Disposition and placental transfer of etidocaine in pregnancy

Summary Following epidural administration of etidocaine hydrochloride to non-pregnant and pregnant patients, a similar rate of absorption was observed and there was no significant difference in total systemic blood clearance (Cl_sb) of etidocaine in the two groups. There were no major differences in the urinary excretion of etidocaine and metabolites in 48 h urine in both groups. The ability of pregnant women to form the N-glucuronide of the metabolite ABX (2-amino-2-butyroxylidide) was similar to that of non-pregnant individuals. In vitro experiments showed that the blood/plasma concentration ratio () of etidocaine was significantly higher in pregnant females than in males, presumably due to the lower haematocrit in females. The fraction unbound in plasma (f_p) of etidocaine was low in control subjects (mean 0.057) and was not significantly different in pregnant women of 35 to 37 weeks gestation. A marked increase in f_p was observed in pregnant women during delivery (mean 0.264). This finding has potentially serious clinical implications because it is the unbound drug in blood which is pharmacologically important. Placental transfer of etidocaine was rapid and the cord/maternal venous blood concentration ratio at delivery (CM_b) was, with one exception, always less than unity (mean 0.342). Following epidural administration of etidocaine to pregnant women in labour, measurable concentrations of mono-dealkylated metabolites of etidocaine, PABX (2-N-propylamino-2-butyroxylidide) and EABX (2-N-ethylamino-2-butyroxylidide) were detectable in maternal blood within 5 min and cord blood within 30 min. The CM_b for PABX and EABX was 0.401 and 0.658 respectively.List of Abbreviations Used ABX 2-Amino-2-butyroxylidide - EABX 2-N-Ethylamino-2-butyroxylidide - PABX 2-N-Propylamino-2-butyroxylidide - Cl_sb Total systemic blood clearance - Cl_sp Total systemic plasma clearance - Blood/plasma concentration ratio - f_p Fraction of unbound drug in plasma - f_pw Fraction of free drug in plasma water in blood - C_mb Cord/maternal venous blood concentration ratio at delivery - C_mp Cord/maternal venous plasma concentration ratio at delivery - t_1/2 Terminal phase half-life - t_p Time of attainment of peak plasma concentration - E Mean hepatic extraction ratio - Q Liver blood flow     

Clonidine antinociceptive activity: Effects of drugs influencing central monoaminergic and cholinergic mechanisms in the rat

Summary Clonidine is able to increase the threshold for vocalisation during stimulation and the threshold for vocalisation after withdrawal of stimulus (vocalisation afterdischarge). These effects of clonidine were investigated after treatment of rats with drugs influencing central monoaminergic and cholinergic mechanisms.Chlorpromazine, atropine and p-chlorophenyl-alanine increased the activity of clonidine at both thresholds while phenoxybenzamine and reserpine pretreatment increased the activity at the threshold for vocalisation only.Yohimbine decreased clonidine activity at both thresholds while 5-HTP and -methyl-p-tyrosine decreased the effects at the threshold for vocalisation afterdischarge. Naloxone did not change the activity of clonidine at either pain response studied.It is concluded from the present findings that influence from several neuronal systems modulate the antinociceptive action of clonidine.The inhibition of the medullary nociceptive response after clonidine might be connected to a decreased activity of noradrenergic neurons. Endogenous noradrenaline seems to be of minor importance in mediating this effect. It is moreover shown that decreased cholinergic receptor activity enhances clonidine antinociceptive action on both medullary and diencephalic-rhinencephalic pain responses. The possible involvement of serotonin in these functional responses after clonidine is also discussed.Data from this investigation was presented at the International Narcotic Research Club Conference, Airlie, Va. 1975.     

Reduction of stress-induced analgesia but not of exogenous opioid effects in mice lacking CB1 receptors

CB1 cannabinoid receptors are widely distributed in the central nervous system where they mediate most of the cannabinoid-induced responses. Here we have evaluated the interactions between the CB1 cannabinoid receptors and the endogenous opioid system by assaying a number of well-characterized opioid responses, e.g. antinociception and stress-mediated effects, on mutant mice in which the CB1 receptor gene was invalidated. The spontaneous responses to various nociceptive stimuli (thermal, mechanical and visceral pain) were not changed in mutant CB1 mice. Furthermore, the absence of the CB1 cannabinoid receptor did not modify the antinociceptive effects induced by different opioid agonists: morphine (preferential mu opioid agonist), D-Pen2-D-Pen5-enkephalin (DPDPE) and deltorphin II (selective delta opioid agonists), and U-50,488H (selective kappa opioid agonist) in the hot-plate and tail-immersion tests. In contrast, the stress-induced opioid mediated responses were modified in CB1 mutants. Indeed, these mutants did not exhibit antinociception following a forced swim in water at 34 degrees C and presented a decrease in the immobility induced by the previous exposure to electric footshock. However, the antinociception induced by a forced swim in water at 10 degrees C was preserved in CB1 mutants. These results indicate that CB1 receptors are not involved in the antinociceptive responses to exogenous opioids, but that a physiological interaction between the opioid and cannabinoid systems is necessary to allow the development of opioid-mediated responses to stress.     

不同频率电针对下肢胫后神经体感诱发电位痛成分P_(250)—N_(350)的影响

目的 :观察不同频率电针穴位的镇痛作用规律。方法 :采用电刺激正常人下肢胫后神经获得痛相关成分P2 50 —N350 复合波作为反映疼痛的客观指标 ,观察不同频率电针穴位对痛相关成分P2 50 —N350 波幅、潜伏期变化的影响。结果 :2Hz组针中 1 0、2 0minP2 50 —N350 波幅明显降低 ,差异显著 ,分别为P <0 0 1、P <0 0 0 1 ;40Hz组针中 2 0minP2 50 —N350 波幅明显降低 ,差异显著 ,P <0 0 0 1 ;2Hz、40Hz组针后波幅仍维持较低水平 ,差异显著 ,分别为P <0 0 0 1、P <0 0 1。结论 :2Hz、40Hz电针对SEPS 皮层痛成分有明显的抑制效应 ;针后具有强而持久的后效应     

温经化瘀合剂药效学研究

目的：观察温经化瘀合剂(当归、川芎、香附、益母草等)治疗痛经、月经不调等作用。方法：对小鼠子宫、卵巢进行重量测定，二甲苯致小鼠耳肿胀法，缩宫素诱发大鼠痛经模型和前列腺素E1诱发小鼠痛经模型法，对大鼠离体子宫收缩活动的影响。结果：温经化瘀合剂能明显增加小鼠子宫重量，减轻二甲苯引起的小鼠耳肿胀度，减少缩宫素所致大鼠扭体反应次数和前列腺素E1所致小鼠扭体反应次数，既能使正常大鼠离体子宫收缩，又能对抗缩宫素对大鼠离体子宫的收缩作用。结论：温经化瘀合剂具有镇痛、抗炎作用，对子宫有双向调节作用。     

胃癌术后镇痛对肠功能恢复的观察与护理

目的　探讨胃癌手术后硬膜外持续镇痛对患者肠功能的影响。方法　对 6 0例胃癌术后病人进行随机分组 ,PCEA(pa tientcontrolledEpiduralanalgesia)组 :采用硬膜外持续镇痛 (30例 ) ;对照组 :采用间断注射镇痛剂 (30例 ) ,观察肠蠕动、肛门排气时间及不良反应。结果　肠蠕动恢复时间PCEA组 (5 2 1± 4 3)h ,对照组 (5 1 5± 4 4 )h。肛门排气时间PCEA组 (6 5 4±7 5 )h ,对照组 (5 6 1± 9 3)h。PCEA组不良反应明显少于对照组。结论　术后镇痛不影响胃癌术后肠蠕动恢复 ,但应加强术后早期活动的指导     

The effect of combined spinal‐epidural (CSE) anaesthesia and size of spinal needle on postoperative hearing loss after elective caesarean section

The effect of combined spinal epidural (CSE) anaesthesia and size of spinal needle on postoperative hearing loss after elective caesarean section The exact aetiology of vestibulocochlear dysfunction after spinal anaesthesia is unknown. Low‐frequency hearing loss occurs after spinal anaesthesia. The aim of this study was to investigate the effects of combined spinal–epidural (CSE) anaesthesia and size of spinal needle on vestibulocochlear dysfunction, using pure tone audiometry performed pre‐ and on the first and the second day postoperatively. Forty‐five patients who were to undergo elective caesarean section were evaluated. In group I, CSE anaesthesia (18 G Tuohy, 25 G Whitacre pencil‐point‐design spinal needles) was performed in 15 patients. In group II, spinal anaesthesia was performed in 15 patients with 25 G Whitacre pencil‐point‐design spinal needles and, in group III, spinal anaesthesia was performed in 15 patients with 22 G Whitacre pencil‐point‐design spinal needles. In the pre‐ and on the first and the second day postoperatively, the pure tone audiogram was performed in the audiology laboratory of our hospital, using a calibrated Kamplex Diagnostic Audiometer AC 40 in a noise‐free room. When the CSE anaesthesia group and 22 G spinal group were compared for change in hearing between the pre‐ and postoperative periods, a statistically significant difference was observed at R‐right ear 125 Hz (P < 0.025) and at L‐left ear 125 Hz (P < 0.023), and at L‐left ear 1000 Hz (P < 0.036) and at R‐right ear 1500 Hz (P < 0.006), and at L‐left ear 1500 Hz (P < 0.022). At other frequencies, the difference was insignificant. When the CSE anaesthesia group and 25 G spinal group were compared for change in hearing between the pre‐ and postoperative periods, no statistically significant difference was detected at any frequency tested. When 22 G spinal group and 25 G spinal group were compared for change in hearing between the pre‐ and postoperative periods, there was some hearing loss at low frequency, although this difference did not reach statistical significance. The positive correlation of low‐frequency hearing loss and increased pressure in the epidural space (which decrease the risk of cerebrospinal fluid leakage through the dura) suggests that cerebrospinal fluid leakage via the spinal puncture hole is not the only factor involved. Perioperative fluid replacement alone may not prevent hearing loss but CSF loss through the dural puncture site should also be prevented.     

左旋精氨酸及左旋精氨酸脱羧酶抗血清对吗啡镇痛及耐受的影响

目的:分析左旋精氨酸及左旋精氨酸脱羧酶(L-ADC)对吗啡镇痛及其所致耐受的影响。方法:用家兔制备L-ADC多克隆抗体;以小鼠热辐射甩尾法和小鼠55℃热板测痛模型分析此抗体及左旋精氨酸对吗啡镇痛和耐受的影响。结果:在热辐射甩尾和热板测痛模型中,0.5-50mg·kg~(-1)的左旋精氨酸(sc)不影响吗啡镇痛和耐受(P>0.05)。L-ADC抗血清(脑室注射,1:1000-1:10稀释)能对抗吗啡镇痛作用,在热辐射甩尾和热板测痛模型中,它能使吗啡可能最大镇痛百分率分别从94.3％和80.6％下降到57.7％和42.9％(P<0.01)。吗啡连续处理小鼠3d后形成耐受:在热辐射甩尾和热板测痛模型中,吗啡的可能最大镇痛百分率分别从90.3％和80.3％下降到47.2％和40.5％;L-ADC抗血清能进一步加重吗啡所致耐受,其可能最大镇痛百分率进一步下降至19.8％和27.7％(P<0.01)。结论:L-ADC可能参与调节了吗啡镇痛及耐受形成过程;而左旋精氨酸不影响吗啡镇痛和耐受。     

腰硬联合麻醉用于分娩镇痛的临床研究

目的：探讨腰硬联合麻醉(CSEA)减轻或消除产痛以及对产程、胎儿、分娩方式的影响。方法：选择305例无产科及麻醉禁忌症的初产妇，在产程进入活跃早期宫口开大3—4cm时，给予腰硬联合麻醉(观察组)，并与同期条件相似、未给予任何镇痛方法的305例初产妇进行对比(对照组)。比较两组产妇产痛程度、产程进展速度、分娩方式及对胎儿的影响。结果：观察组镇痛有效率较对照组明显升高(P＜0．01)，又活跃期较对照组明显缩短，宫颈口扩张速度加快，经阴道分娩助产率增高(P＜0．05)。胎儿窘迫及新生儿窒息、产后出血发生率两组则无显的统计学意义(P＞0．05)。结论：CSEA可有效用于分娩镇痛、加速产程，且对胎儿及产妇无不良影响，值得推广应用。     

剖宫产术后硬膜外镇痛产妇血及初乳中吗啡含量的监测

目的　监测剖宫产术后硬膜外镇痛产妇血及初乳中的吗啡含量 ,探讨微量吗啡对新生儿的影响。　方法　选择剖宫产术的产妇 10 0例 ,分为实验组和对照组各 5 0例 ,两组均为连续硬膜外麻醉 ,穿刺点选择 L1 ～ L3,麻醉药为 2 %利多卡因 15～ 2 0 m l,在手术结束时 ,实验组将吗啡缓慢注入硬膜外管 2 mg然后拔管。于术后 1h取产妇的静脉血 3m l,采集产妇术后 3、6 h尿样及术毕 6～ 12 h采集新生儿尿样 3m l;在产后 4 8h内收集产妇的初乳 3～ 5 m l。　结果　观察组 96 % (48/ 5 0 )的镇痛效果较对照 16 % (8/ 5 0 )明显 ,差异有显著性 (P<0 .0 5 ) ,观察组血吗啡浓度 <5～ 118μg/ m l,初乳吗啡浓度 <5～ 30 .4μg/ L ,产妇尿 92 %呈阳性 ,新生儿尿 13.3%呈阳性。两组产妇和新生儿的生命体征比较差异无显著性。　结论　剖宫产术后硬膜外腔应用吗啡镇痛 ,产妇哺乳对新生儿没有影响 ,是安全可行的。