Local Toxicity from Local Anesthetic Polymeric Microparticles

McAlvin, J. Brian; Reznor, Gally; Shankarappa, Sahadev A.; Ştefănescu, Cristina; Kohane, Daniel S.

doi:10.1213/ane.0b013e31828174a7

Cited by 54 publications

(52 citation statements)

References 48 publications

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“…Tissues were harvested and hematoxylin-eosin stained sections were prepared and scored for myotoxicity and inflammation 11,29 . TTX alone was associated with virtually no myotoxicity at any concentration (Figure 3A) (see Table 1 for results with the highest concentration of TTX).…”

Section: Resultsmentioning

confidence: 99%

Tetrodotoxin, Epinephrine, and Chemical Permeation Enhancer Combinations in Peripheral Nerve Blockade

Santamaria

Zhan

McAlvin

et al. 2017

Anesthesia &Amp; Analgesia

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Background Chemical permeation enhancers (CPEs) have the potential to improve nerve blockade by site 1 sodium channels blockers such as tetrodotoxin (TTX). Here we investigated the efficacy and toxicity of CPE-enhanced nerve blockade across a range of TTX concentrations, using two CPEs (sodium octyl sulfate and octyl trimethyl ammonium bromide). We also tested the hypotheses that CPEs could be used to reduce the concentrations of TTX and/or of a second adjuvant drug (in this case epinephrine) needed to achieve prolonged local anesthesia Methods Sprague-Dawley rats were injected at the sciatic nerve with combinations of TTX and CPEs, with and without epinephrine. Sensory and motor nerve blockade were assessed using a modified hot plate test and a weight-bearing test, respectively. Systemic and local toxicities of the different combinations were assessed. Results Addition of increasing concentrations of TTX to fixed concentrations of CPEs produced a marked concentration-dependent improvement in the rate of successful nerve blocks and in nerve block duration. CPEs did not affect systemic toxicity. At some concentrations, the addition of sodium octyl sulfate increased the duration of block from TTX plus epinephrine, and epinephrine increased that from TTX plus CPEs. The addition of epinephrine did not cause an increase in local toxicity, and markedly reduced systemic toxicity. Conclusions CPEs can prolong the duration of nerve blockade across a range of concentrations of TTX. CPEs could also be used to reduce the concentration of epinephrine needed to achieve a given degree of nerve block. CPEs may be useful in enhancing nerve blockade from site 1 sodium channel blockers.

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Section: Resultsmentioning

confidence: 99%

Tetrodotoxin, Epinephrine, and Chemical Permeation Enhancer Combinations in Peripheral Nerve Blockade

Santamaria

Zhan

McAlvin

et al. 2017

Anesthesia &Amp; Analgesia

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“…In most of the works, microparticles were produced by oil/water (O/W) 32,[34][35][36][37][38][39][40][41][42] or water/oil/water (W/O/W) emulsions 42,43 and solvent evaporation techniques. Usually, particles produced using those methods are solid and smooth microspheres, with a prolonged drug release lasting from 12 hours to 3-4 days.…”

Section: Microstructured Systemsmentioning

confidence: 99%

From micro- to nanostructured implantable device for local anesthetic delivery

Zorzetto

Brambilla

Marcello

et al. 2016

IJN

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Local anesthetics block the transmission of painful stimuli to the brain by acting on ion channels of nociceptor fibers, and find application in the management of acute and chronic pain. Despite the key role they play in modern medicine, their cardio and neurotoxicity (together with their short half-life) stress the need for developing implantable devices for tailored local drug release, with the aim of counterbalancing their side effects and prolonging their pharmacological activity. This review discusses the evolution of the physical forms of local anesthetic delivery systems during the past decades. Depending on the use of different biocompatible materials (degradable polyesters, thermosensitive hydrogels, and liposomes and hydrogels from natural polymers) and manufacturing processes, these systems can be classified as films or micro- or nanostructured devices. We analyze and summarize the production techniques according to this classification, focusing on their relative advantages and disadvantages. The most relevant trend reported in this work highlights the effort of moving from microstructured to nanostructured systems, with the aim of reaching a scale comparable to the biological environment. Improved intracellular penetration compared to microstructured systems, indeed, provides specific drug absorption into the targeted tissue and can lead to an enhancement of its bioavailability and retention time. Nanostructured systems are realized by the modification of existing manufacturing processes (interfacial deposition and nanoprecipitation for degradable polyester particles and high- or low-temperature homogenization for liposomes) or development of novel strategies (electrospun matrices and nanogels). The high surface-to-volume ratio that characterizes nanostructured devices often leads to a burst drug release. This drawback needs to be addressed to fully exploit the advantage of the interaction between the target tissues and the drug: possible strategies could involve specific binding between the drug and the material chosen for the device, and a multiscale approach to reach a tailored, prolonged drug release

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“…McAlvin et al reported inflammation with nerve and tissue injury following the injection of lidocaine-and bupivacaine-loaded microspheres into rats for sciatic nerve blockade [39]. In addition to local toxicity, there are safety concerns following inevitable systemic distribution.…”

Section: Painmentioning

confidence: 99%

Controlled release drug delivery systems to improve post-operative pharmacotherapy

Bhusal

Harrison

Sharma

et al. 2016

Drug Deliv. and Transl. Res.

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Over 230 million surgical procedures are conducted worldwide each year with numbers increasing. Pain, undesirable inflammation and infection are common complications experienced by patients following surgery. Opioids, non-steroidal anti-inflammatory drugs (NSAIDs), local anaesthetics (LAs) and antibiotics are the commonly administered drugs peri-operatively to manage these complications. Post-operative pharmacotherapy is typically achieved using immediate-release dosage forms of drugs, which lead to issues around fluctuating plasma concentrations, systemic adverse effects and poor patient adherence. Controlled release (CR) systems for certain medicines including opioids, NSAIDs and antibiotics have demonstrably enhanced treatment efficacy in the post-surgical setting. However, challenges remain to ensure patient safety while achieving individual therapeutic needs. Newer CR systems in the research and development pipeline have a high level of control over medicine release, which can be initiated, tuned or stopped on-demand. Future systems will self-regulate drug release in response to biological markers providing precise individualized therapy. In this review, we cover currently adopted CR systems in post-operative pharmacotherapy, including drug eluting medical devices, and highlight a series of examples of novel CR technologies that have the potential for translation into post-surgical settings to improve medication efficacy and enhance post-surgical recovery.

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Local Toxicity from Local Anesthetic Polymeric Microparticles

Cited by 54 publications

References 48 publications

Tetrodotoxin, Epinephrine, and Chemical Permeation Enhancer Combinations in Peripheral Nerve Blockade

Tetrodotoxin, Epinephrine, and Chemical Permeation Enhancer Combinations in Peripheral Nerve Blockade

From micro- to nanostructured implantable device for local anesthetic delivery

Controlled release drug delivery systems to improve post-operative pharmacotherapy

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