Analgesic responses to intrathecal morphine in relation to CSF concentrations of morphine-3,beta-glucuronide and morphine-6,beta-glucuronide.

This study was performed to determine whether variations in analgesic responses to intrathecal morphine could be explained by cerebrospinal fluid (CSF) concentrations of morphine metabolites. Twenty-four CSF samples were collected at the beginning, middle and end of treatment periods in seven cancer patients with pain of malignant origin. CSF concentrations of morphine-3,beta-glucuronide (M3G) and morphine-6,beta-glucuronide (M6G) metabolites were measured by gas chromatography/mass spectrometry. Analgesic responses to morphine were estimated concurrent with CSF collection using a visual analog scale representing percentages of pain relief. Effective analgesia was defined as > or = 75% pain relief. CSF concentration of M3G and M6G in the 24 samples were 722 +/- 116 ng/ml and 699 +/- 158 ng/ml, respectively. CSF samples were categorized into two groups: (1) those collected during effective analgesia (N=14), and (2) those collected during ineffective analgesia (N=10). M6G levels detected in group 1 samples (effective analgesia) were significantly greater than those found in group 2 samples (ineffective analgesia) (978 +/- 243 ng/ml vs 309 +/- 68 ng/ml, P<0.05). Intergroup differences in CSF M3G concentrations and M3G/M6G ratios were not significant. It is concluded that CSF M6G may be indicative of effectiveness of analgesia in cancer patients subjected to intrathecal morphine.     

Halothane prevents nitrous oxide teratogenicity in Sprague-Dawley rats; folinic acid does not

The teratogenic effects of nitrous oxide (N2O) administered with halothane or folinic acid (FA) were studied in two separate experiments using a total of 206 timed-pregnant Sprague-Dawley rats. In each experiment, rats were exposed to either 1) air (n = 30-40); 2) N2O (50-75% for 24 h on day 8 of pregnancy, n = 20-30); 3) test agent (i.e., 0.27% halothane for 24 h on day 8 of pregnancy; or 5 mg/kg/day of FA on day 5-13 of pregnancy, subcutaneously by osmotic pump, n = 20-30); or 4) N2O + test agent (n = 20-30). Cesarean sections were performed on day 20, and fetuses were examined for visceral and skeletal abnormalities. There were no differences in pregnancy rate, number of implantations and live fetuses per rat, and fetal weight among any of the groups. Treatment with N2O resulted in significantly higher incidences of resorptions and of major visceral and minor skeletal abnormalities. Halothane administered with N2O protected against these effects; folinic acid did not. Using an additional 65 nonpregnant rats, hepatic methionine synthase activity was measured after treatment with 50% N2O, 50% N2O plus 0.27% halothane, or 50% N2O plus 5 mg/kg/day of folinic acid. Methionine synthase activity was equally depressed in all groups. These findings do not support the commonly held theory that inactivation of methionine synthase is the sole cause of N2O teratogenicity; rather, they suggest a multifactorial etiology, which may include changes in uterine blood flow.     

A Stabilization Device That Promotes the Efficiency of Cardiopulmonary Resuscitation during Ambulance Transportation to the Level as under Non-Moving Conditions

Background

The survival rate of patients with out-of-hospital cardiac arrest is low, and measures to improve the quality of cardiopulmonary resuscitation (CPR) during ambulance transportation are desirable. We designed a stabilization device, and in a randomized crossover trial we found performing CPR in a moving ambulance with the device (MD) could achieve better efficiency than that without the device (MND), but the efficiency was lower than that in a non-moving ambulance (NM).

Purpose

To evaluate whether a modified version of the stabilization device, can promote further the quality of CPR during ambulance transportation.

Methods

Participants of the previous study were recruited, and they performed CPR for 10 minutes in a moving ambulance with the modified version of the stabilization device (MVSD). The primary outcomes were effective chest compressions and no-flow fraction recorded by a skill-reporter manikin. The secondary outcomes included back pain, physiological parameters, and the participants'' rating about the device after performing CPR.

Results

The overall effective compressions in 10 minutes were 86.4±17.5% for NM, 60.9±14.6% for MND, 69.7±22.4% for MD, and 86.6%±13.2% for MVSD (p<0.001). Whereas changes in back pain severity and physiology parameters were similar under all conditions, MVSD had the lowest no-flow fraction. Differences in effective compressions and the no-flow fraction between MVSD and NM did not reach statistical significance.

Conclusions

The use of the modified device can improve quality of CPR in a moving ambulance to a level similar to that in a non-moving condition without increasing the severity of back pain.     

Individual patient meta-analysis of single-dose rofecoxib in postoperative pain

BACKGROUND: Individual patient meta-analysis to determine the analgesic efficacy and adverse effects of single-dose rofecoxib in acute postoperative pain. METHODS: Individual patient information was available from 14 trials; 13 in dental and one in postsurgical pain. For each patient the percentage of maximum possible pain relief (%maxTOTPAR) was determined at different time points. The proportion of patients with at least 50% maxTOTPAR, and number-needed-to-treat (NNT) for at least 50% maxTOTPAR, were then calculated, with time when 50% of patients had remedicated (TTR50) and number-needed-to-harm (NNH) for adverse effects. RESULTS: In dental pain, for rofecoxib 50 mg (1330 patients) compared with placebo (570 patients) the NNT was 1.9 (95% confidence interval 1.8 to 2.1) for six hours, 2.0 (1.8 to 2.1) at eight, 2.4 (2.2 to 2.6) at 12, and 2.8 (2.5 to 3.1) at 24 hours. The TTR50 was 15.5 hours. Adverse effects were uncommon, though post-extraction alveolitis (dry socket) occurred more often with rofecoxib 50 mg than with placebo, NNH 24 (14 to 80). For postsurgical pain in one trial (163 patients), the NNT for rofecoxib 50 mg for six hours was 3.9 (2.6 to 7.8), the TTR50 was 5.8 hours, and multiple-dose adverse effects over five days occurred at similar rates with rofecoxib 50 mg and placebo. CONCLUSIONS: Single-dose rofecoxib 50 mg is an effective treatment with long-lasting analgesia and few adverse effects in dental pain. More information is required to confirm efficacy in postsurgical pain.     

An Observational Study of Patient Characteristics Associated with the Mode of Admission to Acute Stroke Services in North East,England

Objective

Effective provision of urgent stroke care relies upon admission to hospital by emergency ambulance and may involve pre-hospital redirection. The proportion and characteristics of patients who do not arrive by emergency ambulance and their impact on service efficiency is unclear. To assist in the planning of regional stroke services we examined the volume, characteristics and prognosis of patients according to the mode of presentation to local services.

Study design and setting

A prospective regional database of consecutive acute stroke admissions was conducted in North East, England between 01/09/10-30/09/11. Case ascertainment and transport mode were checked against hospital coding and ambulance dispatch databases.

Results

Twelve acute stroke units contributed data for a mean of 10.7 months. 2792/3131 (89%) patients received a diagnosis of stroke within 24 hours of admission: 2002 arrivals by emergency ambulance; 538 by private transport or non-emergency ambulance; 252 unknown mode. Emergency ambulance patients were older (76 vs 69 years), more likely to be from institutional care (10% vs 1%) and experiencing total anterior circulation symptoms (27% vs 6%). Thrombolysis treatment was commoner following emergency admission (11% vs 4%). However patients attending without emergency ambulance had lower inpatient mortality (2% vs 18%), a lower rate of institutionalisation (1% vs 6%) and less need for daily carers (7% vs 16%). 149/155 (96%) of highly dependent patients were admitted by emergency ambulance, but none received thrombolysis.

Conclusion

Presentations of new stroke without emergency ambulance involvement were not unusual but were associated with a better outcome due to younger age, milder neurological impairment and lower levels of pre-stroke dependency. Most patients with a high level of pre-stroke dependency arrived by emergency ambulance but did not receive thrombolysis. It is important to be aware of easily identifiable demographic groups that differ in their potential to gain from different service configurations.     

Use of Entonox in the Ambulance Service

An analgesic mixture of nitrous oxide and oxygen (Entonox) has been used in nine ambulances in Gloucestershire for self-administration by patients in severe pain. Over a period of three and a half months 66 patients have been treated. In all cases the pain was wholly or partially relieved, and in no instance was the patient''s condition worsened. No undesirable side-effects attributable to Entonox were produced. It is recommended that other ambulance authorities should consider the use of Entonox in this context.     

Dezocine for Preventing Postoperative Pain: A Meta-Analysis of Randomized Controlled Trials

Background

Dezocine is considered to be an alternative medication for managing postoperative pain. The aim of this study was to assess the efficacy and safety of this drug in this regard.

Methods

Medline, EMBASE and the Cochrane Central Register of Control Trials (CENTRAL) were searched to identify all randomized controlled trials (RCTs) that compare dezocine with placebo or dezocine with morphine on postoperative pain. The data were extracted and pooled using Mantel-Haenszel random effects model. Heterogeneity was tested using the I ² statistic with values >50% and Chi² test with P ≤ 0.05 indicating obvious heterogeneity between the studies.

Results

Seven trials evaluating 665 patients were included. The number of patients with at least 50% pain relief was increased (N = 234; RR 3.04, 95% CI 2.27 to 4.08) and physician (N = 465; RR 2.84, 95% CI 1.66 to 4.84) and patient satisfaction (N = 390; RR 2.81, 95% CI 1.85 to 4.26) were improved following the administration of dezocine compared with the placebo. The effects of dezocine were similar to those of morphine in terms of the number of patients reporting at least 50% pain relief within 2–6 h after surgery (N = 235; RR 1.29, 95% CI 1.15 to 1.46) and physician (N = 234; RR 1.18, 95% CI 0.93 to 1.49) and patient (N = 158; RR 1.33, 95% CI 0.93 to 1.92) satisfaction. While, the number of patients with at least 50% pain relief within 0–1 h after surgery increased following dezocine compared with morphine treatment (N = 79; RR 1.45, 95% CI 1.18 to 1.77). There was no difference in the incidence of postoperative nausea and vomiting (PONV) following dezocine treatment compared with the placebo (N = 391; RR 1.06, 95% CI 0.42 to 2.68) or morphine treatment (N = 235; RR 0.65, 95% CI 0.14 to 2.93).

Conclusion

Dezocine is a promising analgesic for preventing postoperative pain, but further studies are required to evaluate its safety.     

Comparison of Transversus Abdominis Plane Infiltration with Liposomal Bupivacaine versus Continuous Epidural Analgesia versus Intravenous Opioid Analgesia

Epidural analgesia is considered the standard of care but cannot be provided to all patients Liposomal bupivacaine has been approved for field blocks such as transversus abdominis plane (TAP) blocks but has not been clinically compared against other modalities. In this retrospective propensity matched cohort study we thus tested the primary hypothesis that TAP infiltration are noninferior (not worse) to continuous epidural analgesia and superior (better) to intravenous opioid analgesia in patients recovering from major lower abdominal surgery. 318 patients were propensity matched on 18 potential factors among three groups (106 per group): 1) TAP infiltration with bupivacaine liposome; 2) continuous Epidural analgesia with plain bupivacaine; and; 3) intravenous patient-controlled analgesia (IV PCA). We claimed TAP noninferior (not worse) over Epidural if TAP was noninferior (not worse) on total morphine-equivalent opioid and time-weighted average pain score (10-point scale) within first 72 hours after surgery with noninferiority deltas of 1 (10-point scale) for pain and an increase less of 20% in the mean morphine equivalent opioid consumption. We claimed TAP or Epidural groups superior (better) over IV PCA if TAP or Epidural was superior on opioid consumption and at least noninferior on pain outcome. Multivariable linear regressions within the propensity-matched cohorts were used to model total morphine-equivalent opioid dose and time-weighted average pain score within first 72 hours after surgery; joint hypothesis framework was used for formal testing. TAP infiltration were noninferior to Epidural on both primary outcomes (p<0.001). TAP infiltration were noninferior to IV PCA on pain scores (p = 0.001) but we did not find superiority on opioid consumption (p = 0.37). We did not find noninferiority of Epidural over IV PCA on pain scores (P = 0.13) and nor did we find superiority on opioid consumption (P = 0.98). TAP infiltration with liposomal bupivacaine and continuous epidural analgesia were similar in terms of pain and opioid consumption, and not worse in pain compared with IV PCA. TAP infiltrations might be a reasonable alternative to epidural analgesia in abdominal surgical patients. A large randomized trial comparing these techniques is justified.     

全麻术后患者苏醒期躁动发生情况及影响因素分析

目的:统计全麻术后患者苏醒期躁动(EA)的发生率,并分析其影响因素。方法:本研究为回顾性研究,分析2021年5月~2021年6月期间我院收治的204例全麻手术患者的临床资料,采用躁动-镇静程度量表(RASS)评分评价患者术后是否发生EA,观察全麻术后患者EA发生率,并根据患者术后是否发生EA进行分组,采用logistic回归分析其影响因素。结果:204例患者中有47例发生EA,发生率为23.04%,纳为EA组,剩余的157例未发生EA,纳为非EA组。EA组、非EA组在性别、全麻方式、术前用药、苏醒时间方面对比差异无统计学意义(P>0.05)。EA组、非EA组在年龄、手术类型、手术时间、留置胃管/导尿管、麻醉时间、美国麻醉医师协会(ASA)分级、术后镇痛、术后疼痛方面对比差异有统计学意义(P<0.05)。logistic回归分析结果显示,年龄≥50岁、手术类型为妇科手术或泌尿外科手术、留置胃管/导尿管、ASA分级为Ⅱ级、术后疼痛是EA发生的危险因素,而术后镇痛是EA发生的保护因素(P<0.05)。结论:年龄、手术类型、留置胃管/导尿管、ASA分级、术后疼痛、术后镇痛是全麻术后患者EA发生的影响因素,临床需重点关注并给予相应防控措施。     

Continuous Epidural Analgesia for Labour and Delivery: Review of 1000 Cases

In six years in London, Ontario, the use of continuous lumbar epidural analgesia in deliveries increased from 5% to over 50%. Its effect was assessed in 1000 consecutive cases, all vertex presentations. In established labour, epidural analgesia was started for pain relief and was maintained with intermittent injections until delivery; in 34% the duration exceeded four hours. Labour was not retarded, but there was an inadvertent selection of patients with slow and painful progress. Forceps delivery was used in 89%, mid-forceps in 11.8% and forceps rotation in 17.7%; 2.4% required Cesarean section. Fetal condition was excellent (Apgar rating of 7 or greater in 96.7%). Postpartum complications could not be directly related to the technique. Continuous epidural analgesia gives superior relief of pain but calls for experienced anesthetists and adjustments in obstetrical management and nursing care.     

Systematic review of the relative efficacy of non-steroidal anti-inflammatory drugs and opioids in the treatment of acute renal colic

Objective To examine the relative benefits and disadvantages of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids for the management of acute renal colic.Data sources Cochrane Renal Group''s specialised register, Cochrane central register of controlled trials, Medline, Embase, and reference lists of retrieved articles.Review methods Randomised controlled trials comparing any opioid with any NSAID in acute renal colic if they reported any of the following outcomes: patient rated pain, time to pain relief, need for rescue analgesia, rate of recurrence of pain, and adverse events.Results 20 trials totalling 1613 participants were identified. Both NSAIDs and opioids led to clinically important reductions in patient reported pain scores. Pooled analysis of six trials showed a greater reduction in pain scores for patients treated with NSAIDs than with opioids. Patients treated with NSAIDs were significantly less likely to require rescue analgesia (relative risk 0.75, 95% confidence interval 0.61 to 0.93). Most trials showed a higher incidence of adverse events in patients treated with opioids. Compared with patients treated with opioids, those treated with NSAIDs had significantly less vomiting (0.35, 0.23 to 0.53). Pethidine was associated with a higher rate of vomiting.Conclusions Patients receiving NSAIDs achieve greater reductions in pain scores and are less likely to require further analgesia in the short term than those receiving opioids. Opioids, particularly pethidine, are associated with a higher rate of vomiting.     

四肢骨折矫形术后患者慢性手术后疼痛的发生率及其危险因素分析

目的:研究四肢骨折矫形术后患者慢性手术后疼痛的发生率及其危险因素。方法:以2014年12月-2017年10月于我院接受四肢骨折矫形术患者300例为研究对象,于术后6个月分析慢性手术后疼痛的发生率。收集所有患者年龄、性别、体重、术前疼痛程度、二次手术、麻醉方式、术后镇痛、术后引流、合并骨质疏松、骨折类型以及骨折部位等资料,并采用单因素以及多因素Logistic回归分析术后疼痛的危险因素。结果:术后6个月内有96名患者术后发生慢性手术后疼痛,发生率为32.00%(96/300)。单因素分析结果显示:慢性手术后疼痛患者与术前疼痛程度、是否二次手术、麻醉方式、术后有无镇痛、是否合并骨质疏松、骨折类型、骨折部位有关(P0.05),与患者的性别、年龄、体重、术后是否引流无关(P0.05)。多因素Logistic回归分析结果显示:术前重度疼痛、二次手术、麻醉方式为非全麻、术后无镇痛、合并骨质疏松、开放性骨折以及下肢骨折均是四肢骨折矫形术后发生慢性手术后疼痛的独立危险因素(P0.05)。结论:四肢骨折矫形术后患者慢性手术后疼痛的发生率较高,术前重度疼痛、二次手术、麻醉方式为非全麻、术后无镇痛、合并骨质疏松、开放性骨折以及下肢骨折均增加了慢性手术后疼痛的发生风险,临床应根据危险因素给予针对性的干预措施。     

Anxiolytic-like action in mice treated with nitrous oxide and oral triazolam or diazepam

Few animal studies have explored the interaction of nitrous oxide (N2O) with a benzodiazepine (BNZ) administered by the oral route, as used in clinical procedures involving "conscious sedation". The purpose of this study was to evaluate the relative "anxiolytic-like" and sedative effectiveness of N2O, oral triazolam (TRIAZ; Halcion) or oral diazepam (DIAZ; Valium), either alone or in various combinations of drugs and doses. One hundred and twelve Swiss Webster male mice, 35-45 days old, were assigned to 28 groups, each of which contained four mice. The mouse staircase test was used for the assessment of anxiety (number of rearings) and sedation (number of steps ascended). Three doses of oral TRIAZ (0.1, 0.3, 1.0 mg/kg) or DIAZ (2.0, 3.5, 5.0 mg/kg) were given in combination with room air, or N2O/O2 at a N2O concentration of 25, 50 or 75%. Each mouse was tested once. N2O alone did not reduce NR in any concentration, but caused a significant increase in locomotion. DIAZ without N2O reduced NR only with the middle and high doses, but the addition of N2O significantly enhanced the anxiolytic-like effect of all DIAZ doses. TRIAZ, alone, reduced NR only in the highest dose, but added N2O resulted in anxiolytic-like behavior with all three TRIAZ doses. The sedative effects of the BNZs were extremely variable. Only the middle dose of DIAZ plus 25% N2O unequivocally reduced the number of steps ascended, i.e., caused sedation. TRIAZ lacked the inverted U-shaped dose-response relationship with NR usually seen with DIAZ. TRIAZ, therefore, provides better dose control. This behavioral animal model indicates that the optimal combinations for reduction of anxiety-like behavior with minimal effects on sedation are 0.1 mg/kg oral TRIAZ with 25% N2O or 2.0 mg/kg oral DIAZ with 25% N2O.     

Peripheral regional analgesia with femoral catheter versus intravenous patient controlled analgesia after total knee arthroplasty: a prospective randomized study

The aim of this study is to compare the effects of femoral analgesia (FA) with 0.25% levobupivacain and intravenous patient controlled analgesia (PCA) with morphine on postoperative pain assessed by a visual-analog scale (VAS) score and their complications during the first 24 postoperative hours after the a total knee arthroplasty in a prospective randomized study. Secondary outcomes included: morphine use, patient satisfaction, complication of analgesia and duration of hospital stay. We analyzed 71 patients with an ASA score of II or III. The patients were randomized into two groups: group PCA (n = 36) was given the PCA pump, which contained morphine; and group FA (n = 35) was given first a bolus dose, then a continuous infusion 0.25% levobupivacain via a femoral catheter. The assessment of VAS was performed every 2 hours. There were no differences between the PCA and FA groups regarding demographic characteristics, operation duration, ASA score distribution, duration of hospital stay and satisfaction with analgesia (although there were more satisfied patients in the FA group). Significant differences were noted in the quantity of morphine used (higher values were in the PCA group; p < 0.001). More complications were recorded in PCA group (p < 0.001). The VAS score was lower in the FA group (p < 0.001). The highest difference occurred 4 hours after the operation, with the PCA group having significantly higher VAS score values compared to the FA group. Femoral analgesia leads to a stronger pain relief with less side effects, less morphine use and more patient satisfaction than intravenous PCA with morphine.     

骨科术后疼痛的原因分析及对策研究

目的:总结骨科术后疼痛的原因,并采取合适对策,以期降低骨科患者疼痛,提高满意度。方法:选取2012年1月-2015年1月1500例骨科手术患者为研究对象,总结引起疼痛的原因,并按照住院号单双号分成2组,对照组给予双氯芬酸钠栓镇痛,观察组采用镇痛泵镇痛,根据麻醉情况选择静脉镇痛或硬膜外镇痛,给予舒芬太尼或地佐辛镇痛,观察两组治疗前后相关指标的变化情况。结果:骨科术后疼痛原因以手术创伤为主,占92.93%,其次是手术体位限制,占53.07%,尿潴留占37.07%。两组治疗后SAS、SDS评分均较治疗前显著下降,差异具有统计学意义(P0.05),观察组治疗后SAS、SDS评分较对照组治疗后改善更加显著(P0.05)。观察组治疗后3 h、10 h、1 d、3 d、7 d VAS评分均较治疗前显著下降(P0.05),对照组治疗后3 d、7 d VAS评分较治疗前显著下降(P0.05),观察组治疗后3 h、10 h、1 d、3 d VAS评分较对照组改善更加显著(P0.05)。结论:骨科术后疼痛原因主要与手术创伤、手术体位限制有关,使用镇痛泵辅以及心理疏导能有效缓解骨科术后患者的对疼痛的感知,改善患者术后的生活质量。     

中枢催产素在电针镇痛中的作用

本工作以钾离子透入法引起大鼠甩尾反应的电流强度(mA)为痛反应指标,观察了侧脑室注射催产素(OT)及抗催产素血清(AOTS)对大鼠痛阈和电针镇痛效应的影响。注射50 ngOT 后80min 内,大鼠痛阈比注药前增加20—38%。与注射生理盐水组的痛阈相比有非常明显的增高(p<0.01—0.001),侧脑室注射 OT 后电针期内,痛阈增加139—234%,与生理盐水电针组相比,有显著差异(P<0.05—0.01)。OT 的剂量在25—100ng 范围内,其增强电针镇痛效应有明显的剂量-效应关系。注射 AOTS 后,电针镇痛应明显低于注射正常兔血清(NRS)组(p<0.05—0.01)。上述结果表明,侧脑室注射 OT,既可提高痛阈又可明显地增强电针镇痛效应,而用 AOTS消除内源性 OT 的作用后,电针镇痛效应明显降低。这提示,中枢神经系统内的 OT 在电针镇痛过程中,发挥一定的作用     

Intra-articular patient-controlled analgesia improves early rehabilitation after knee surgery

The influence of patient-controlled intra-articular analgesia with ropivacaine, morphine and ketorolac (RMK) on postoperative pain relief and early rehabilitation after anterior cruciate ligament reconstruction was studied. Twenty six patients, randomized into two groups, were enrolled in a placebo-controlled, double-blind study. At the end of surgery a catheter was placed intra-articularly and connected to a patient-controlled pump, programmed to deliver 10 mL bolus and 60 min lockout interval. RMK group received 0.25% ropivacaine, morphine 0.2 mg/mL and ketorolac 1 mg/mL; P group saline. Pain was measured with 10 cm visual analog scale. At pain scores > 3 cm, all patients were instructed to self-administer morphine intravenously using a patient-controlled pump. Daily rescue morphine consumption was noted and 48 h rehabilitation programme was evaluated. Daily morphine consumption was significantly lower in the RMK group (p < 0.001). At 24h after surgery, the patients in the RMK group experienced significantly less pain (p < 0.05). The patients in the RMK group achieved higher maximum degree of knee flexion in supine (p < 0.001) and in prone position (p < 0.05) compared to placebo group and better pain free flexion with assistance on day 1 (p < 0.05) and 2 (p > 0.05). The results show that patient-controlled intra-articular analgesia with RMK combination provides effective pain relief following anterior cruciate ligament reconstruction and improves early physical rehabilitation.     

Changes in pain sensitivity under increased atmospheric pressure]

It has been established that augmentation of air pressure from 0.1 to 1.1 MPa (with 0.1 MPa intervals) was accompanied in rats with the development of progressive analgesia which was measured according to the threshold of vocalization in the test of electrical stimulation of the tail. The highest analgesic response arose at 0.7-1.1 MPa. All the animals might be divided into two groups: group 1-72% of the animals with a 200% increase of the threshold, group 2--animals with such an increase by 15%. The augmentation of the pressure of heliox (79.1% of helium, 20.9% of oxygen) also caused analgesia, but not so strong. In patients pain thresholds to the mechanical nociceptive stimulation also increased by about 43-67% and 95-100% under the influence of increased air pressure of 0.4 and 0.7 MPa, respectively. In group 1 patients (67%) pain threshold increased by 50-100%, in group 2 by 15-25%. Pretreatment with naloxone (1 mg/kg), atropine (1 mg/kg), yohimbine (1 mg/kg), parachloramphetamine (5 mg/kg) and prasosin (1 mg/kg) decreased hyperbaric analgesia in rats by 41-56, 41-56, 17-19, 17-19%, respectively. The role of increased partial pressure of nitrogen in hyperbaric analgesia and possible neurochemical mechanisms of its realization are discussed.     

Synthesis, SAR, and preliminary mechanistic evaluation of novel antiproliferative N⁶,5'-bis-ureido- and 5'-carbamoyl-N⁶-ureidoadenosine derivatives

We have developed efficient methods for the preparation of N(6),5'-bis-ureidoadenosine derivatives and their 5'-carbamoyl-N(6)-ureido congeners. Treatment of 5'-azido-5'-deoxy-N(6)-(N-alkyl or -arylurea)adenosine derivatives (6a-d) with H(2)/Pd-C or Ph(3)P/H(2)O, followed by N-methyl-p-nitrophenylcarbamate gave N(6),5'-bis-ureido products 7a-d in 49-78% yield. Analogous derivatives in the 5'-carbamoyl-N(6)-ureido series were prepared by treatment of 2',3'-bis-O-TBS-adenosine (11) with N-methyl-p-nitrophenylcarbamate followed by acylation with appropriate isocyanates which gave 13a-d in 45-69% yield. A more versatile route for obtaining potentially vast libraries of compounds from both series was achieved by treatment of 5'-N-methylureido- or 5'-N-methylcarbamoyladenosine derivatives with ethylchlorformate to give N(6)-ethoxycarbonyl derivatives (9 and 14) in 55-63% yields, respectively. Simple heating of 9 or 14 in the presence of primary alkyl- or arylamines gave the corresponding N(6),5'-bis-ureido- or 5'-carbamoyl-N(6)-ureidoadenosine derivatives in good yields (33-72% and 39-83%; 10a-e and 15a-e, respectively). Significant antiproliferative activities (IC(50)≈4-10 μg/mL) were observed for a majority of the N(6),5'-bis-ureido derivatives, whereas the 5'-carbamoyl-N(6)-ureido derivatives were generally less active (IC(50) >100 μg/mL). A 2',3'-O-desilylated derivative (5'-amino-5'-deoxy-5'-N-methylureido-N(6)-(N-phenylcarbamoyl)adenosine, 16) was shown to inhibit binding of 16 of 441 protein kinases to immobilized ATP-binding site ligands by 30-40% in a competitive binding assay at 10 μM. Compound 16 was also shown to bind to bone morphogenetic protein receptor 1b (BMPR1b) with a Kd=11.5 ± 0.7 μM.