Shan-Wu Feng

Is cardiolipin the target of local anesthetic cardiotoxicity

BACKGROUND AND OBJECTIVES Local anesthetics are used broadly to prevent or reverse acute pain and treat symptoms of chronic pain. Local anesthetic-induced cardiotoxic reaction has been considered the accidental event without currently effective therapeutic drugs except for recently reported intralipid infusion whose possible mechanism of action is not well known. CONTENTS Cardiolipin, an anionic phospholipid, plays a key role in determining mitochondrial respiratory reaction, fatty acid metabolism and cellular apoptosis. Mitochondrial energy metabolism dysfunction is suggested as associated with local anesthetic cardiotoxicity, from an in vitro study report that the local anesthetic cardiotoxicity may be due to the strong electrostatic interaction of local anesthetics and cardiolipin in the mitochondria membrane, although there is a lack for experimental evidence. Herein we hypothesized that local anesthetic-cardiolipin interactions were the major determinant of local anesthetic-associated cardiotoxic reaction, established by means of theoretic and structural biological methods. This interacting model would give an insight on the underlying mechanism of local anesthetic cardiotoxicity and provide clues for further in depth research on designing preventive drugs for such inadvertent accidence in routine clinical practice. CONCLUSIONS The interaction between local anesthetic and mitochondrial cardiolipin may be the underlying mechanism for cardiotoxicity affecting its energy metabolism and electrostatic status.

A cardiolipina é o alvo da cardiotoxicidade dos anestésicos locais

JUSTIFICATIVA E OBJETIVOS: Os anestesicos locais sao amplamente utilizados na prevencao ou na reversao de dor aguda e no tratamento de dor cronica. A reacao de cardiotoxicidade induzida pelos anestesicos locais e um evento acidental sem terapia farmacologica, exceto a infusao de intralipides relatados recentemente cujo mecanismo de acao ainda nao e bem compreendido. CONTEUDO: A cardiolipina, um fosfolipidio anionico, desempenha papel relevante na determinacao de reacao respiratoria mitocondrial, metabolismo de acidos graxos e apoptose celular. A disfuncao do metabolismo energetico mitocondrial e sugerida em associacao com a cardiotoxicidade dos anestesicos locais, a partir de um estudo in vitro de que ela talvez se deva a fortes ligacoes eletrostaticas entre os anestesicos locais e a cardiolipina na membrana mitocondrial. Nao ha, contudo, evidencia experimental. Portanto, levantamos a hipotese de que as interacoes anestesico-cardiolipina sejam o principal determinante associado a reacao de cardiotoxicidade, o que pode ser estabelecido com a adocao de metodos teoricos e biologicos estruturais. Esse modelo de interacao nos daria uma pista sobre o mecanismo da cardiotoxicidade dos anestesicos locais, visando a futuras pesquisas na area de desenvolvimento de farmacos de prevencao a esse evento na pratica clinica. CONCLUSOES: A interacao entre a cardiolipina mitocondrial e os anestesicos locais pode ser a principal fonte de sua cardiotoxicidade, em funcao de seus efeitos sobre o metabolismo energetico e o estado eletrostatico.

Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity.

The neural balance between facilitation and inhibition determines the final tendency of central sensitization. Nerve injury-induced hypersensitivity was considered as the results from the enhanced ascending facilitation and the diminished descending inhibition. The role of dopaminergic transmission in the descending inhibition has been well documented, but its underlying molecular mechanisms are unclear. Previous studies demonstrated that the lysine dimethyltransferase G9a/G9a-like protein (Glp) complex plays a critical role in cocaine-induced central plasticity, and given cocaine’s role in the nerve system is relied on its function on dopamine system, we herein proposed that the reduced inhibition of dopaminergic transmission was from the downregulation of tyrosine hydroxylase expression by G9a/Glp complex through methylating its gene Th. After approval by the Animal Care and Use Committee, C57BL/6 mice were used for pain behavior using von Frey after spared nerve injury, and Th CpG islands methylation was measured using bisulfite sequencing at different nerve areas. The inhibitor of G9a/Glp, BIX 01294, was administered intraventricularly daily with bolus injection. The protein levels of G9a, Glp, and tyrosine hydroxylase were measured with immunoblotting. Dopamine levels were detected using high-performance liquid chromatography. The expression of G9a but not Glp was upregulated in ventral tegmental area at post-injury day 4 till day 49 (the last day of the behavioral test). Correspondingly, the Th CpG methylation is increased, but the tyrosine hydroxylase expression was downregulated and the dopamine level was decreased. After the intracerebroventriclar injection of BIX 01294 since the post-injury days 7 and 14 for consecutive three days, three weeks, and six weeks, the expression of tyrosine hydroxylase was upregulated with a significant decrease in Th methylation and increase in dopamine level. Moreover, the pain after G9a/Glp inhibitor was attenuated significantly. In sum, methytransferase G9a/Glp complex partially controls dopaminergic transmission by methylating Th in peripheral nerve injury-induced neuropathic pain.

Comparison Between the Use of Ropivacaine Alone and Ropivacaine With Sufentanil in Epidural Labor Analgesia.

AbstractTo compare the analgesic efficacy and safety of the sole local anesthetic ropivacaine with the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil given epidurally on the labor pain control.After institutional review board approval and patient consent, a total of 500 nulliparas requesting epidural labor analgesia were enrolled and 481 eventually were randomized into 2 groups: a sole local anesthetic group (ropivacaine 0.125%) and a combination of local anesthetic and opioidergic analgesic group (0.125% ropivacaine + 0.3 &mgr;g/mL sufentanil). After the test dose, a 10-mL epidural analgesic solution was given in a single bolus, followed by intermittent bolus injection of 10 to 15 mL of the solution. The primary outcome was the analgesic efficacy measured using Numerical Rating Scale (NRS) of pain. Other maternal and infant variables were evaluated as secondary outcomes.A total of 346 participants completed the study. The median NRS pain score during the 1st stage of labor was significantly lower in the combination group 2.2 (interquartile range [IQR]: 1.8–2.7) comparing to the sole local analgesic group 2.4 (IQR: 2.0–2.8) (P < 0.0001). No significant difference was observed in NRS pain score prior epidural analgesia and during the 2nd stage of labor. Patients in both groups rated same satisfaction of analgesia. Patients in the sole local analgesic group experienced fewer side effects than those in the combination group (37.7% vs 47.2%, P = 0.082). The individual analgesia-related cost in the sole local analgesic group was less (

Effectiveness of A Single Dose of Epidural Morphine for Postpartum Perineal Pain: A Randomized Controlled Trial

5.7 ± 2.06) than that in the combination group (

Addition of Adrenaline to Chloroprocaine Provides a Moderate Duration Time for Epidural Anaesthesia in Elective Caesarean Section

9.76 ± 3.54) (P < 0.0001). The incidence of 1-minute Apgar ⩽ 7 was lower in the sole local analgesic group 2 (1.2%) than the combination group 10 (5.5%) (P = 0.038). No difference was found between other secondary outcomes.The sole local anesthetic ropivacaine produces a comparable labor analgesic effect as the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil at different stages of labor (&Dgr;NRS = 0.2) but the former has less side effects, lower cost, and less incidence of lower 1-minute Apgar scoring. These results imply the necessity of a systematic reevaluation of epidural labor analgesia with sole local anesthetics against combination regimens of local anesthetics and other opioids.

Spinal or epidural analgesia? Difference in methods.

MATERIALS AND METHODS After institutional review board approval and patient consent, a total of 200 parturients with perineal trauma undergoing epidural analgesia were randomized into three groups: C, M1, and M2, wherein sole saline 10ml, morphine 1mg dissolved in saline 10ml, or morphine 2mg dissolved in saline 10ml was epidurally given immediately after umbilical cord clamp, respectively. Within 24 hours after vaginal delivery, perineal pain at rest and movement evaluated with present pain intensity (PPI) as well as the time to the first request for additional analgesia were recorded. Besides, epidural morphine related side effects including nausea, vomiting, pruritus, and urinary retention were observed as well.

Analgesia espinal ou epidural?: diferenças entre métodos

OBJECTIVE: Epidural anaesthesia using chloroprocaine with or without adrenaline and lidocaine with adrenaline were compared. METHODS: Sixty parturients undergoing elective caesarean section under epidural anaesthesia were randomized to receive 3% chloroprocaine (group C), 3% chloroprocaine with adrenaline (group CA) or 2% lidocaine with adrenaline (group LA). Onset time, duration time and various maternal, fetal and neonatal parameters were monitored. Pain was assessed using a visual analogue scale. RESULTS: The onset time of analgesia in group CA was similar to that in group C but was shorter than that in group LA. Duration of analgesia, loss of cold sensation and motor blockade in group CA were prolonged compared with group C, but were shorter than those in group LA. No differences in maternal, fetal or neonatal effects were seen. A higher pain score was reported in group C than in groups CA or LA at the end of surgery. CONCLUSIONS: Epidural anaesthesia using chloroprocaine with adrenaline has a quick onset and moderate duration and is an attractive alternative to lidocaine and adrenaline or chloroprocaine alone for caesarean section.

Preemptive combined preventive delivery of flurbiprofen axetil produced effective analgesia after lumpectomy

We read the paper published in the Journal with great interest on the comparative study of the analgesic role of bupivacaine (S75-R25) and ropivacaine in labor pain control 1. The study gave original information regarding the analgesic effect of the newly mixed solution of bupivacaine containing 75% of the S isomer and 25% of the R isomer and ropivacaine, and the authors declared that these two drugs can provide good conditions for spinal anesthesia with small indices of adverse events. After careful reading of the whole methods of the study, we are confused about the study protocol. In the title and abstract of the paper, the authors used “spinal anesthesia”, at first sight, to indicate that they administered these two drugs into subarachnoid space, but after following reading of the whole paper, we found the authors in fact performed continuous epidural analgesia, but not what they have demonstrated “spinal anesthesia”. Although spinal and epidural anesthesia all belong to regional anesthesia, there are big differences between these two techniques. Spinal anesthesia requires the injection of local anesthetics into subarachnoid space, but into peridural space when epidural anesthesia is performed. All theses two methods produce contrasting effect on anesthesia or analgesia with different mechanisms 2. As declared, the authors used “spinal anesthesia” in their study; this was a big error in definition of these two anesthetic methods. So we really do not know what anesthesia was used in their study. If such reply is not provided, the results of their paper will mislead readers and produce negative effects on the scientific research and clinical practice. Therefore, this paper should be withdrawn.

Anaesthesiologist-associated risk factors for inadequate postoperative pain management

. El estudio nos suministro informaciones iniciales sobre el efecto analgesico de la solucion recientemente combinada de bupiva-caina conteniendo un 75% del isomero S y un 25% del isomero R y ropivacaina. Los autores declararon que esos dos farmacos pueden proporcionar buenas condiciones para la anestesia es-pinal con pequenos indices de eventos adversos. Despues de leer cuidadosamente los metodos de todo el estudio, nos que-damos confundidos sobre el protocolo del estudio. En el titulo y en el resumen del trabajo, los autores utilizan “anestesia espi-nal”, a primera vista, para indicar que ellos administraron esos dos farmacos en el espacio subaracnoideo. Al continuar leyen-do el trabajo, descubrimos que los autores de hecho realizaron la analgesia epidural continua, y que no habian mencionado “anestesia espinal”. Aunque tanto la anestesia espinal como la epidural per-tenecen a la anestesia regional, existen grandes diferencias entre las dos tecnicas. La anestesia espinal necesita la inyec-cion de anestesicos locales en el espacio subaracnoideo, pero cuando la anestesia es epidural, la inyeccion se aplica en el espacio epidural. Esos dos metodos producen efectos contrastantes sobre la anestesia o analgesia con diferentes mecanismos