两种β-受体阻断剂中间体的合成及表征

目的合成两种β-受体阻断剂的中间体烯烃。方法通过成醚、消除两步反应或消除一步反应合成目标产物。结果所得产物结构经¹HNMR、¹³CNMR和MS确证。产率分别为81.6%和87.96%。结论此法简便可行。为两种药物光学异构体的不对称合成奠定了基础。     

β-受体阻断剂对异丙肾上腺素提高心肌耗氧量作用的影响

The blockade effect of β-receptor blockers bupranolol and ACC9089 on the increase of heart muscle oxygen consumption by isoprenaline was studied according to Castellucci's method with Warburg's apparatus on thin slices of swine heart muscle instead of the rabbit heart muscle. The results showed that Bupranolol was about 2.5 times more stronger than practolol and about 2 times more stronger than ACC-9089 to block the increase of effects of isoprenaline for swine heart muscle oxygen consumptions on equal molar concentration levels. The results showed also that only the secondary higher concentration of 4 different concentrations of ACC-9089 could block the β-receptor to decrease the heart muscle oxygen consumption in comparison with the control. It was suggested that the highest molar cone. (1.72×10^-3M) of ACC-9089 would probably show an intrinsic sympathomimetic effect which could overlay its blockade effect to β-receptors. That the β-receptor blockers would act as the competitions with isoprenaline to the β-receptors according to their similarity of the side chain chemical structures has been discussed.     

7α和7β-甲基-10β,17β-二乙酰氧基-4-雌甾烯-3-酮的合成

由于7α-甲基或10β-乙酰氧基4(5)烯-3-酮雌(雄)甾化合物具有显著的抗着床或抗蜕膜活性,我们合成了既具有7α-甲基或7β-甲基又具有10β-乙酰氧基的两个新甾族化合物(1_a)和(1_b)。经药理试验表明(1_a)和(1_b)对孕鼠均有抗早孕作用。     

7α-和7β-甲基-10β,17β-二乙酰氧基-△4-雌甾烯-3酮的抗早孕作用

7α-和7β-甲基-10β,17β-二乙酰氧基-△⁴-雌甾烯-3酮(简称7α-和7β-甲-乙氧雌酮)对小鼠抗早孕ED₅₀分别为1.6和5.5 mg/kg。7α-甲-乙氧雌酮在大鼠也有抗早孕作用并使血浆孕酮浓度降低,应用10 μg/ml浓度能抑制离体妊娠大鼠卵巢孕酮合成。7α-和7β-甲-乙氧雌酮与兔子宫胞浆雌二醇受体的相对结合亲和力(RBA)分别为10.8和1.5,与孕酮受体的RBA均<1.7α-和7β-甲-乙氧雌酮都有较弱的雌激素和抗雌激素活性。     

氚标记强效镇痛剂N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺的制备以及与阿片受体的结合试验

本文报道以N-[1-(对-溴苯甲酰甲基)-3-甲基-4-哌啶基]-N-丙酰苯胺(Ⅲ)为前体,以PdO/BaSO₄作催化剂,用氚气进行卤—氚置换,氚化还原羰基的反应。反应产物经硅胶纸层析纯化后,用甲基橙比色法定量测定,得到N-{1-[β-羟基-β-氚-β-(对-氚苯基)乙基]-3-甲基-4-哌啶基}-N-丙酰苯胺(Ⅳ,[³H]F-7302),其比放射性为59 Ci/mM,放化纯度为98%。[³H]F-7302与小鼠脑内阿片受体的特异性结合在浓度为4.5×10^-9M时达到饱和,解离常数Kd=1.25×10^-9M,最大结合量B_max=93.08×10¹²M/g蛋白,其特异性结合与非特异性结合比值达10～15。     

β-丁香烯代谢产物和结构改造的研究

从β-丁香烯代谢产物中分离得到一种有药理活性的化合物,经光谱分析及化学反应证明其结构为β-丁香酮(8)。根据代谢产物的化学结构以及构-效关系理论,对β-丁香烯进行了结构改造研究,结果得到一种活性较强的半合成产物,为无定形长丝状物,其结构被鉴定为β-丁香烯醇(3)。药理实验表明化合物(8)及(3)对豚鼠离体气管平滑肌均有较强的松弛作用,化合物(3)还能明显抑制组织胺和乙酰胆碱诱发的豚鼠哮喘,其作用持久而毒性低,可望成为一种新型的平喘药物。     

血吸虫病化学治疗的研究——Ⅳ.β-(5-硝基-2-呋喃)丙酰胺类及其α,β-二溴取代衍生物的合成

本文报道38个β-(5-硝基-2-呋喃)丙酰胺及其α,β-二溴取代衍生物的合成。这类化合物的制备是以相应的β-(5-硝基-2-呋喃)丙烯酰胺类化合物(Ⅰ)进行催化氢化或与溴加成而得。经动物筛选发现β-(5-硝基-2-呋喃)丙烯酰胺类的丙烯双键以氢饱和以后生成丙酰胺类化合物(Ⅱ),对感染日本血吸虫病的小白鼠完全失去治疗或预防作用。而以溴饱和双键的α,β-二溴化合物(Ⅲ)则仍然有较显著的杀虫作用。其中尤以β-(5-硝基-2-呋喃)-α,β-二溴丙酰异丙胺(Ⅲ₁₁)和β-(5-硝基-2-呋喃)-α,β-二溴丙酰甘氨酸乙酯(Ⅲ₂₄)最为显著,后者曾试用于临床,证明有一定疗效。     

血吸虫病化学治疗的研究——ⅩⅩⅩⅦ.β-(5-硝基-4-溴-2-呋喃)-及β-(4,5-二溴-2-呋喃)丙烯酰胺及其酯类的合成

本文报道β-(4,5-二溴-2-呋喃)-及β-(5-硝基-4-溴-2-呋喃)丙烯酰胺及其酯类衍生物26个的合成。动物筛选结果表明;化合物Ⅲ₆,Ⅲ₈和Ⅲ₁₃对感染日本血吸虫小白鼠有明显的治疗作用。化合物Ⅱ₆有较明显的预防作用。     

强效镇痛剂研究——Ⅴ.N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7302)酯类衍生物的合成及镇痛活性

本文报道了一系列N-[1-(β-酰氧基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺类衍生物及其化学结构与镇痛强度之间的关系,并测定了几个代表化合物的镇痛作用时间及与阿片受体亲和力。实验结果表明,7302的β-羟基酯化后,均能维持一定的镇痛强度,其镇痛作用时间与母体化合物7302相近。从受体结合试验来看,酯化后与受体亲和的能力显著下降。     

磺酸化-β-环糊精为手性选择剂分离5种β-受体阻断剂类药物

目的建立高效毛细管电泳法分离索他洛尔、贝凡洛尔、美托洛尔、普萘洛尔和阿替洛尔5种β-受体阻断剂药物的对映体。方法采用未涂层的熔融毛细管柱,以磺酸化-β-环糊精(sulfated-β-cyclodextrin,S-β-CD)为手性选择剂,磷酸盐缓冲液为背景电解质,分离电压20 k V。结果在最佳条件下,5种药物均得到完全分离,分离度分别为6.7、5.2、1.7、3.1和1.6。结论 S-β-CD对5种药物具有较好的对映体选择性。     

肿瘤专科医院门诊麻醉性镇痛药品使用分析

目的了解肿瘤专科医院门诊麻醉性镇痛药品使用情况。方法采用回顾性分析方法对2012年门诊4836张麻醉性镇痛药品处方进行分析和评估。结果处方使用频率最高的药品为盐酸羟考酮缓释片,其次为芬太尼透皮贴剂和硫酸吗啡缓释片。除磷酸可待因DUI值略大于1外,其余品种DUI值均小于1。结论该院麻醉性镇痛药使用合理,阿片类缓释剂型为癌痛患者的首选药物。     

The effect of narcotic analgesics on the homovanillic acid content of rat nucleus caudatus

L. AHTEE and I. KÄÄRIÄINEN, The effect of narcotic analgesics on the homovanillic acid content of rat nucleus candatus, European J. Pharmacol. 22 (1973) 206–208.The cataleptogenic effects of 10 narcotic analgesics and related drugs were compared to their effects on the content of homovanillic acid (HVA) in the nucleus caudatus of the rat. Generally the HVA increasing and the cataleptogenic properties of the drugs ran parallel. The results Indicate that the structural requirements for the cataleptogenic and HVA-increasing properties of the narcotic analgesics bear some relation to those required for the pain-relieving properties of these drugs.     

Dose- and time-dependent effects of narcotic analgesics on intracranial self-stimulation in the rat

Rats were trained to bar-press in order to obtain electrical stimulation of the medial forebrain bundle through chronically implanted electrodes. Dose-response and time-effect curves were determined for morphine (1.0–30 mg/kg), levorphanol (0.1 to 3.0 mg/kg), methadone (0.1–3.0 mg/kg), meperidine (1.0–30 mg/kg), oxymorphone (0.03–1.0 mg/kg), and d-amphetamine (0.1–3.0 mg/kg). Dose-response and time-effect curves were also determined for morphine (1.0–30 mg/kg) in rats that had received multiple injections of morphine over a period of 3 days. All of the narcotic analgesics produced dose-related decreases in responding; the durations of these decreases were also dose-related. The relative potencies of the five narcotic analgesics with respect to the rate-decreasing effects for self-stimulation responding were: oxymorphone > levorphanol > methadone > morphine > meperidine. In morphine-tolerant rats the rate-decreasing effects of morphine on responding for self-stimulation were attenuated. These findings suggest that narcotic analgesics from diverse chemical families have a similar, predominantly depressant, effect on self-stimulation behavior and that the relative potencies of a series of narcotics for this effect are similar to those demonstrated for other properties of these drugs.     

Rates of onset and offset of action of narcotic analgesics in isolated preparations.

In isolated preparations of the myenteric plexus--longitudinal muscle of the guinea-pig ileum and the mouse vas deferens, the rates of onset and offset of action of narcotic analgesics are inversely related to lipid solubility; this effect is probably due to drug binding at secondary lipid-rich binding sites. These findings are in contrast to observations in vivo by A. Herz and his colleagues, who showed that the rates of onset of action and of recovery are directly related to lipid solubility because of the presence of lipid-rich barriers. In view of the opposite effects, an optimum may be expected when a drug has a degree of lipid solubility which ensures rapid penetration of the blood--brain barrier without seriously slowing down of receptor association and dissociation. From the interaction of rapidly acting quaternary antagonists, e.g. N-methylnalorphinium, with slowly acting agonists, e.g. methadone, it is concluded that at least a part of the receptor site is on the surface of the cell membrane, and the possibility of an allosteric agonist--antagonist interaction is considered.     

An electromyographic method for the quantitative evaluation of narcotic analgesics in rats

A new electromyographic (EMG) method described by Bieger et al. (1972) was developed for the quantitative evaluation of narcotic analgesics in rats anesthetized with urethane. d-Amphetamine increased the amplitude and the frequency of myoclonic twitch activities (MTA) of suprahyoideal muscle. Morphine and several other narcotic analgesics antagonized the amphetamine-induced MTA and their relative inhibitory potency closely paralleled their analgesic potencies. Etorphine was 2000–3500 times more potent than morphine, while meperidine showed only 2% of the activity of morphine. Levorphanol was 3–4 times more potent than morphine, while dextrorphan was inactive. l-Methadone was 10 times as potent as d-methadone. The inhibition of MTA by morphine was completely reversed by naloxone. On the other hand, the inhibition of MTA by haloperidol or by pentobarbitone was not influenced by naloxone. The measurement of the EMG of suprahyoideal muscle in rats appears to provide a convenient test and reliable means to assess the central effect of narcotic analgesics.     

上海浦东新区人民医院麻醉性镇痛药使用情况分析

目的：分析上海浦东新区人民医院麻醉性镇痛药的使用情况。方法：统计2000—2002年全院麻醉性镇痛药的用量；统计2002年医院门、急诊各科室使用麻醉性镇痛药的处方数和用量，并对晚期癌症病人的麻醉性镇痛药使用情况进行处方分析。结果和结论：我院麻醉性镇痛药的使用基本合理，吗啡缓释片在我院的使用量逐步上升，尤其是晚期癌症病人；吗啡注射剂和哌替啶注射剂的使用仍存在不合理的情况，临床使用有待改进。     

A simple,reliable method for predicting the physical dependence liability of narcotic antagonist analgesics in the rat

The rat intraperitoneal infusion procedure was used to chronically administer drugs for evaluation of the physical dependence liability of narcotic antagonist analgesics. Three methods were used to assess dependence liability: presence of withdrawal signs upon abrupt cessation of chronic infusion (primary dependence), attenuation of the withdrawal signs produced by cessation of chronic morphine infusion (morphine substitution), and production of withdrawal signs when chronically morphine-infused rats were administered the drugs (precipitated withdrawal). Butorphanol, nalbuphine and pentazocine all caused a mild withdrawal in the rat primary dependence model which agrees with the conclusions from experiments with monkey and man. None of these agents substituted for morphine in the rat and all three appeared to precipitate withdrawal. Two experimental drugs, Codorphone and TR5400, did not induce primary dependence in the rat, and in chronic-morphinized rats, they precipitated a withdrawal syndrome comparable to naloxone. Another experimental drug, TR5257, substituted for morphine. The correlation between these observations in the rat and previously published data from the monkey are excellent. It is proposed that the rat could be used as a reliable indicator of potential physical dependence liability for the narcotic antagonist analgesics.     

A new method for the evaluation of analgesic activity using adjuvant-induced arthritis in the rat

A bioassay was developed for the assessment of analgesic activity by using pain resulting from a reproducible pathological condition. The vocalization displayed by rats with adjuvant-induced polyarthritis was defined as an expression of pain, and a decrease of this response was established as specifically demonstrating analgesic activity. This method was capable of detecting the analgesic activity of morphine-like and narcotic antagonist-type analgesics, as well as the activity of the antipyretic analgesics. The relative potencies of known analgesic agents determined with this technique closely approximated the potencies of these analgesics in man. The instrumentation for recording and measuring the vocal response of arthritic rats is described.     

某三甲肿瘤专科医院2014—2015年麻醉性镇痛药应用情况分析

目的 调查分析某三甲肿瘤专科医院麻醉性镇痛药使用情况,为临床合理用药提供参考.方法 对某三甲肿瘤专科医院2014年1月至2015年12月麻醉性镇痛药的用量、使用金额、用药频度(DDDs)、销售金额、日均费用(DDC)、品种规格、排序比(药品销售金额排序B/用药频度排序A)等指标进行统计分析.结果 2014年1月至2015年12月医院麻醉性镇痛药的用量、使用金额呈逐年增长态势,用药频度中盐酸羟考酮缓释片(40 mg)、盐酸吗啡片(5 mg)和芬太尼透皮贴剂的DDDs均较高(2014年分别为283.12、928.53、375.50,2015年分别为217.03、945.57、478.00)、销售金额及DDC最高的为盐酸羟考酮缓释片,由排序比(B/A)显示经济效益与社会效益相一致的同样是盐酸羟考酮缓释片.结论 某三甲肿瘤专科医院麻醉性镇痛药品种规格相对齐全,用药选择范围广,使用比较合理.     

The effects of narcotic analgesics on the turning behaviour of rats with 6-hydroxydopamine-induced unilateral nigro-striatal lesions

Morphine at 5, 10 and 20 mg/kg intraperitoneally caused a dose-dependent, naloxone-reversible, antagonism of d-amphetamine-induced ipsilateral circling in rats lesioned with 6-hydroxydopamine in one substantia nigra. Morphine (10 mg/kg) weakly antagonized apomorphine-induced contralateral circling. Morphine, levorphanol and phenazocine were potent antagonists of d-amphetamine-induced circling in rats with a 6-hydroxydopamine lesion of one neostriatum. Pentazocine, pethidine and ethyl-ketocyclazocine were weak antagonists. It is proposed that a major action of morphine and some closely related opiate analgesics is to reduce the release of dopamine from nigro-striatal nerve terminals in the rat by acting upon specific opiate receptors.