter after pararectal laparotomy and were randomly allocated to one of three groups: 5 mL/h infusion of saline (group A), CP 1.5% (group B) and CP 0.5% (group C). Blood sampling was performed to assess absorption and systemic inflammation at 0, 3, 6, 12, 24, 48, 72, 96, 102 and 108 hours. The wound and contralateral healthy abdominal wall were sampled for histological analyses. Absorption of CP from the site of infusion, evaluated as the plasmatic concentrations of CP and its metabolite, 4-amino-2-chlorobenzoic acid (CABA), showed a peak during the first 6 hours, but both CP and its metabolite rapidly disappeared after stopping CP infusion. Local inflammation was reduced in groups B and C (CP-treated p < 0.001), in a CP dose-dependent fashion. While CP inhibited in a dose-dependent manner pig mononuclear cells (MNCs) in vitro proliferation to a polyclonal activator, no effect on systemic cytokines’ concentrations or on ex vivo monocytes’ responsiveness was observed, suggesting the lack of systemic effects, in line with the very short half-life of CP in plasma. CP showed a very good profile for use in CWI, with dose-dependent local anti-inflammatory effects, limited absorption and rapid clearance from the bloodstream upon discontinuation. No cytotoxicity or side effects were observed. CP, therefore, may represent an optimal choice for clinical CWI, adaptable to each patient’s need, and protective on wound inflammatory response (and hyperalgesia) after surgery.

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          Most cited references 27

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          Anti-inflammatory properties of local anesthetics and their present and potential clinical implications.

          Development of new local anesthetic agents has been focused on the potency of their nerve-blocking effects, duration of action and safety and has resulted in a substantial number of agents in clinical use. It is well established and well documented that the nerve blocking effects of local anesthetics are secondary to their interaction with the Na+ channels thereby blocking nerve membrane excitability and the generation of action potentials. Accumulating data suggest however that local anesthetics also possess a wide range of anti-inflammatory actions through their effects on cells of the immune system, as well as on other cells, e.g. microorganisms, thrombocytes and erythrocytes. The potent anti-inflammatory properties of local anesthetics, superior in several aspects to traditional anti-inflammatory agents of the NSAID and steroid groups and with fewer side-effects, has prompted clinicians to introduce them in the treatment of various inflammation-related conditions and diseases. They have proved successful in the treatment of burn injuries, interstitial cystitis, ulcerative proctitis, arthritis and herpes simplex infections. The detailed mechanisms of action are not fully understood but seem to involve a reversible interaction with membrane proteins and lipids thus regulating cell metabolic activity, migration, exocytosis and phagocytosis.
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            Systematic review and meta-analysis of continuous local anaesthetic wound infiltration versus epidural analgesia for postoperative pain following abdominal surgery.

            Local anaesthetic wound infiltration techniques reduce opiate requirements and pain scores. Wound catheters have been introduced to increase the duration of action of local anaesthetic by continuous infusion. The aim was to compare these infiltration techniques with the current standard of epidural analgesia.
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              COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites.

              Despite the diverse chemical structure of aspirin-like drugs, the antinociceptive effect of NSAIDs is mainly due to their common property of inhibiting cyclooxygenases involved in the formation of prostaglandins. Prostaglandins are potent hyperalgesic mediators which modulate multiple sites along the nociceptive pathway and enhance both transduction (peripheral sensitizing effect) and transmission (central sensitizing effect) of nociceptive information. Inhibition of the formation of prostaglandins at peripheral and central sites by NSAIDs thus leads to the normalisation of the increased pain threshold associated with inflammation. The contribution of peripheral and central mechanisms to the overall antinociceptive action of NSAIDs depends on several factors including the location of the targets of drug action, the site of drug delivery and the uptake and distribution to the site of action. The present work reviews the data on the regulation and location of cyclooxygenases at central and peripheral sites of the nociceptive pathway and focuses on the role of COX in the generation and maintenance of pain hypersensitivity. Experimental and clinical evidences are used to evaluate the significance of the peripheral and central antihyperalgesic effects of NSAIDs.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2017
                31 October 2017
                : 10
                : 2515-2524
                Affiliations
                [1 ]Department of Medicine and Surgery, University of Parma, Parma
                [2 ]SIMPAR Group (Study in Multidisciplinary PAin Research)
                [3 ]Department of Anaesthesia and ICU, ASST Papa Giovanni XXIII, Bergamo
                [4 ]Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo
                [5 ]Laboratory of Transplant Immunology/Cell Factory, IRCCS Foundation Policlinico San Matteo
                [6 ]Clinical epidemiology and Biometrics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia
                [7 ]Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan
                [8 ]I.B.I.M., C.N.R., Palermo
                [9 ]PhD School, University of Pavia
                [10 ]Department of Pediatric Surgery, Fondazione IRCCS Policlinico San Matteo, Pavia
                [11 ]Department of Pediatric Surgery, “V. Buzzi” Children’s Hospital, Milan
                [12 ]Department of Public Health, Experimental and Forensic Medicine, University of Pavia
                [13 ]Department of Surgical, Clinical, Paediatric and Diagnostic Science, University of Pavia
                [14 ]General Surgery 1, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
                Author notes
                Correspondence: Lorenzo Cobianchi, Department of Surgical, Clinical, Pediatric and Diagnostic Science, University of Pavia, and General Surgery 1, IRCCS Fondazione Policlinico San Matteo, P.LE Golgi 19, 27100 Pavia, Email l.cobianchi@ 123456smatteo.pv.it
                Article
                jpr-10-2515
                10.2147/JPR.S139856
                5673045
                29184436
                © 2017 Allegri et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. 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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                Original Research

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