精氨酸及精氨酸脱羧酶抗体对痛阈及吗啡镇痛作用的影响(英文)

目的进一步阐明胍丁胺对阿片药理作用的影响。方法采用小鼠醋酸扭体法、小鼠热辐射甩尾法、小鼠热板法评价了精氨酸及精氨酸脱羧酶抗体对痛阈、吗啡镇痛及其耐受作用的影响。结果在小鼠醋酸扭体实验中,脑室注射精氨酸能剂量依赖性地抑制小鼠扭体次数,最大抑制率达84 %。在小鼠热辐射甩尾模型中,精氨酸不影响小鼠的甩尾时间,但能剂量依赖性地增强吗啡的镇痛作用,使吗啡2 .5 mg·kg-1的最大可能镇痛百分率从23 %增加到71 %。此外,在小鼠热辐射甩尾实验中,精氨酸能抑制吗啡100 mg·kg-1所诱导的急性耐受。精氨酸上述作用可被咪唑啉受体拮抗剂咪唑克生(3mg·kg-1,ip)所抑制。在小鼠热辐射甩尾实验和小鼠55℃热板实验中,精氨酸脱羧酶抗体能抑制吗啡镇痛,并能加重吗啡所致的耐受。结论上述结果提示,精氨酸及精氨酸脱羧酶在痛阈、吗啡镇痛及吗啡依赖形成过程中具有重要作用。     

咪唑克生对吗啡镇痛、耐受和身体依赖的影响

目的:观察咪唑克生对吗啡镇痛及吗啡所致耐受和躯体依赖的影响.方法:采用小鼠醋酸扭体实验和55℃热板实验观察咪唑克生对基础痛阈及吗啡镇痛作用的影响;采用小鼠热辐射甩尾实验和小鼠55℃热板实验观察咪唑克生对吗啡耐受形成过程的影响;采用大鼠、小鼠身体依赖模型观察咪唑克生对吗啡所致身体依赖的影响.结果:咪唑克生(3-9mg/kg)能显著降低小鼠基础痛阈,抑制吗啡镇痛;加重吗啡所致耐受;诱发大、小鼠发生戒断综合征.结论:咪唑啉受体参与痛阈形成;咪唑克生能抑制吗啡镇痛,加重吗啡所致耐受;并诱发吗啡依赖性动物发生戒断综合征.     

利鲁唑对吗啡镇痛、耐受和依赖作用的影响(英文)

目的　研究利鲁唑对阿片镇痛、耐受及躯体功能的调节。方法　采用冰醋酸扭体 ,5 5℃热板法和热辐射甩尾法观察利鲁唑对小鼠痛阈及吗啡镇痛效应的影响 ;采用小鼠急性和慢性吗啡耐受模型及小鼠吗啡依赖模型 ,观察利鲁唑对吗啡耐受和依赖的作用。结果　单独皮下注射利鲁唑 2 .5～ 10mg·kg- 1在以上 3种模型无镇痛作用 ,然而能剂量依赖性地增强吗啡镇痛效应。利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地对抗吗啡引起的急性和慢性耐受。在小鼠吗啡依赖模型中 ,利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地抑制吗啡戒断症状的产生。结论　利鲁唑自身无镇痛作用 ,但能显著增强吗啡镇痛效应 ,并能预防吗啡所引起的耐受和依赖     

Y-IP5对小鼠吗啡镇痛、耐受及躯体依赖的影响

目的:评价化合物Y-IP5对小鼠吗啡镇痛、耐受及躯体依赖的影响。方法:采用55℃热板测痛模型分析Y-IP5对小鼠吗啡镇痛和耐受的影响;采用剂量递增法皮下注射吗啡5 d,建立小鼠吗啡依赖模型,评价Y-IP5对小鼠吗啡躯体依赖的影响。结果:在热板测痛模型中,Y-IP5(2.5,5,10 mg.kg-1)不能明显增强小鼠吗啡镇痛作用(P>0.05),Y-IP5(1.25,2.5,5 mg.kg-1)能明显抑制小鼠吗啡镇痛耐受的形成(P<0.05)。伴随吗啡给予Y-IP5(1.25,2.5,5 mg.kg-1)能剂量依赖性地抑制小鼠躯体依赖的形成(P<0.05);在纳洛酮催促前单次给予Y-IP5(1.25,2.5,5 mg.kg-1),不能显著抑制小鼠吗啡躯体依赖的表达(P>0.05)。结论:Y-IP5对吗啡耐受及躯体依赖的形成可能有一定的干预作用。     

济泰片对小鼠诱发性疼痛及对吗啡躯体依赖小鼠戒断症状的影响

目的:观察济泰片对诱发的小鼠疼痛的镇痛作用和对吗啡依赖小鼠催促戒断症状的影响。方法:(1)采用小鼠醋酸扭体法,观察经胃给予2.4 g.kg-1,3.6 g.kg-1,4.8 g.kg-1三种浓度济泰片的镇痛作用;(2)采用小鼠热板法,观察经胃给予6.0 g.kg-1,9.0 g.kg-1,12.0 g.kg-1三种浓度济泰片的镇痛作用;(3)采用连续递增给药法建立吗啡依赖小鼠模型,观察经胃给予1.2 g.kg-1,2.4 g.kg-1,3.6 g.kg-1济泰片后对吗啡依赖小鼠的纳洛酮催促戒断跳跃反应的影响。结果:(1)济泰片溶液呈剂量依赖性的抑制醋酸诱发的小鼠扭体次数(P<0.01),对扭体次数的抑制率最高可达71.7%;(2)济泰片溶液能明显提高热板法诱发的小鼠疼痛痛阈值,其镇痛的ED50=8.34 g.kg-1;(3)伴随给予济泰片溶液能剂量依赖性地抑制纳洛酮催促所引起的吗啡躯体依赖戒断症状,使吗啡依赖小鼠跳跃次数明显减少(P<0.01)。结论:济泰片对诱发的小鼠疼痛有明显的镇痛作用,并能抑制吗啡躯体依赖小鼠的戒断症状。     

白川胶囊的镇痛镇静作用

目的:研究白川胶囊的镇痛镇静作用。方法:热板法测定小鼠痛阈,观察白川胶囊对小鼠痛阈的影响;醋酸致痛法,观察药物对小鼠扭体次数的影响;计数给药前后小鼠自主活动次数,研究该药对自主活动的影响。结果:白川胶囊0.6g.kg-1组的痛阈与常水组相比较P<0.05,镇痛率为58.3%;0.3,0.15g.kg-1组的痛阈有降低趋势,但无统计学意义;0.6,0.3g.kg-1两个剂量均可减少小鼠的扭体次数,镇痛率分别为67.9%和55.8%;组间比较及与给药前比较,大、中、小剂量均可显著减少小鼠自主活动次数(P<0.05)。结论:白川胶囊有明显的镇痛镇静作用。     

Analgesic effect of agmatine and its enhancement on morphine analgesia in mice and rats

目的：观察胍丁胺镇痛和对吗啡镇痛的作用．方法：在小鼠热辐射甩尾,醋酸扭体,大鼠４％盐水实验中观察胍丁胺的镇痛作用;在小鼠和大鼠热辐射甩尾实验中观察其对吗啡和可乐定镇痛的作用．结果：胍丁胺不延长小鼠甩尾潜伏期,使小鼠醋酸扭体次数减少,完全抑制大鼠盐水扭体．在小鼠甩尾实验中,胍丁胺剂量依赖性地增强吗啡和可乐定的镇痛,使吗啡和可乐定的镇痛ＥＤ５０减小了７５％．胍丁胺的上述作用可被咪唑克生所对抗．结论：胍丁胺通过激动咪唑啉受体而具有较弱镇痛和加强吗啡及可乐定镇痛作用     

三氟拉嗪对吗啡镇痛耐受性的翻转作用

目的··:研究三氟拉嗪对吗啡镇痛耐受性的影响。方法··:热板测痛法,测定三氟拉嗪对小鼠热板(55℃)痛阈值(s)的影响;慢性吗啡处理使小鼠对吗啡的镇痛作用产生耐受性 ,观察低剂量三氟拉嗪对吗啡耐受小鼠最大镇痛效率的影响。结果··:(1)三氟拉嗪(2-20mg·kg-1)呈剂量依赖性延长小鼠的热板(55℃)痛阈值(s) ;(2)慢性吗啡处理使6mg·kg-1 吗啡最大镇痛效率降低42.2%(P<0.05),9mg·kg-1 吗啡最大镇痛效率降低9.8%(P>0.05) ;(3)合用低剂量三氟拉嗪(2mg·kg-1)和吗啡(6mg.kg-1)可以使吗啡耐受小鼠的最大镇痛效率提高47.9 %(P<0.01),其最大镇痛效率与单独急性吗啡(6mg·kg-1)处理相同。结论··:三氟拉嗪对小鼠的吗啡镇痛耐受性存在翻转作用     

胍丁胺抗阿片精神依赖作用及其神经生物学机制

阿片依赖是慢性复发性脑病，对我国社会稳定、经济发展和公共卫生造成了严重威胁。我们前期研究发现胍丁胺增强吗啡镇痛、对抗吗啡耐受及躯体依赖，本研究进一步分别采用反映精神依赖不同侧面的多种动物模型评价了胍丁胺抗吗啡精神依赖及防复吸作用，并探讨了其可能机制。在大鼠条件性位置偏爱（CPP）、行为敏化、辨别给药（DD）、自身给药（SA）模型上，从药物的奖赏、     

伊痛舒注射液的镇痛、抗炎作用

目的　观察伊痛舒注射液的镇痛、抗炎作用。方法　热板法、醋酸扭体法、K+皮下透入致痛法和尾压痛法测大、小鼠痛阈 ,蛋清性足跖肿胀法测大鼠足跖容积。结果　伊痛舒注射液 4 ,2 ,1g生药· kg-1可明显提高热板法小鼠痛阈 ,减少醋酸致小鼠的扭体次数 ,镇痛率 2 8.2 %～ 6 6 .2 %。 2 .4 g生药· kg-1在药后 2和 4 h可明显提高大鼠 K+ 皮下透入的致痛痛阈(P <0 .0 5 )。小鼠鼠尾压痛法结果显示 ,伊痛舒注射液 2 .4 ,1.2 ,0 .6 g生药· kg-13个剂量组均可明显提高压痛阈值。伊痛舒注射液 2 .4 ,1.2 ,0 .6 g生药· kg-13个剂量组能减轻蛋清引起的大鼠足跖肿胀。结论　伊痛舒注射液具有明显的镇痛、抗炎作用     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.