Unique spirocyclopiperazinium salt. Part 4: modification of dispirocyclopiperazinium (DSPZ) salts as analgesics

In order to improve the analgesic activity of lead compound 7a, two series of dispirocyclopiperazinium (DSPZ) salts 9a-h, 10a-e and compounds 14, 15 were synthesized and evaluated for their in vivo analgesic activity both by acetic acid induced writhing test and hot plate test. Compounds 9h, 14, and 15 exhibited better analgesic activities than 7a. Several important structure-activity relationships were revealed from this study: (1) the introduction of aryl group would obviously improve the activity; (2) it was favorable to enhance the analgesic activity and reduce the toxicity to incorporate alkyl group with suitable length in the molecule; (3) carbamate analogues displayed lower toxicity than carboxylic ester analogues; (4) hydroxylation and chlorination of lead compound could increase the analgesic activity in hot plate test.     

Unique spirocyclopiperazinium salt III: further investigation of monospirocyclopiperazinium (MSPZ) salts as potential analgesics

Two novel classes of monospirocyclopiperazinium salts were designed, synthesized, and evaluated for their in vivo analgesic activities. Some interesting structure-activity relationships are revealed: (1) Spirocyclopiperazinium moiety is favorable to improve the analgesic activity; (2) The size and conformation of spirocyclopiperazinium moiety significantly affects the analgesic activity; (3) Phenylethyl group of 3d is a crucial pharmacophore. Among the compounds synthesized, 3d exhibited the most potent activity with low toxicity. Further antinociceptive mechanism studies of 3d showed that these compounds will be a new kind of analgesics.     

Unique spirocyclopiperazinium salt. Part 2: synthesis and structure-activity relationship of dispirocyclopiperazinium salts as analgesics

Three series of spirocyclopiperazinium derivatives 5a-d, 6a-f and 17a-d were synthesized and evaluated for their in vivo analgesic activities. Compounds 5a, 17a and 17b exhibited excellent analgesic activity. Two important structure-activity relationships were observed from this study: (1) the quaternary ammonium functionality is a critical pharmacophore for analgesic activity; (2) it is important to adjust the lipophilic property of compounds to improve analgesic activity.     

Novel benzodiazepines derivatives as analgesic modulating for Transient receptor potential vanilloid 1

A new series of derivatives of 3-(7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoic acid were designed and synthesized as analgesic modulating for Transient receptor potential vanilloid 1. They were investigated for TRPV1 antagonistic activity in vitro, analgesic activity and sedative activity in vivo and aqueous solubility. Preliminary studies identified 3-(7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-N,N-dimethylpropanamide(Compound 11), as a potent analgesic modulating for TRPV1 with potent activity and good aqueous solubility.     

4-Aza-2,3-dehydro-4-deoxypodophyllotoxins: simple aza-podophyllotoxin analogues possessing potent cytotoxicity

4-Aza-2,3-dehydro-4-deoxypodophyllotoxin analogues 3a-n were synthesized through quinolines 2a-n. Comparison of their cytotoxicity against P-388 leukemia cells revealed that the steric effects of the ring B substituents on the activity are greater than the electronic effects, while the presence of a methoxy group on the ring E is not essential to exhibit potent cytotoxicity. Analogues 3a and 3b proved to be more than twice as cytotoxic as natural podophyllotoxin (1).     

快通道麻醉在小儿先天性心脏病手术中的应用及对镇静、镇痛效果的影响

目的:探讨快通道麻醉在小儿先天性心脏病手术中的应用及对镇静、镇痛效果的影响。方法:选择2016年6月至2018年5月在桂林医学院附属医院进行手术治疗的小儿先天性心脏病患儿82例,按照随机数字表法分为对照组(41例)和观察组(41例),对照组进行常规麻醉,观察组则采用快通道麻醉。对比两组患儿麻醉药物用量、手术时间、阻断时间、体外循环时间、术后拔管时间、住院时间、住院费用及并发症发生情况,观察两组患儿术后12h镇静、镇痛效果。结果:观察组患儿芬太尼和罗库溴铵用量明显低于对照组(P0.05)。两组患儿的术中各指标比较无统计学差异(P0.05),而与对照组相比,观察组患儿术后住院时间、拔管时间均缩短,且住院费用减少(P0.05)。观察组患儿术后12h的镇静及镇痛效果均优于对照组(P0.05)。观察组患儿术后并发症发生率为17.07%(7/41),低于对照组的39.02%(16/41)(P0.05)。结论:快通道麻醉可减少小儿先天性心脏病手术的芬太尼和罗库溴铵用量,不仅缩短术后拔管时间和住院时间,降低住院费用,而且可改善镇静及镇痛效果,安全有效。     

Cardiopulmonary effects of nalbuphine hydrochloride and butorphanol tartrate in sheep

The cardiopulmonary, sedative and analgesic effects of butorphanol tartrate and nalbuphine hydrochloride were evaluated in six adult crossbred Dorset sheep (Ovis aries). The animals were divided randomly into two groups of three. The first group received butorphanol tartrate (0.5mg/Kg s.c.) followed in 3 days by nalbuphine hydrochloride (1 mg/Kg, s.c.). The second group received nalbuphine followed in 3 days by butorphanol. Cardiopulmonary parameters were evaluated at baseline (once the animal had accommodated to restraint); immediately following analgesic administration; and at 15, 30, 60, 90 and 120 minutes after analgesic administration. No significant changes (alpha greater than .05) from baseline were seen in any of the measured cardiopulmonary parameters from either the butorphanol or nalbuphine groups. Butorphanol produced the most dramatic analgesic and sedative effects with onset of both within 15 minutes of administration and peak effects occurring 30 minutes post injection. The degree of analgesia was diminished at 120 minutes while the sedative effect returned to near baseline by 90 minutes. The nalbuphine group also showed an onset of analgesia 15 minutes post injection reaching a peak effect after 30 minutes. However, onset of sedation occurred 30 minutes post injection achieving a peak effect at 60 minutes which was markedly less than that of butorphanol. As in the butorphanol group, analgesia was diminished at 120 minutes.     

Nociceptive Transmission to Rat Primary Somatosensory Cortex – Comparison of Sedative and Analgesic Effects

CO₂-laser C-fibre evoked cortical potentials (LCEPs) is a potentially useful animal model for studies of pain mechanisms. A potential confounding factor when assessing analgesic effects of systemically administered drugs using LCEP is sedation. This study aims to clarify: 1) the relation between level of anaesthesia and magnitude of LCEP, 2) the effects of a sedative and an analgesic on LCEP and dominant EEG frequency 3) the effects of a sedative and analgesic on LCEP when dominant EEG frequency is kept stable. LCEP and EEG were recorded in isoflurane/nitrous-oxide anaesthetized rats. Increasing isoflurane level gradually reduced LCEPs and lowered dominant EEG frequencies. Systemic midazolam (10 μmol/kg) profoundly reduced LCEP (19% of control) and lowered dominant EEG frequency. Similarly, morphine 1 and 3 mg/kg reduced LCEP (39%, 12% of control, respectively) and decreased EEG frequency. When keeping the dominant EEG frequency stable, midazolam caused no significant change of LCEP. Under these premises, morphine at 3 mg/kg, but not 1 mg/kg, caused a significant LCEP reduction (26% of control). In conclusion, the present data indicate that the sedative effects should be accounted for when assessing the analgesic effects of drug. Furthermore, it is suggested that LCEP, given that changes in EEG induced by sedation are compensated for, can provide information about the analgesic properties of systemically administrated drugs.     

Glycosylation of 2-thiohydantoin derivatives. Synthesis of some novel S-alkylated and S-glucosylated hydantoins

3-Aryl-5-((Z)-arylidene)-3-aryl-2-(2-methylthioethyl)-2-thiohydantoins 3a-f and 3-aryl-5-((Z)-arylidene)-2-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyl)-2-thiohydantoins 7a-n were prepared from the reaction of 3-aryl-5-((Z)-arylidene)-2-thiohydantoins 2a-n with methylthioethyl chloride or 2',3',4',6'-tetra-O-acetyl-alpha-D-glucopyranosyl bromide via three different routes. The compounds did not display any antiviral and antitumoral activity.     

Comparison of Neurologic Responses to the Use of Medetomidine as a Sole Agent or Preanesthetic in Laboratory Beagles

Different dose regimens of medetomidine (a potent α2-adrenergic agonist), adding up to a combined dose of 80 µg/kg, were administered to laboratory beagles to determine physiologic responses including neurologic. The study was intended to determine EEG responses where sufficient sedative and analgesic effects are reached with medetomidine and in contrast its effects when used with ketamine or halothane. Cardiopulmonary responses were very similar in each dose regimen, showing the characteristic properties of single doses of 80 µg/kg of medetomidine. Effective sedative and analgesic duration seemed to be a function of when the largest dose was administered. Adequate additional sedative and analgesic could be gained from injections at doses of half of the initial one. The potent sedative and analgesic effects of medetomidine confirmed by neurologic evaluation supports its potential use as a premedication to general anesthesia in dogs. In this study, 2 different doses of medetomidine were also tested as premedication to both ketamine HCl and halothane anesthesia. Neorologic responses were determined at the same time cardiopulmonary parameters, anesthetic quality, and dose requirements were recorded. Medetomidine was found to have favorable qualities in conjunction with these anesthetics. Cardiopulmonary parameters remained satisfactory in both groups as preanesthetic medication prior to halothane, but no additional benefits could be seen from doses of 40 µg/kg medetomidine compared to 20 µg/kg, except a significant 30% reduction in halothane requirement. The positive chronotropic and inotropic properties of ketamine restored the medeto-midine-induced bradycardia and produced a short anesthetic period of 15 to 30 min depending on the dose of medetomidine. The quality of anesthesia was better when 40 µg/kg medetomidine was used, but recorvery was quicker with 20 µg/kg medetomidine. Medetomidine significantly reduced cerebral activity as demonstrated by recordings of total amplitude and frequency evaluation of the EEG with compressed spectral analysis. This analytical method was effective in confirming clinical signs of sedation, analgesia, and anesthesia in canine subjects.     

舒芬太尼复合小剂量咪达唑仑在下肢骨折椎管内麻醉前的应用观察

目的观察舒芬太尼复合小剂量咪达唑仑在下肢骨折椎管内麻醉前的应用效果。方法选取我院收治的下肢骨折患者450例,采取数字随机法分为观察组和对照组。对照组在椎管内麻醉前给予小剂量咪达唑仑,观察组在对照组的基础上于椎管麻醉前加用舒芬太尼,比较两组的应用效果。结果观察组给药后收缩压(SBP)、舒张压(DBP)、心率(HR)水平均低于入室时(P0.05),而且也明显低于对照组(P0.05)。两组血氧饱和度(SpO2)水平在入室时、给药后比较,差异无统计学意义(P0.05)。观察组给药后30、45min的镇静、镇痛效果评分均高于对照组(P0.05),而且观察组给药后45min的镇静、镇痛效果评分低于给药后30min(P0.05)。结论舒芬太尼复合小剂量咪达唑仑在下肢骨折椎管内麻醉前的应用效果显著,可达到镇静、止痛作用。     

Synthesis and anti-inflammatory activity of 2-aryloxy methyl oxazolines

A series of potential biologically active 2-aryloxy methyl oxazolines 3a-n have been synthesized from substituted hydroxybenzenes 1a-n with good chemical yield. The compounds 3a-n were screened for their anti-inflammatory, ulcerogenic, cyclooxygenase activities and also for their acute toxicity. The potency of the compounds was compared with that of the standard drugs, aspirin and phenyl butazone. The outcome indicates that compounds 3b (48.2%), 3h (48.5%) and 3l (46.5%) offered significant anti-inflammatory activity with low ulcerogenic activity than the standard drugs.     

In vivo pharmacological investigation of Monotheca buxifolia and Bosea amherstiana using animal models

Experimental based evidence suggests that most of the medicinal plants possess wide-ranging pharmacological and biological activities that may possibly use in treatment of inflammation-related diseases. The current study was aimed to explore the acute toxicity, analgesic, sedative and antipyretic activities of Monotheca buxifolia and Bosea amherstiana in mices. In vivo experimental models were used in this study. Acute toxicity was evaluated for 24 h’ interval at concentration of 500, 1000, 1500 and 2000 mg/kg. The analgesic activity was estimated by acetic acid induced writhing test. White wood apparatus enclosed in stainless steel was used for sedative experiment and antipyretic activity was evaluated in brewer’s yeast induced hyperthermic at 50, 100 and 150 mg/kg i.p. Both plants were found safe at all tested doses. Monotheca buxifolia and Bosea amherstiana dose-dependently reduced abdominal constrictions in mice. Both plants exhibited significant (P < 0.0001) sedative effects in dose of 50, 150 and 150 mg/kg. Both plants markedly (P < 0.0001) reduced yeast induced hyperthermia. The inhibitions were dose-dependent and remained significant up to five hours of administration. These investigational results have linked a pharmacological indication for the traditional claim of the drugs to be used as an anti-inflammatory, analgesics and antipyretic agents.     

Anti-nociceptive,anti-inflammatory and sedative activities of the extracts and chemical constituents of Diospyros lotus L.

Diospyros lotus L. is traditionally used in various diseases including pain and sleep disorders. The pain and inflammation are the common problems, which are treated with various synthetic analgesic drugs, and associated the side effects. The natural products have gained significant importance over synthetic drugs. The importance of phyto-medicine the current study has been designed with the aim to investigate the analgesic and anti-inflammatory effects of Diospyros lotus and bioassay guided isolation from its crude fractions. Seven known compounds; lupeol (1), 7-methyljuglone (2), β-Sitosterol (3), stigmasterol (4) betulinic acid (5), diospyrin (6; DS) and 8-hydroxyisodiospyrin (7; HDS) which were hitherto unreported from D. lotus. The chloroform fraction (CFDL) and isolated compounds DS and HDS were evaluated for anti-nociceptive, sedative and anti-inflammatory effects. The acetic acid induced writing was significantly (p < 0.001) protected by CFDL (72.43%), DS (40.87%) and HDS (65.76%) at higher doses which exhibited peripheral and central analgesic effects in acetic acid and hot-plat pain paradigms. Regarding the anti-inflammatory effect the CFDL (77.43%), DS (80.54%) and HDS (75.87%) protected the carrageenan paw edema after 3rd h. The central analgesic effect was significantly antagonized with naloxone (0.5 mg/kg), showing opiodergic mechanism of action. The CFDL, DS and HDS were also proved sedative in open field animal models. In acute toxicity study the chloroform fraction [CFDL (50, 100 and 150 mg/kg)], DS (5 and 10 mg/kg) and HDS (5 and 10 mg/kg) were found safe.Our study concluded that CFDL, DS and HDS have marked anti-nociceptive, anti-inflammatory and sedative effect. The anti-nociceptive and anti-inflammatory effects of the roots of D. lotus are partially attributed due to the presence of analgesic constituents like diospyrin (DS), 8-hydroxyisodiospyrin (HDS) and strongly supports the ethno-pharmacological uses of D. lotus as anti-nociceptive, anti-inflammatory and sedative.     

Phytoecdysones from Parana discifera

From the aerial parts of Parana discifera, 10 phytoecdysones, β- ecdysterone (1) and its 2 -acetate (2) , 3 - acetate (3), 25 - acetate (4) ,2,3- acetonide (5) , 20, 22 - acetonide (6) , and 2 -deoxyecdysterone (7) and its 20, 22 - acetonide (8), 3-O-β-D- glucopyranoside (9) and posterone (10) were isolated. They have no anti - inflammatory, analgesic, sedative, anti - convulsant and anti -cerebra- hypoxic activities in animal testing with Kunming mice.     

甜菜树属——我国云南产山柚子科一原始新属及其植物地理学意义

报道了产于我国云南红河流域山柚子科的一个原始新属——甜菜树属,该属具大型圆锥花序,两性,是Lepionurus, Melientha和Champereia 3个单型属的祖型,无疑起源于康滇古陆即今之云南高原,其发现对研究山柚子科的起源与分化具重要意义。     

超声引导下前锯肌平面阻滞对乳腺癌改良根治术患者血清疼痛介质、血流动力学及免疫功能的影响

摘要 目的：探讨超声引导下前锯肌平面（SP）阻滞对乳腺癌改良根治术患者血流动力学、血清疼痛介质、免疫功能的影响。方法：选择2020年9月-2022年5月期间我院收治的120例乳腺癌改良根治术患者,采用随机双盲对照原则将患者分为对照组和研究组,各为60例。对照组患者接受常规麻醉,研究组患者在常规麻醉基础上接受超声引导下SP阻滞。观察两组患者的镇静镇痛效果,对比两组患者疼痛介质、血流动力学及免疫功能的变化情况,记录两组围术期间不良反应发生情况。结果：研究组手术开始后10 min、术毕心率（HR）、平均动脉压（MAP）高于对照组（P<0.05）。研究组术后24 h CD8⁺低于对照组,CD3⁺、CD4⁺、CD4⁺/CD8⁺高于对照组（P<0.05）。研究组术后24 h神经肽Y（NPY）、前列腺素E2（PGE2）、P物质（SP）低于对照组（P<0.05）。研究组术后24 h疼痛视觉模拟评分（VAS）评分低于对照组,Ramsay镇静评分高于对照组（P<0.05）。两组不良反应发生率对比,无统计学差异（P>0.05）。结论：超声引导下SP阻滞可加强乳腺癌改良根治术患者的镇静镇痛效果,维持血流动力学稳定,降低血清疼痛介质,减轻免疫抑制。     

Post-Surgical Analgesia in Rainbow Trout: Is Reduced Cardioventilatory Activity a Sign of Improved Animal Welfare or the Adverse Effects of an Opioid Drug?

The use of fish models in biomedical research is increasing. Since behavioural and physiological consequences of surgical procedures may affect experimental results, these effects should be defined and, if possible, ameliorated. Thus, the use of post-surgical analgesia should be considered after invasive procedures also in fish, but presently, little information exists on the effects of analgesics in fish. This study assessed the effects of an opioid drug, buprenorphine (0.05 mg/kg IM), on resting ventilation and heart rates during 7 days of postsurgical recovery in rainbow trout (Oncorhynchus mykiss) at 10°C by non-invasively recording bioelectric potentials from the fish via electrodes in the water. Baseline ventilation and heart rates were considerably lower compared to previously reported values for rainbow trout at 10°C, possibly due to the non-invasive recording technique. Buprenorphine significantly decreased both ventilation and heart rates further, and the effects were most pronounced at 4–7 days after anaesthesia, surgical procedures and administration of the drug. Somewhat surprisingly, the same effects of buprenorphine were seen in the two control groups that had not been subject to surgery. These results indicate that the reductions in ventilation and heart rates are not caused by an analgesic effect of the drug, but may instead reflect a general sedative effect acting on both behaviour as well as e.g. central control of ventilation in fishes. This resembles what has previously been demonstrated in mammals, although the duration of the drug effect is considerably longer in this ectothermic animal. Thus, before using buprenorphine for postoperative analgesic treatment in fish, these potentially adverse effects need further characterisation.     

Structure–activity relationships for ketamine esters as short-acting anaesthetics

A series of aliphatic esters of the non-opioid anaesthetic/analgesic ketamine were prepared and their properties as shorter-acting analogues of ketamine itself were explored in an infused rat model, measuring the time after infusion to recover from both the anaesthetic (righting reflex) and analgesic (response to stimulus) effects. The potency of the esters as sedatives was not significantly related to chain length, but Me, Et and i-Pr esters were the more dose potent (up to twofold less than ketamine), whereas n-Pr esters were less potent (from 2- to 6-fold less than ketamine). For the Me, Et and i-Pr esters recovery from anaesthesia was 10–15-fold faster than from ketamine itself, and for the n-Pr esters it was 20–25-fold faster than from ketamine. A new dimethylamino ketamine derivative (homoketamine) had ketamine-like sedative effects but was slightly less potent than, but ester analogues of homoketamine had very weak sedative effects.     

A Double-Blind Comparison of Two Analgesics with Placebo Control

The value of adding a sedative to commonly used analgesic agents to promote further the relief of pain was studied by a double-blind procedure in 90 post-surgical patients during 188 pain episodes. In moderate pain episodes, no statistically significant difference between the analgesic-sedative combination (Fiorinal-C¼) and the analgesic (APC-C) was observed, although both compounds were superior to placebo (p <0.001). In severe pain episodes, the analgesic-sedative combination was superior to the analgesic alone; the analgesic, in turn, was superior to placebo (p <0.001).It is concluded that analgesia is more effective if associated apprehension is relieved by sedation.