Controlled release ibuprofen-poloxamer gel for epidural use - A pharmacokinetic study using microdialysis in pigs

In order to avoid the risks of sideeffects of epidural local anesthetics and opioids, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) epidurally would be an interesting option of analgesic therapy. The fairly short duration of action of spinally administered NSAIDs, e.g., ibuprofen, may be prolonged by using controlled release poloxamer gel formulation. Using a microdialysis technique we studied the epidural and intrathecal pharmacokinetics of ibuprofen after its epidural administration as a poloxamer 407 formulation or a solution formulation. In addition, plasma ibuprofen concentrations were analyzed from central venous blood samples. Ibuprofen concentrations in the epidural space were significantly higher and longer lasting after the epidural gel injection compared with the epidural solution injection. The epidural AUC of ibuprofen was over threefold greater after epidural ibuprofen gel injection compared with the ibuprofen solution injection (p <0.001). The systemic absorption of ibuprofen from 25% poloxamer 407 gel was very low. The in situ forming poloxamer gel acted as a reservoir allowing targeted ibuprofen release at the epidural injection site and restricted ibuprofen molecules to a smaller spinal area. Ibuprofen diffusion from the epidural space to the intrathecal space was steady and prolonged. These results demonstrate that the use of epidurally injectable poloxamer gel can increase and prolong ibuprofen delivery from epidural space to the CSF enhancing thus ibuprofen entry into the central neuroaxis for spinal analgesia. Further toxicological and dose-finding studies are justified. (C) 2016 Elsevier B.V. All rights reserved.Peer reviewe

Effect of epinephrine on lidocaine clearance in vivo: a microdialysis study in humans.

Background: Local anesthetic nerve block prolonged by epinephrine is thought to result from local vasoconstriction and consequent decreased local anesthetic clearance from the injection site. However, no study has yet confirmed this directly in humans by measuring tissue concentrations of local anesthetic over time. In addition, recent studies have shown that the ␣ 2 -adrenergic receptor agonist, clonidine, also prolongs nerve block without altering local anesthetic clearance. Because epinephrine is also an ␣ 2 -adrenergic receptor agonist, it is possible that epinephrine prolongs local anesthetic block by a pharmacodynamic mechanism and not a pharmacokinetic one. This study was designed to address this issue. Methods: Microdialysis probes were placed adjacent to the superficial peroneal nerve in both feet of eight volunteers. Plain lidocaine (1%) was injected along one peroneal nerve and lidocaine with epinephrine (2.5 g/ml) was injected along the other nerve in a double-blinded, randomized manner. The concentration of lidocaine in tissue was measured at 5-min intervals, and sensory block and cutaneous blood flow were assessed by laser Doppler at 10-min intervals for 5 h. The resulting data for lidocaine concentration versus time were fit to a two-compartment model using modeling software. Results: Epinephrine prolonged sensory block by decreasing local blood flow and slowing clearance. There was no evidence of a pharmacodynamic effect of epinephrine. Conclusion: Although epinephrine activates ␣ 2 -adrenergic receptors, its mechanism for prolonging the duration of local anesthetic block rests on its ability to decrease local anes

Skeletal Muscle Fiber Adaptations Following Resistance Training Using Repetition Maximums or Relative Intensity

The purpose of the study was to compare the physiological responses of skeletal muscle to a resistance training (RT) program using repetition maximum (RM) or relative intensity (RISR). Fifteen well-trained males underwent RT 3 d·wk−1 for 10 weeks in either an RM group (n = 8) or RISR group (n = 7). The RM group achieved a relative maximum each day, while the RISR group trained based on percentages. The RM group exercised until muscular failure on each exercise, while the RISR group did not reach muscular failure throughout the intervention. Percutaneous needle biopsies of the vastus lateralis were obtained pre-post the training intervention, along with ultrasonography measures. Dependent variables were: Fiber type-specific cross-sectional area (CSA); anatomical CSA (ACSA); muscle thickness (MT); mammalian target of rapamycin (mTOR); adenosine monophosphate protein kinase (AMPK); and myosin heavy chains (MHC) specific for type I (MHC1), type IIA (MHC2A), and type IIX (MHC2X). Mixed-design analysis of variance and effect size using Hedge’s g were used to assess within- and between-group alterations. RISR statistically increased type I CSA (p = 0.018, g = 0.56), type II CSA (p = 0.012, g = 0.81), ACSA (p = 0.002, g = 0.53), and MT (p \u3c 0.001, g = 1.47). RISR also yielded a significant mTOR reduction (p = 0.031, g = −1.40). Conversely, RM statistically increased only MT (p = 0.003, g = 0.80). Between-group effect sizes supported RISR for type I CSA (g = 0.48), type II CSA (g = 0.50), ACSA (g = 1.03), MT (g = 0.72), MHC2X (g = 0.31), MHC2A (g = 0.87), and MHC1 (g = 0.59); with all other effects being of trivial magnitude (g \u3c 0.20). Our results demonstrated greater adaptations in fiber size, whole-muscle size, and several key contractile proteins when using RISR compared to RM loading paradigm

Skeletal Muscle Fiber Adaptations Following Resistance Training Using Repetition Maximums or Relative Intensity

The purpose of the study was to compare the physiological responses of skeletal muscle to a resistance training (RT) program using repetition maximum (RM) or relative intensity (RISR). Fifteen well-trained males underwent RT 3 d·wk−1 for 10 weeks in either an RM group (n = 8) or RISR group (n = 7). The RM group achieved a relative maximum each day, while the RISR group trained based on percentages. The RM group exercised until muscular failure on each exercise, while the RISR group did not reach muscular failure throughout the intervention. Percutaneous needle biopsies of the vastus lateralis were obtained pre-post the training intervention, along with ultrasonography measures. Dependent variables were: Fiber type-specific cross-sectional area (CSA); anatomical CSA (ACSA); muscle thickness (MT); mammalian target of rapamycin (mTOR); adenosine monophosphate protein kinase (AMPK); and myosin heavy chains (MHC) specific for type I (MHC1), type IIA (MHC2A), and type IIX (MHC2X). Mixed-design analysis of variance and effect size using Hedge’s g were used to assess within- and between-group alterations. RISR statistically increased type I CSA (p = 0.018, g = 0.56), type II CSA (p = 0.012, g = 0.81), ACSA (p = 0.002, g = 0.53), and MT (p \u3c 0.001, g = 1.47). RISR also yielded a significant mTOR reduction (p = 0.031, g = −1.40). Conversely, RM statistically increased only MT (p = 0.003, g = 0.80). Between-group effect sizes supported RISR for type I CSA (g = 0.48), type II CSA (g = 0.50), ACSA (g = 1.03), MT (g = 0.72), MHC2X (g = 0.31), MHC2A (g = 0.87), and MHC1 (g = 0.59); with all other effects being of trivial magnitude (g \u3c 0.20). Our results demonstrated greater adaptations in fiber size, whole-muscle size, and several key contractile proteins when using RISR compared to RM loading paradigms

Divergent Performance Outcomes Following Resistance Training Using Repetition Maximums or Relative Intensity

Purpose: The purpose of our investigation was to compare repetition maximum (RM) to relative intensity using sets and repetitions (RISR) resistance training (RT) on measures of training load, vertical jump, and force production in well-trained lifters. Methods: Fifteen well-trained (isometric peak force= 4403.61+664.69 N, mean+SD) males underwent RT 3 d·wk-1 for 10-weeks in either an RM group (n=8) or RISR group (n=7). Weeks 8-10 consisted of a tapering period for both groups. The RM group achieved a relative maximum each day while the RISRgroup trained based on percentages. Testing at five time-points included unweighted ( Results: Moderate between-group effect sizes were observed for all SJ and CMJ conditions supporting the RISR group (g=0.76-1.07). A small between-group effect size supported RISR for allometrically-scaled isometric peak force (g=0.20). Large and moderate between-group effect sizes supported RISR for rate of force development from 0-50ms (g=1.25) and 0-100ms (g=0.89). Weekly volume load displacement was not different between groups (p\u3e0.05), however training strain was statistically greater in the RM group (p\u3c0.05). Conclusions: Overall, this study demonstrated that RISR training yielded greater improvements in vertical jump, rate of force development, and maximal strength compared to RM training, which may partly be explained by differences in the imposed training stress and the use of failure/non-failure training in a well-trained population

ASRA Practice Advisory on Local Anesthetic Systemic Toxicity

Abstract: The American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity assimilates and summarizes current knowledge regarding the prevention, diagnosis, and treatment of this potentially fatal complication. It offers evidence-based and/or expert opinion-based recommendations for all physicians and advanced practitioners who routinely administer local anesthetics in potentially toxic doses. The advisory does not address issues related to local anesthetic-related neurotoxicity, allergy, or methemoglobinemia. Recommendations are based primarily on animal and human experimental trials, case series, and case reports. When objective evidence is lacking or incomplete, recommendations are supplemented by expert opinion from the Practice Advisory Panel plus input from other experts, medical specialty groups, and open forum. Specific recommendations are offered for the prevention, diagnosis, and treatment of local anesthetic systemic toxicity. (Reg Anesth Pain Med 2010;35: 152Y161

ASRA Practice Advisory on Local Anesthetic Systemic Toxicity

Abstract: The American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity assimilates and summarizes current knowledge regarding the prevention, diagnosis, and treatment of this potentially fatal complication. It offers evidence-based and/or expert opinion-based recommendations for all physicians and advanced practitioners who routinely administer local anesthetics in potentially toxic doses. The advisory does not address issues related to local anesthetic-related neurotoxicity, allergy, or methemoglobinemia. Recommendations are based primarily on animal and human experimental trials, case series, and case reports. When objective evidence is lacking or incomplete, recommendations are supplemented by expert opinion from the Practice Advisory Panel plus input from other experts, medical specialty groups, and open forum. Specific recommendations are offered for the prevention, diagnosis, and treatment of local anesthetic systemic toxicity. (Reg Anesth Pain Med 2010;35: 152Y161