鞘内注射罗哌卡因-葡萄糖液对大鼠脊髓蛋白质组的影响

目的研究鞘内注射混合了葡萄糖的罗哌卡因对大鼠行为学指标及脊髓蛋白质组的影响。方法 36只大鼠随机分为3组,经腰椎鞘内置管后,按组别给予0.5%罗哌卡因(R1组)、10%葡萄糖+等体积1%罗哌卡因配制成的0.5%罗哌卡因(R2组)及对照组(N组)。每次注入40μL,每间隔1.5 h 1次,共3次。首次注药前5 min及每次注药后10 min测一次血压;置管后1 h、末次注药后1 h及24 h,以BBB神经功能评分法及斜板试验记录运动恢复情况。最后一次评分结束后断头法处死大鼠,以导管尖端为中心切取5 mm脊髓组织提取蛋白并定量,采用双向凝胶电泳-飞行时间质谱技术鉴定差异蛋白质。结果 R2组在末次给药后收缩压较基础值明显下降(P<0.05),与同时点对照组比较差异有统计学意义(P<0.05);该组BBB评分及斜板实验结果较基础值也略有下降,但差异无统计学意义(P>0.05)。R1组无上述改变。与对照组相比,R2组中谷氨酰胺合成酶及醛糖还原酶的表达升高,NAD依赖的去乙酰化酶2表达下降。结论由葡萄糖稀释的0.5%罗哌卡因用于大鼠蛛网膜下腔,24 h后其脊髓蛋白质中与细胞能量代谢相关的酶ALDR及GS表达升高,与细胞增殖分化相关的SIRT-2表达下调。     

Delayed neurotoxicity of leptophos and related compounds: differential effects of subchronic oral administration of pure, technical grade and degradation products on the hen

Pure and technical grade leptophos (O-4-bromo-2,5-dichlorophenyl O-methyl phenylphosphonothioate) and some of its degradation products were screened for delayed neurotoxicity following daily oral administration to hens. Minor modification of the leptophos molecule did not abolish its neurotoxic effect. In contrast, the hydrolytic products, 4-bromo-2,5-dichlorophenol and phenylphosphonic acid, had no neurotoxic action. The effectiveness of esters to induce delayed neurotoxicity was, in descending order: O-2,5-dichlorophenyl O-methyl phenylphosphonothioate (desbromoleptophos) >; pure leptophos > technical grade leptophos > O-4-bromo-2,5-dichlorophenyl O-methyl phenylphosphonate (leptophos oxon). Leptophos oxon was only weakly effective as a neurotoxic agent probably because it was unstable in the body and by the time it had reached the target for neurotoxic action it had been hydrolyzed to nonneurotoxic products. Histopathologic examination of hens that died during the study or were killed 30 days after completion of treatment showed marked axon and myelin degeneration in the sciatic, peroneal, and tibial nerves and spinal cord of most hens. The lesions in peripheral nerves were generally seen earlier and in fewer hens than those in spinal cord. The most consistent histopathological changes were degeneration of axons and myelin in the spinal cord. Leptophos oxon was the most potent inhibitor of brain and plasma cholinesterases. Also, the activity of plasma butyryl cholinesterase was more inhibited than brain acetylcholinesterase. Controls consisted of four groups of hens given daily oral doses of 10 mg/kg tri-o-cresyl phosphate (TOCP), 1.0 mg/kg O,O-diethyl-O-4-nitrophenyl phosphorothioate (parathion), and an empty gelatin capsule. TOCP-treated hens developed delayed neurotoxicity while those given parathion showed initial leg weakness but subsequently recovered without developing delayed neurotoxicity. Control hens receiving gelatin capsules remained normal. This study suggests that changes in structure of leptophos as it is absorbed, metabolized, accumulated, and eliminated in vivo, significantly affect the development and severity of delayed neurotoxicity. The chicken continues to be an ideal model for screening organophosphorus pesticides for their capacity to produce delayed neurotoxicity.     

谷氨酸诱导体外培养的鸡胚脊髓神经细胞释放NO

用鸡胚脊髓神经细胞的原代培养,测定细胞中亚硝酸盐的含量,研究了谷氨酸(Glu)对原代培养神经细胞中NO的影响。结果表明,谷氨酸作用于原代培养的鸡胚脊髓神经细胞,在诱导神经细胞释放乳酸脱氢酶(LDH)的同时,还可诱导细胞释放一氧化氮(NO)。如先用NO合成酶抑制剂L-NOARG作用细胞,再加入Glu,则发现L-NOARG能降低Glu导致的培养液中LDH活性升高。提示NO可能参与介导Glu的神经毒性作用。     

Failure rate and complications associated with the use of spinal catheters for the management of inadvertent dural puncture in the parturient: a retrospective comparison with re-sited epidural catheters

Objective To report on the failure rate of spinal catheters placed following inadvertent dural puncture (IDP) compared with re-sited epidural catheters in the obstetric population.

Research design and methods Patients who experienced IDP during epidural or combined spinal epidural placement with 17 or 18 gauge Tuohy needles for labor analgesia between 2003 and 2014 were identified using our post-dural puncture headache (PDPH) database. Patients were categorized into two groups: those who had spinal catheters inserted and those who had epidural catheters re-sited.

Main outcome measure Failure rate associated with spinal or re-sited epidural catheters (defined as need for repeat block or alternative analgesic modality). Secondary outcomes were incidence of PDPH, need for epidural blood patch (EBP), and adverse events.

Results A total of 109 patients were included in the final analysis; 79 ultimately had spinal catheters and 30 ultimately had re-sited epidural catheters. There were no differences between spinal catheters and re-sited epidural catheters in failure rate (22% vs. 13%, P?=?0.33), incidence of PDPH (73% vs. 60%, P?=?0.24), need for EBP (42% vs. 30%, P?=?0.28), number of headache days, or maximum headache scores. There was also no difference in the rate of adverse events including high block levels, hypotension, and fetal bradycardia (9% vs. 7%, P?=?1.0) between the two groups.

Conclusions There were no differences in failure rates, PDPH outcomes, or adverse events between spinal catheters and re-sited epidural catheters following IDP in parturients receiving labor analgesia. Limitations of the study include its single-center retrospective non-randomized design, and the uneven number of patients in the two groups with a relatively small number in the re-sited epidural catheter group.     

Delayed neurotoxicity of leptophos: toxic effects on the nervous system of hens.

Delayed neurotoxicity in hens fed a single oral dose of leptophos, O-(4-bromo-2,5-dichlorophenyl) O-methyl phenylphosphonothioate, has been studied. Three doses of the insecticide were given: 200, 400, and 800 mg/kg. Leptophos produced neurotoxicity in hens similar to that reported for other neurotoxic organophosphorus compounds. Thus leptophos caused ataxia which progressed to paralysis and death, caused loss of appetite and weight, and reduced the number and weight of eggs laid. Acetylcholinesterase in red blood cells showed an initial inhibition, then a substantial recovery. On the other hand, plasma cholinesterase, after initial inhibition and recovery, was severely inhibited as the signs of neurotoxicity progressed. Histological examination revealed marked axon and myelin degeneration of the sciatic nerve and spinal cord. Less severe changes were seen in the medulla, and nonspecific degeneration of muscle fibers was present.     

Delayed neurotoxicity from long-term low-level topical administration of leptophos to the comb of hens.

The production of delayed neurotoxicity in hens following percutaneous administration of leptophos [O-(4-bromo-2,5-dichlorophenyl) O-methyl phenylphosphonothioate] has been investigated. By applying a solution of the insecticide in acetone to the comb, seven groups of three laying hens were given daily a single percutaneous dose of 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, or 20.0 mg/kg of leptophos for 183–323 days. All hens given 0.5–20 mg/kg developed ataxia. The group of hens given a daily dose of 0.1 mg/kg of leptophos showed no abnormalities in gait or behavior. The severity of the clinical condition depended on the size of the daily applied dose. The “latent period” and “total administered dose” before onset of ataxia depended on the daily topically applied dose. The most consistent histopathological changes were degeneration of myelin and axons in spinal cords of intoxicated birds. The severity of change was greatest in hens receiving the highest doses. While plasma cholinesterase was inhibited in all treated birds, plasma acid phosphatase activity was significantly increased. The present investigation shows that long-term low-dose applicaton of leptophos to the comb produced delayed neurotoxicity in hens similar to that reported for the oral administration of this compound.     

咪达唑仑对局部麻醉药致惊厥神经毒性的影响

目的从致惊厥的行为学角度探讨咪达唑仑对局部麻醉药罗哌卡因、布比卡因、利多卡因及氯普鲁卡因致惊厥毒性的影响。方法 160只小鼠随机平行进入罗哌卡因、布比卡因、利多卡因和氯普鲁卡因4个实验。每个实验又随机分为咪达唑仑0(正常对照),0.25,0.5和1.0mg.kg-1组。各组小鼠先sc给予咪达唑仑20min后,再分别ip给予罗哌卡因85.9mg.kg-1,布比卡因48mg.kg-1,利多卡因80mg.kg-1或氯普鲁卡因250mg.kg-1,咪达唑仑0mg.kg-1对照组ip给予生理盐水;观察小鼠惊厥潜伏期、持续时间等;另外180只小鼠随机平行进入罗哌卡因、布比卡因、利多卡因和氯普鲁卡因4个实验。每个实验再随机分为咪达唑仑0(正常对照),0.5和1.0mg.kg-1组。按序贯法分析咪达唑仑对罗哌卡因、布比卡因、利多卡因及氯普鲁卡因致惊厥半数有效量(ED50)的影响。结果与正常对照组相比,咪达唑仑0.25,0.5和1mg.kg-1可延长局部麻醉药致小鼠惊厥潜伏期〔罗哌卡因:从162±21延长到186±50,352±229和(420±255)s;布比卡因:从136±19延长到227±40,485±355和(234±223)s(P<0.01);利多卡因:从164±34延长到247±101,216±54和(421±168)s;氯普鲁卡因:从183±63延长到238±131,392±219和(420±211)s〕;可缩短惊厥持续时间〔罗哌卡因:从914±306缩短到336±172,248±70和(290±42)s(P<0.01);布比卡因:从537±175缩短到442±129,131±147和(30±62)s;利多卡因:从26±9缩短到23±5,27±4和(16±5)s;氯普鲁卡因:从304±93缩短到269±184,123±145和(114±140)s〕;咪达唑仑0.5和1.0mg.kg-1可增加局部麻醉药致惊厥的ED50〔罗哌卡因:从51.2增加到68.1和89.3mg.kg-1;布比卡因:从38.6增加到50.3和57.2mg.kg-1;利多卡因:从48.8增加到71.5和86.2mg.kg-1;氯普鲁卡因:从152.5增加到254.1和190.6mg.kg-1(P<0.01)〕。结论咪达唑仑可拮抗局部麻醉药的致惊厥作用,降低其中枢神经系统毒性。     

Transdermal absorption enhancing effect of the essential oil of Rosmarinus officinalis on percutaneous absorption of Na diclofenac from topical gel

Abstract

Context: Rosemary essential oil has been used topically for several purposes (analgesic, anti acne, and anti-inflammatory) in Iranian traditional medicine.

Objectives: This investigation aimed to study the effect of essential oil of Rosmarinus officinalis L. (Lamiaceae) on the transdermal absorption of Na diclofenac from topical gel.

Material and methods: Diclofenac sodium topical gel was prepared with HPMC K4M and Carbopol 934P as a gelling agent, and several vehicles. The most stable gel was chosen and enhancing effects of the essential oil with different concentrations (0.1, 0.5, and 1.0% w/w) on the permeation of diclofenac were evaluated. The anti-nociceptive effect of preparations was evaluated based on the formalin and tail flick tests in mice.

Results: The major constituents of the essential oil were 1,8-cineol (15.96%), α-pinene (13.38%), camphor (7.87%), bornyl acetate (6.54%), verbenone (5.82%), borneol (5.23%), camphene (4.96%), and (E)-caryophyllene (3.8%). Topical diclofenac containing 0.5% essential oil showed more analgesic effect after 25, 30, and 35?min (p?<?0.001) than the reference drug in the tail flick test. The analgesic effect of preparation containing 1% essential oil was more than reference gel after 15?min (p?<?0.05). This difference was observed after 20, 25, 30, 35, and 40?min (p?<?0.001) too. Rosemary essential oil 1% promoted analgesic effect of drug in comparison with diclofenac gel in the formalin early phase (p?<?0.05). The enhancing effect of rosemary was observed in 0.5 and 1% concentration (p?<?0.05 and p?<?0.001, respectively) in the late phase.

Conclusion: This study proved the enhancing effect of 0.5 and 1% of rosemary essential oil on diclofenac percutaneous absorption.     

The relative neurotoxicities of n-hexane,methyl n-butyl ketone, 2,5-hexanediol,and 2,5-hexanedione following oral or intraperitoneal administration in hens

The sensitivity of the hen to neurotoxicity produced by po and ip administration of n-hexane, methyl n-butyl ketone (MnBK), 2,5-hexanediol (2,5-HDOH), and 2,5-hexanedione (2,5-HD) was investigated. While po administration of one or two doses of these chemicals at a 21-day interval caused acute effects, it did not induce neuropathy in treated hens. Subchronic po or ip administration of n-hexane caused only weakness, which subsided after cessation of administration. By contrast, subchronic administration of the other three related compounds caused neurotoxicity characterized by ataxia, which progressed to paralysis in some hens. Severity of the neurotoxic effect was dependent on both the test compound and its route of administration of a similar dosage. Generally, ip injection caused more severe effects than po administration. Pathological examination of nervous system tissues of hens treated with the 2,5-HD, 2,5-HDOH, and MnBK showed giant paranodal axonal swelling followed by Wallerian degeneration of axons and myelin in peripheral nerve and spinal cord. Wallerian degeneration in the spinal cord was observed almost exclusively in the ventral columns of the lower spinal cord. n-Hexane failed to produce the characteristic pathological features produced by related compounds. The neurotoxic potency of these chemicals which considers onset and magnitude of clinical signs and severity of histopathologic changes was in descending order: 2,5-HD > 2,5-HDOH > MnBK > n-hexane when given by either method.     

Delayed neurotoxicity of O-ethyl O-4-nitrophenyl phenylphosphonothioate: Subchronic (90 days) oral administration in hens

Delayed neurotoxicity in hens was produced following daily oral administration of 0.1, 0.5, 1.0, 2.5, 5.0, and 10.0 mg/kg of technical (85%) O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) in gelatin capsules for 90 days. Daily, three groups of hens were given empty gelatin capsules, 10 mg/kg of tri-o-cresyl phosphate (TOCP), or 1 mg/kg of parathion (O,O-diethyl O-4-nitrophenyl phenylphosphorothioate) and served as gelatin capsule controls, positive controls, and negative controls, respectively. TOCP-Treated hens developed delayed neurotoxicity, and those given parathion showed leg weakness with subsequent recovery when the administration of this agent had stopped. The clinical condition of most ataxic hens deteriorated during the 30-day observation period following the end of the oral administration of EPN. Severity of the clinical condition depended on the size of the daily ingested dose, i.e., while hens given small doses showed only ataxia, those treated with large doses progressed to paralysis and died. Days of administration and “total administered dose” before onset of ataxia depended on the daily dose. Degeneration of myelin and axons in the spinal cord was the most consistent histologic change and was identical to that found in TOCP control hens. Only one hen showed sciatic nerve degeneration. Livers from two hens given the highest dose of EPN manifested a moderate degree of hemosiderosis. Plasma cholin esterase was significantly inhibited in all surviving hens given EPN or TOCP at the end of the observation period. A group of hens treated daily with 0.01 mg/kg of EPN showed no abnormality in gait or behavior, and its plasma cholinesterase activity was not significantly different from that of the control. Hens treated with parathion had plasma cholinesterase activity comparable to that of the control 30 days after the administration of the last dose.     

Epidural fentanyl does not affect cervical dilation and progress of first stage of vaginal delivery: a randomized,double-blind study

Objective: Local anesthetics combined with opioids are commonly used in labor epidural analgesic schemes. This study investigated if the addition of fentanyl to epidural ropivacaine can affect cervical dilation and progress of vaginal delivery.

Methods: Sixty-two nulliparous parturients were randomized to receive epidurally 8?ml ropivacaine 0.2% combined with fentanyl 20?μg (F/R-group, n?=?31) or with normal saline 0.4?ml (R-group, n?=?31), every hour. Rescue doses of 5?ml ropivacaine 0.2% were also administered. Measurements were performed every 60?min until full cervical dilation. The primary end-point was the time to reach 10-cm cervical dilation. Secondary outcomes were Bishop scores, mode of delivery, total ropivacaine dose, pain, and satisfaction scores (numerical scale, 0–10).

Results: Data from 60 parturients (29 in the F/R and 31 in the R-group) were analyzed. The F/R-group had 26 vaginal deliveries (four instrumentally assisted), and three cesarean deliveries. The R-group had 27 vaginal deliveries (six instrumentally assisted) and 4 cesarean deliveries. Time to 10-cm cervical dilation did not differ between the groups (4?±?2.4?h in the F/R-group vs 4.4?±?2.1?h in the R-group, p?=?.341). The number of women remaining in the study every hour until full cervical dilation and Bishop scores for a 4-h period did not differ between the groups (p?=?.617). Total ropivacaine dose was comparable between the groups, but the F/R-group reported significantly lower pain (p?=?.01) and higher satisfaction scores (p?=?.001).

Conclusions: The addition of fentanyl to ropivacaine 0.2% solution did not affect cervical dilation and progress of the first stage of labor, but improved both analgesia and satisfaction.     

Current options for drug delivery to the spinal cord

Introduction: Spinal cord disorders (SCDs) are among the most devastating neurological diseases, due to their acute and long-term health consequences, the reduced quality of life and the high economic impact on society. Here, drug administration is severely limited by the blood–spinal cord barrier (BSCB) that impedes to reach the cord from the bloodstream. So, developing a suitable delivery route is mandatory to increase medical chances.

Areas covered: This review provides an overview of drug delivery systems used to overcome the inaccessibility of the cord. On one side, intrathecal administration, either with catheters or with biomaterials, represents the main route to administer drugs to the spinal cord; on the other side, more recent strategies involve chemical or electromagnetic disruption of the barrier and synthesis of novel functionalized compounds as nanoparticles and liposomes able to cross BSCB.

Expert opinion: Both the multifactorial pathological progression and the restricted access of therapeutic drugs to the spine are probably the main reasons behind the absence of efficient therapeutic approaches for SCDs. Hence, very recent highlights suggest the use of original strategies to overcome the BSCB, and new multidrug delivery systems capable of local controlled release of therapeutic agents have been developed. These issues can be addressed by using nanoparticles technology and smart hydrogel drug delivery systems, providing an increased therapeutic compound delivery in the spinal cord environment and multiple administrations able to synergize treatment efficacy.     

帕罗西汀对糖尿病大鼠神经病理性疼痛的影响及其作用机制

目的 探讨帕罗西汀对糖尿病大鼠神经病理性疼痛的影响及其可能的作用机制。方法 将健康成年♂SD大鼠随机分为3组,每组8只,包括正常对照组、糖尿病组、糖尿病+帕罗西汀治疗组。采用链脲佐菌素（75 mg·kg^-1）一次性腹腔注射建立糖尿病模型,并分别于注射前、注射后7,14,28 d检测机械性缩足反应痛阈（PWMT）。于注射佐脲酶菌素28 d后处理大鼠;取L₄~L₆段脊髓,运用尼氏体染色法检测脊髓组织的形态变化,TUNEL染色检测背角脊髓神经元的凋亡情况,免疫印迹技术检测脊髓神经元血红素加氧酶-1（HO-1）的表达。结果 与正常对照组比较,糖尿病组和糖尿病+帕罗西汀治疗组机械性痛阈明显降低（P<0.05）;与糖尿病组比较,糖尿病+帕罗西汀治疗组大鼠在注射佐脲酶菌素后28 d机械性痛阈显著升高（P<0.05）。糖尿病组大鼠脊髓背角萎缩,神经元变性坏死,细胞数降低,并且尼氏体减少,甚至消失;而糖尿病+帕罗西汀治疗组相对于糖尿病组大鼠脊髓背角萎缩降低,神经元数量升高,可见尼氏体。正常对照组大鼠脊髓背角神经元有较多HO-1表达,而糖尿病组HO-1表达量较低;相对于糖尿病组,糖尿病+帕罗西汀治疗组大鼠脊髓背角神经元有大量HO-1表达。结论 帕罗西汀可以减轻糖尿病大鼠神经病理性疼痛,对脊髓背角神经元具有保护作用,其作用机制可能与上调脊髓背角神经元HO-1的表达有关。     

Biochemical changes in the central nervous system of rats exposed to 1-bromopropane for seven days.

1-Bromopropane is used widely as an alternative to ozone-depleting solvents. The neurotoxic effects of this agent have been described in humans and experimental animals. Here we investigated the underlying mechanisms of the neurotoxic effects of 1-bromopropane by examining the initial biochemical changes in the central nervous system. Four groups of 9 Wistar male rats each were exposed to 200, 400, or 800 ppm 1-bromopropane or only fresh air, 8 h per day for 7 days. At the end of the experiment, the cerebrum, cerebellum, brain stem and lumbar enlargement of the spinal cord were dissected out from each rat (n = 8) for biochemical analyses. Morphological examinations of the nervous system were performed in the remaining rat of each group. 1-Bromopropane dose-dependently decreased neurospecific gamma-enolase, total glutathione, and nonprotein sulfhydryl groups in the cerebrum and cerebellum. Creatine kinase activity decreased dose-dependently in the brain and spinal cord. Histopathological examination showed swelling of preterminal axons in gracile nucleus and degeneration of myelin in peripheral nerves. Our results of low levels of gamma-enolase suggested that 1-bromopropane might primarily cause functional or cellular loss of neurons in the cerebrum and cerebellum. Glutathione depletion or modification to functional proteins containing a sulfhydryl base as a critical site might be the underlying mechanism of 1-bromopropane neurotoxicity.     

L-type Amino Acid Transporter 1 (SLC7A5)-Mediated Transport of Pregabalin at the Rat Blood-Spinal Cord Barrier and its Sensitivity to Plasma Branched-Chain Amino Acids

Pregabalin is an anti-neuropathic pain drug inhibiting the α2δ subunit of the voltage-dependent calcium channel in the spinal cord. The aim of this study is to characterize the transport mechanism of pregabalin at the blood-spinal cord barrier (BSCB) by means of in vivo experiments in rats and in vitro studies using primary-cultured rat spinal cord endothelial cells. We isolated endothelial cells by culturing rat spinal cord tissue in the presence of puromycin, and confirmed the expression of BSCB markers such as Cd31, Mdr1a, and Claudin-5. The uptake of pregabalin by primary-cultured rat spinal cord endothelial cells was sodium-independent and was significantly inhibited by L-leucine, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, and JPH203. These results suggest the involvement of L-type amino acid transporter (LAT) 1. LAT1 mRNA and protein was expressed in primary-cultured rat spinal cord endothelial cells, which is consistent with LAT1 expression at the BSCB. In the in vivo study, the transfer of pregabalin to rat spinal cord and brain was significantly decreased by the pre-administration of branched chain amino acids (BCAAs), which are endogenous substrates of LAT1. Our results indicate that pregabalin transport across the BSCB is mediated at least in part by LAT1 and is inhibited by plasma BCAAs.     

Distribution,Biotransformation and Excretion of Bupivacaine in the Rat and the Monkey

Abstract

1. Following subcutaneous administration of [pipecolyl-G-³H]bupivacaine, radioactivity was slowly absorbed from the injection site; the absorbed radioactivity was distributed rapidly in all tissues examined.

2. Tissue levels peaked between 0·25 and 1 h, but by 24 h were very low.

3. The monkey excreted 80% of the radioactivity in the urine; in the rat only 50% was excreted by this route and the remainder in the bile.

4. The major metabolite in rat urine was a conjugate of 1-butyl-3′-hydroxy-pipecolo-2′,6′-xylidide. Debutylated bupivacaine was not found in rat urine.

5. In the monkey, the amide hydrolysis product, pipecolic acid, was the major metabolite.

6. Debutylation and hydroxylation of bupivacaine also occurred in the monkey; however, only the 4′-hydroxy metabolite was detected.     

Epidural block with ropivacaine and bupivacaine for elective caesarean section: maternal cardiovascular parameters,comfort and neonatal well-being*

SUMMARY

Objective: To determine cardiovascular effects and neonatal outcome of ropivacaine 0.75% and bupivacaine 0.5% for elective epidural caesarean section.

Research design and methods: Healthy pregnant women, scheduled for elective caesarean section, were enrolled in this randomised, double-blind study. Epidural block was obtained with 20-30?ml of ropivacaine 0.75% (Group R) or bupivacaine 0.5% (Group B) and surgery did not commence until anaesthesia was achieved bilaterally to T6.

Main outcome measures: Maternal heart rate and blood pressure were assessed before the main dose of local anaesthetic and at 5-min

intervals until 35?min. Neonatal umbilical pH and Apgar scores were determined after delivery. Ten, twenty and thirty minutes after the main dose, sensory and motor block characteristics were determined. Quality of analgesia was assessed by the anaesthetist, surgeon and the patient. Adverse events were recorded.

Results: Sixty-two patients were enrolled and the data of 60 of them were eligible for analysis: 31 in Group R and 29 in Group B. The area under the curve (AUC) for maternal heart rate decreased significantly less in Group B than in Group R (p?=?0.038). Twenty-five and thirty minutes after administration of the main local anaesthetic dose, heart rate decreased significantly less in Group B

than in Group R (p?=?0.006 and p?=?0.007). There was no difference in AUC for maternal blood pressure (p?=?0.32). Repeated measurement analysis showed no difference between groups in motor block (p?=?0.78) and in spread of the sensory block (lower level: p?=?0.83, upper level: p?=?0.88). There was no statistical difference in neonatal umbilical pH (p?=?0.22) and Apgar score (p?=?0.59). Multiple linear regression analysis showed a significant influence of maternal body mass index on neonatal pH (p?=?0.004), but not of maternal blood pressure (p?=?0.323), nor of maternal heart rate (p?=?0.12). The quality of analgesia and incidence of adverse events were similar in both groups.

Conclusions: Both drugs produced equally satisfactory epidural block. Although ropivacaine 0.75% resulted in a greater decrease of maternal heart rate, this effect did not influence neonatal well-being. Both ropivacaine 0.75% and bupivacaine 0.5% can therefore be recommended for epidural anaesthesia in elective caesarean section.     

Delayed neurotoxicity of O-ethyl O-2,4-dichlorophenyl phenylphosphonothioate: effects of a single oral dose on hens.

Delayed neurotoxicity was produced in hens after the administration of a single oral dose of technical (96.43%) O-ethyl O-2,4-dichlorophenyl phenylphosphonothioate (S-Seven) in a gelatin capsule. Doses ranged from 800 to 5000 mg/kg. Hens given 5000 mg/kg also received atropine sulfate to protect them against acute toxicity. S-Seven caused loss of appetite and weight and resulted in ataxia which progressed in some hens to paralysis and death. Controls consisted of four groups of hens given a single oral dose of 500 mg/kg tri-o-cresyl phosphate (TOCP), 10 mg/kg parathion, 30 mg/kg atropine sulfate, or an empty gelatin capsule. TOCP-Treated hens developed delayed neurotoxicity while those given parathion showed weakness but subsequently recovered. Atropine sulfate and gelatin capsule controls remained normal. Degeneration of axons and myelin in the spinal cord was the most consistent histologic change and was identical to that found in TOCP control hens. Only one hen showed sciatic nerve degeneration. Three groups of hens which were given single oral doses of 100, 200, or 400 mg/kg S-Seven showed no neurologic signs of delayed neurotoxicity and their nerve tissues were not damaged. These results add strong confirmative evidence to the hypothesis that delayed neurotoxicity is a general feature of phenylphosphonothioate insecticides.     

Neurotoxicity of ethyl methacrylate in rats

Ethyl methacrylate (ethyl 2-methyl-2-propenoate, EMA) has been implicated in the development of neurologic impairment following occupational exposure. The potential of EMA to produce neurotoxicity was investigated in adult male Sprague-Dawley rats in two experiments. In the first experiment, animals were administered 100, 200, 400, or 800 mg/kg by daily intraperitoneal (i.p.) injections for 60 d. Control rats received daily i.p. injections of 1 ml saline/kg. Clinical observations, spontaneous motor activity, and performance in the Morris water maze were assessed. Alterations in clinical parameters in the higher dose groups included lethargy, impaired breathing, decreased weight gain, and increased mortality. Alterations in motor activity were observed at 100 mg/kg, a dose that did not cause alterations in clinical parameters, body weight gain, or mortality. There was also a dose-dependent impairment in performance in the Morris water maze. In the second experiment, animals were administered EMA in drinking water at concentrations of 0.1, 0.2, or 0.5% for 60 d. Control rats were administered tap water. Animals were perfused at the termination of exposure and samples of brain, spinal cord, and sciatic nerve were prepared for histological examination. Spongiform alterations were observed in fiber tracts of the forebrain, brainstem, and spinal cord. Clusters of axonal swellings were scattered throughout the dorsal, ventral, and lateral columns of the spinal cord, and typically involved internodal segments of two or three neighboring axons. Shrunken axons with separated myelin lamellae and large axons with thinner than normal myelin sheaths were apparent in the sciatic nerve. The patterns of alterations in the white matter of the spinal cord and the sciatic nerve are consistent with myelinopathy, but additional experiments are necessary to confirm whether oligodendroglia and Schwann cells are the primary sites of injury. In addition to the alterations associated with myelin, there was a decrease in the density of neurons in the ventral horn of the spinal cord. While the observed effects of EMA on the nervous system of rats are consistent with neurologic symptoms of workers exposed to EMA, additional experiments are necessary to determine if the level and route of exposures associated with occupational use produce these impairments in experimental animals.     

On the specific molecular configuration of neurotoxic aliphatic hexacarbon compounds causing central-peripheral distal axonopathy

A total of 56 young rats were fed 10 different hydrocarbon derivatives to determine the molecular configuration required for the production of nervous system disease of the type characterized by giant axonal degeneration in the distal regions of long and large, central and peripheral nerve fibers (central-peripheral distal axonopathy). For periods up to 14 weeks, animals drank ad libitum aqueous solutions containing 0.5% 2-heptanone, 0.5% 3,5-heptanedione, 0.5% 2,5-hexanedione, 0.5% 2,5-hexanediol, 0.5% 2,4-hexanedione, 0.5% 2,3-hexanedione, 0.5% 1,6-hexanediol, 0.5% 1,4-butanediol, 0.05, 0.1, or 0.25% glutaraldehyde, and 0.5 or 1% acetone. Animals treated with 2,5-hexanedione or 2,5-hexanediol failed to gain weight normally and slowly developed hindlimb weakness typical of a symmetrical peripheral neuropathy. Pathological examination of these animals revealed giant axonal swelling and secondary myelin changes in the distal regions of (1) the spino-cerebellar tracts in the cerebellar vermis and medulla oblongata, (2) the dorsal columns of the cervical, thoracic, and upper lumbar spinal cord, and (3) the sciatic, tibial, and plantar nerves. These characteristic clinical and pathological features of central-peripheral distal axonopathy failed to develop in the other groups of rats.