Local Anesthetics in Lipid-Depot Formulations—Neurotoxicity in Relation to Duration of Effect in a Rat Model

Dyhre, Henrik; Söderberg, Lars; Björkman, Sven; Carlsson, Christer

doi:10.1016/j.rapm.2006.05.008

Cited by 22 publications

(21 citation statements)

References 36 publications

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“…In a similar study in rats, formulations containing 2%, 4%, 8%, 16%, 32%, or 64% of a mixture of bupivacaine and lidocaine base 4 : 1 in medium-chain triglyceride were evaluated, together with 0.5%, 1.0%, and 2.0% bupivacaine HCl solutions, bupivacaine 4.2% or 7.0% in medium-chain triglyceride, and 20% lidocaine base in a polar lipid vehicle [30]. Histopathologic examination of sciatic nerves by light microscopy revealed slight to moderate signs of neurotoxicity only after administration of the 64% formulation, a week after dosing.…”

Section: Discussionmentioning

confidence: 99%

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

Richard

Newton

Ott

et al. 2012

Journal of Drug Delivery

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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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Section: Discussionmentioning

confidence: 99%

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

Richard

Newton

Ott

et al. 2012

Journal of Drug Delivery

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“…The assessment of motor blockade used was limited to a subjective assessment of the intrinsic paw musculature based on paw positioning and toe curling. Whereas a similar subjective measure has been previously described,12,24,25 it does not provide objective data concerning motor blockade. The paw thrust measures that have been used in similar studies21-23 are dependent upon the positioning and level of consciousness of the rat and are also subject to variability.…”

Section: Discussionmentioning

confidence: 99%

“…All rats were monitored for at least 210 min. In addition, the motor function of the surgical hind paw was assessed every 30 min by observation as either a curled paw (motor score = 1, indicates motor blockade) or normal paw position (motor score = 0, no motor blockade) 12,24,25. Once the rat had returned to baseline sensory and motor function, it was returned to its home cage.…”

Section: Methodsmentioning

confidence: 99%

Perineural Dexmedetomidine Added to Ropivacaine Causes a Dose-dependent Increase in the Duration of Thermal Antinociception in Sciatic Nerve Block in Rat

Brummett

Padda²,

Amodeo³

et al. 2009

Anesthesiology

172

143

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Background The present study was designed to test the hypothesis that dexmedetomidine added to ropivacaine would increase the duration of antinociception to a thermal stimulus in a dose-dependent fashion in a rat model of sciatic nerve blockade. Methods Fifty adult Sprague Dawley rats (10 rats/group) received unilateral sciatic nerve blocks with 0.2 ml of 0.5% ropivacaine or 0.2 ml of 0.5% ropivacaine plus dexmedetomidine (2.7 μM [0.5 μg/kg], 11.7 μM [2 μg/kg], 34.1 μM [6 μg/kg], or 120.6 μM [20 μg/kg]) in a randomized, blinded fashion. Time to paw withdrawal latency to a thermal stimulus for both paws and an assessment of motor function were measured every 30 min after the nerve block until a return to baseline. Results Dexmedetomidine added to ropivacaine increased the duration of dense sensory blockade and time for return to normal sensory function in a dose-dependent fashion (p < 0.005). There was a significant time (p < 0.005), dose (p < 0.005), and time by dose effect (p < 0.005) on paw withdrawal latencies of the operative paws. There were no significant differences in paw withdrawal latencies of the control paws, indicating little systemic effect of the dexmedetomidine. The duration of motor blockade was also increased with dexmedetomidine. High-dose dexmedetomidine (120.6 μM) was not neurotoxic. Conclusion This is the first study showing that dexmedetomidine added to ropivacaine increases the duration of sensory blockade in a dose-dependent fashion in rat. The findings are an essential first step encouraging future efficacy studies in humans.

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“…Motor function was quantified as 0 = normal motor function, 1 = normal dorsiflexion ability and the mouse walking with curled toes, 2 = moderate dorsiflexion ability and the mouse walking with curled toes, and 3 = no dorsiflexion ability and the mouse walking with curled toes. 7,18,19 Histological Evaluation…”

Section: Behavioral Testingmentioning

confidence: 99%

A New Step Toward Evidence of In Vivo Perineural Dexamethasone Safety

Marty¹,

Bennis

Legaillard

et al. 2017

Regional Anesthesia and Pain Medicine

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Local Anesthetics in Lipid-Depot Formulations—Neurotoxicity in Relation to Duration of Effect in a Rat Model

Cited by 22 publications

References 36 publications

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

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

Perineural Dexmedetomidine Added to Ropivacaine Causes a Dose-dependent Increase in the Duration of Thermal Antinociception in Sciatic Nerve Block in Rat

A New Step Toward Evidence of In Vivo Perineural Dexamethasone Safety

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