Anesthetic activity of the lipospheres bupivacaine delivery system in the rat (original) (raw)
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Prolongation of Nerve and Epidural Anesthetic Blockade by Bupivacaine in a Lipid Emulsion
Anesthesia & Analgesia, 1999
We assessed the effect of a lipid emulsion of bupivacaine on prolonging peripheral nerve and epidural anesthetic blockade in the rat. The intensity and duration of motor and sensory blockade produced by a single injection of aqueous solution (BPV-as) and lipid emulsion (BPV-em) preparations of 0.5% bupivacaine were evaluated by electrophysiological methods. Both preparations induced complete, reversible motor and sensory blockade after injection. The latency time to the maximal blockade and the duration of anesthetic blockade were more prolonged for BPV-em than for BPV-as. The increase in duration of maximal blockade was 1.4 times for nerve and 1.3 times for epidural anesthesia. Histological evaluation of spinal roots and spinal cord sections did not show any abnormalities or differences between animals injected with BPV-as and those injected with BPV-em. Pharmacokinetic studies showed lower plasma peak concentration and a longer elimination half-life for BPV-em than for BPV-as. Thus, BPV-em prolongs the effects of local anesthetics, allows a similar degree of blockade, and reduces the systems toxic effects of anesthetics compared with BPV-as. Implications: We assessed a lipid emulsion containing bupivacaine for peripheral nerve and epidural anesthetic blockade in the rat. The emulsion allowed a complete blockade, while increasing the duration of the anesthetic effect (by 30%-40%), compared with the standard bupivacaine aqueous solution.
A dose–response study of epidural liposomal bupivacaine in rabbits
Journal of Controlled Release, 1999
Liposomes are drug delivery systems used to prolong local effects of bupivacaine. We studied the relationships between motor and hemodynamic changes and epidural doses of plain bupivacaine (P) and liposomal bupivacaine (L) in rabbits equipped with chronical lumbar epidural and femoral arterial catheters. Liposomal (phosphatidylcholine-cholesterol) 21 suspensions contained 20 mg ml of lipid, and different doses of bupivacaine (Lipo 7.557.5-; Lipo 3.753.75-; Lipo 2.552.5-; Lipo 1.251.25-; and Lipo 0.750.65-mg of bupivacaine per ml). Forty rabbits were randomly assigned to five groups to receive epidural anesthesia (1 ml) as follows: Groups I to V received 0.65 to 7.5 mg of bupivacaine as P then as L. Release rate of bupivacaine from liposome was significantly slower using Lipo 3.7 than after Lipo 2.5 (T was 3.9 h and 1.7 d h respectively). Increasing the doses of L and P resulted in faster onset time for complete motor blockade and in a prolonged duration of motor effects. Liposomal formulation appears to be a powerful delivery system to prolong the motor effects of bupivacaine since E was lower and E higher than after the use of plain solution (E 4.4961.81 mg and E 152640 50 max 50 max min for P; and E 2.6160.23 mg and E 20269 min for L). Hemodynamic changes were linearly related to doses of 50 max bupivacaine injected. The best bupivacaine-to-lipid ratio to prolong motor effects using our model was 3.75 mg and 20.0 mg respectively (Lipo 3.7).
An in vivo method for the quantitative evaluation of local anesthetics
Journal of Pharmacological and Toxicological Methods, 2000
We describe a mouse model for evaluation of skin anesthesia after infiltration of local anesthetic. The method involves subcutaneous injection of the anesthetic over the abdomen, and monitoring the vocalization response to electrical stimulus as a measure of analgesia. Prior to drug injection, the vocalization threshold was determined. Mice that vocalized at 8 mA were included in the study. The model was tested using representative agents of the two classes of local anesthetics, bupivacaine, an amide, and chloroprocaine, an ester. The time course and dose response were assessed after injection. The median analgesic time was 15, 40, and 55 min for 0.015%, 0.0625%, and 0.25% bupivacaine and 30, 50, and 55 min for 0.125%, 0.25%, and 2.0% chloroprocaine, respectively. Statistical analysis of the data showed that this method is sufficiently sensitive to detect differences between the dose and duration of local anesthesia ( p < 0.05, by log rank test of the survival curves). To further validate the model, we compared the duration of anesthesia between the 0.5% bupivacaine and a new long -acting liposomal formulation of 2% bupivacaine. The results showed that the new formulation significantly prolonged the duration of anesthesia ( p < 0.05). This simple and reliable method may facilitate research on the pharmacology of infiltration anesthesia and the development of new local anesthetics and / or formulations. D
TURKISH JOURNAL OF MEDICAL SCIENCES, 2019
2.1. Preparation of liposome formulations Structurally multilamellar liposomes were prepared from dipalmitoyl phosphatidyl choline (DPPC)-cholesterol in 50% ratio using the dry-film hydration by vortex mixer Background/aim: Based on our previous in vitro study with multilamellar liposomal bupivacaine (MLB) versus bupivacaine alone in artificial cerebrospinal fluid, we aimed to investigate in vivo antinociceptive effect of intrathecal MLB by determining tail flick latency (TFL) time after thermal stimulation in rats. Materials and methods: After preparing MLB and high-yield drug entrapment in liposome (HYDEL) bupivacaine, 18 female Wistar rats were assigned to 3 groups as control (bupivacaine) and study groups (MLB and HYDEL bupivacaine) including 6 rats in each group to administer these drugs intrathecally. Antinociceptive activity was determined in terms of TFL time after thermal stimulation. Maximum possible effect (MPE) calculated from TFL times and rats with motor block were documented. Results: TFL times after intrathecal injection of HYDEL bupivacaine were significantly longer than that of the control and MLB groups (P < 0.05) and returned to baseline 180 min after intrathecal injection. MPE (100%) with intrathecal HYDEL bupivacaine occurred between 10 to 45 min. Afterwards, MPEs were 70% and 50% for the control and MLB groups, respectively. Motor block disappeared after 20 min in the study groups while it lasted 75 min in the control. Conclusion: Intrathecal administration of MLB and HYDEL bupivacaine in rats resulted in longer duration of antinociceptive activity with shorter motor block duration.
British Journal of Anaesthesia, 2018
Background: An injectable liposomal bupivacaine suspension (EXPAREL™) is approved by the US Food and Drug Administration for analgesia by tissue infiltration and interscalene brachial plexus, but not for use in the neuraxial space. This pilot study describes neurological and histological outcomes of escalating doses of this extended-release formulation of bupivacaine after subarachnoid administration. Methods: Twenty-five pigs (Sus scrofa domesticus) weighing 36.2 (4.4) kg were randomly assigned to one of five groups to receive a subarachnoid injection of sodium chloride 0.9%, 3 ml (negative control), preservative-free bupivacaine hydrochloride 0.5%, 3 ml (positive control), or one of three doses of liposomal bupivacaine suspension 1.33%: 1.5, 3, or 5 ml. After recovering from general anaesthesia, neurological outcomes were assessed by blinded observers. Three weeks later, the animals were sacrificed for histological evaluations of neurotoxicity. Results: Animals that received sodium chloride 0.9%, bupivacaine hydrochloride, or liposomal bupivacaine 1.5 ml recovered within 2, 5, or 4 h, respectively. Animals that received liposomal bupivacaine 3 or 5 ml exhibited signs of neuraxial block (decreased nociception and proprioception) up to 32 h after injection. No histological evidence of neurotoxicity was found in any of the groups. Conclusions: Subarachnoid administration of liposomal bupivacaine in pigs exhibited a dose-response effect, and resulted in longer duration of neuraxial block than bupivacaine hydrochloride without histological evidence of neurotoxicity. Our study contributes preliminary data to inform further toxicological assessments and regulatory approval before subarachnoid administration in humans.
Journal of Pharmacy and Pharmacology, 2002
The pharmacodynamics and pharmacokinetics of bupivacaine in solution and in liposome preparations following subcutaneous administration were studied in rats. Multilamellar vesicles entrapping bupivacaine solution were prepared. The local anaesthetic effect was estimated by the tail-flick test in Wistar rats treated with 1 mg bupivacaine in 0.2-ml. preparations. Plasma concentrations of bupivacaine were determined by high-performance liquid chromatography. The results showed that both bupivacaine solution and bupivacaine liposomes revealed local anaesthetic effects in the initial tail-flick test (15 min after injection). With bupivacaine liposomes, the duration of action was 5-fold (447 ± 28.9 vs 87 ± 6.7 min), the maximum possible effect was 2-fold (100 ± 0 vs 47.6 ± 13%), and the peak plasma concentration (Cmax) was less than one-fifth (0.12 ± 0.04 vs 0.65 ± 0.04 μg mL−1) that with bupivacaine solution. The sensory block effect of bupivacaine solution completely resolved at 90 min,...
Journal of Pharmacy and Pharmacology, 2002
The aim of this study was to develop an in-vitro release method suitable for injectable slowrelease lipid formulations of local anaesthetics (or other drugs). We also aimed that the results of the in-vitro measurements should have a clear relationship to duration of action in-vivo. Six formulations of bupivacaine base in medium-chain triglyceride-glyceryl dilaurate mixtures were developed. A new apparatus was constructed for determination of their in-vitro release pro les. A bulbous glass tube was xed inside a standard glass bottle, which was then lled with release medium. A stirring magnet was enclosed in the perforated polypropylene cylinder holding the glass tube. The stirring created a continuous, rotating downward ow of medium inside the tube, which kept the lipid phase, introduced by means of a syringe, suspended as a single, free drop. Release pro les were obtained by sampling of the release medium for up to 72 h and analysis by gas-liquid chromatography. The duration of action in-vivo of the respective formulations was tested by the hot-plate method in rats. The release pro les of bupivacaine invitro were mono-exponential for four formulations and bi-exponential for the other two.
Evidence of presynaptic and postsynaptic action of local anesthetics in rats
Acta Cirurgica Brasileira, 2013
To assess the probable actions of ropivacaine, 50% enantiomeric excess bupivacaine mixture (S75-R25) and levobupivacaine on neuromuscular transmission in vitro. METHODS: Thirty rats were distributed into groups (n=5) according to the drug used: ropivacaine, bupivacaine (S75-R25) and levobupivacaine. The concentration used for the three local anesthetics (LA) was 5 µg.mL.-1 The following parameters were evaluated: 1) LA effects on membrane potential (MP) and miniature end plate potential (MEPP). A chick biventer cervicis preparation was also used to evaluate LA effects on the contracture response to acetylcholine. RESULTS: LA did not alter MP values and decreased the frequency and amplitude of MEPP. In a chick biventer cervicis preparation, bupivacaine (S75-R25) and levobupivacaine decreased the contracture response to acetylcholine with statistical significance, in comparison to ropivacaine. CONCLUSIONS: In the concentrations used, levobupivacaine and bupivacaine (S75-R25) exhibited presynaptic and postsynaptic actions evidenced by alterations in miniature end plate potentials and contracture response to acetylcholine. Ropivacaine only had a presynaptic action.
Veterinary Anaesthesia and Analgesia, 2018
Objective To test whether neurotoxic effects of a bupivacaine liposome injectable suspension differ from those of a standard formulation of bupivacaine hydrochloride (HCl) after intraneural injection into the sciatic nerves in pigs. Study design Prospective, randomized study. Animals Fifteen pigs, hybrids of Landrace and Large White. Methods After the National Ethics Committee approval, 15 pigs were randomly allocated to three groups (n ¼ 5/group) to receive intraneural injections of 4 mL of 1.33% bupivacaine liposome injectable suspension, 0.5% bupivacaine HCl or normal saline. Serial neurologic examinations were conducted to detect sensory and motor response to noxious stimuli using a modified Thalhammer's scale at 2 hour intervals for the first 12 hours after injection and daily thereafter for 2 weeks. Fiber characteristics (density) of the harvested sciatic nerves were measured during histomorphometric analysis. Inflammatory response was studied using immunohistochemical analysis. Data were tested using analyses of variance; p values for paired comparisons were Bonferroni adjusted. Results Compared with bupivacaine HCl, bupivacaine liposome injectable suspension provided longer sensory (11.2 ± 1.8 hours versus 3.2 ± 1.1 hours, respectively, p < 0.0001) and motor (10.0 ± 2.0 hours versus 4.0 ± 1.4 hours respectively, p < 0.0001) blockade. Histomorphometric parameters were similar among the groups. No changes in axonal density or myelin structure indicative of injury to the sciatic nerves were observed in any of the groups. Number of immunopositive cells did not differ between the bupivacaine liposome injectable suspension (23 ± 6 cells per mm 2) and the bupivacaine HCl groups (21 ± 4 cells per mm 2), p > 0.90. Conclusions and clinical relevance Intraneural injections of bupivacaine liposome injectable suspension or bupivacaine HCl in our porcine model did not result in evidence of neurotoxicity.