白细胞介素-1受体阻滞剂滴眼液耐受性研究

目的:评价白细胞介素-1受体阻滞剂(IL-1Ra)滴眼液在中国健康人的安全性和耐受性。方法:依据其临床前安全资料确定初剂量及最大剂量,评价其安全性。采用单次给药、连续多次给药的方法,观察用药后生命体征、眼局部安全指标和全身安全性指标。结果:IL-IRa的耐受性试验未引起受试者全身、局部症状的异常,未引发不良反应症状。结论:IL-1Ra滴眼液在25～100μg·mL-1范围内,人体耐受性良好。推荐进行Ⅱ期临床试验的用药剂量及疗程为50μg·mL-1滴眼液qid,每次0．05 mL,共用药5 d。     

国产重组人血小板生成素单次皮下注射的药代动力学研究

目的研究国产重组人血小板生成素单次皮下注射在人体内的药代动力学特征.方法24名健康志愿者随机分为0.5 mg.kg-1,1.0 mg.kg-1和2.0 mg.kg-13个剂量组,单次皮下注射相应剂量的重组人血小板生成素.于给药前和给药后不同时间取血,分离血清,采用ELISA测定血药浓度.结果正常人皮下注射重组人血小板生成素0.5,1.0和2.0 μg.kg-1后,tpeak分别为9.0±1.9 h,10.8±2.4 h和11.8±5.1 h,Cmax分别为0.298±0.081 mg.L-1,0.438±0.076 mg.L-1和0.831±0.079 μg.L-1,AUC与给药剂量基本成正比.人体内重组人血小板生成素的消除较缓慢,3个组的t1/2ke分别为46.3±6.9 h,40.2±9.4h和38.7±11.9 h.结论当以0.5～2.0μg.     

重组人血小板生成素治疗白血病患者化疗诱导血小板减少73例

目的:评价国产重组人血小板生成素(rhTPO)对白血病患者化疗后血小板减少的疗效和安全性.方法:73例完全缓解白血病患者进行自身对照多中心临床试验,均接受方案和剂量相同的2个周期化疗,第1个周期作对照,第2个周期化疗结束后6～24h皮下注射rhTPO 1.0μg·kg-1·d-1,连续用药最长14d.实验室检测血尿常规、肝肾功能、凝血功能、胸片、心电图及血清抗rhTPO抗体.结果:用药周期与对照周期化疗后血小板最低值分别为20.8×109和16.3×109·L-1(P＞0.05);血小板恢复最高值分别为226.9×109和144.9×109·L-1(P＜0.001),用药周期明显高于对照周期.用药周期和对照周期化疗后血小板＜50×109·L-1的持续时间分别为10.9和12.8d(P＜0.05).用药周期化疗后血小板恢复至≥75×109和≥100×109·L-1所需的时间分别为22.0和24.1d,明显短于对照周期25.0和27.8d(P分别＜0.01和＜0.001).用药周期血小板输注次数及剂量少于对照周期(P＜0.05).2个周期相比,化疗后血红蛋白(Hb),白细胞(WBC)及肝肾功能和凝血功能的变化无明显差异.1例患者产生低滴度血清抗rhTPO抗体.不良反应有发热、关节痛、头晕和头痛.结论:白血病患者化疗后给予国产rbTPO,可减少血小板降低程度和持续时间,促进血小板恢复,减少血小板输注.化疗后注射国产rhTPO是安全的.     

血小板减少患者多次皮下注射重组人血小板生成素的药代动力学研究

目的研究国产重组人血小板生成素(rhTPO)多次皮下注射在人体内的药代动力学。方法8例血小板减少患者分为隔日给药组,隔日皮下注射rhTPO 1.0 mg.kg-1,共7次;每日给药组,每日皮下注射rhTPO 1.0 mg.kg-1,共14次,每组4例。在给药前及给药后不同时间取血,分离血清。用酶联免疫吸附实验法测定血清rhTPO浓度。结果随给药次数的增加,血药浓度随之升高,隔日给药组和每日给药组的谷浓度(Cmin)分别在5,7次给药后达到稳态水平,稳态Cmin分别为1.64 ±0.97和2.91 ± 1.74mg.L-1。2组Cmax的变化趋势与Cmin相似,稳态峰Cmax分别为2.14 ± 1.10和 4.19±3.44mg.L-1。首次给药与末次给药后的药代动力学参数无明显差异。结论 血小板减少患者多次皮下注射rhTPO后,血药浓度升高的水平与累积给药量呈正相关;在给药14次后,药物在体内无蓄积倾向。     

重组人血小板生成素对肿瘤化疗后血小板计数的影响

目的 :观察重组人血小板生成素 (rhTPO )对肿瘤化疗后血小板降低的影响。方法 :选择以往肿瘤化疗后血小板小于 6 0× 10 9·L- 1的病人 (共 9例 ,其中淋巴瘤 7例 ,肺癌 2例 ,男性 4例 ,女性 5例。)予相似的化疗方案 ,在化疗结束后 2 4h内开始使用rhTPO(1.0 μg·kg- 1·d- 1,皮下注射 ) ,比较使用与不使用rhTPO病人血小板恢复情况。结果 :化疗后使用与不使用rhTPO血小板最低值分别为 (2 6±s 2 8)× 10 9·L- 1,(33± 30 )× 10 9·L- 1,P >0 .0 5。血小板最高值分别为 (2 0 3± 84 )× 10 9·L- 1,(110±76 )× 10 9·L- 1,P <0 .0 5。输注血小板的数量分别为 (0 .3± 0 .5 )U ,(0 .7± 0 .9)U ,P >0 .0 5。结论 :rhTPO未能减少化疗后血小板的下降程度 ,也未能减少血小板的输注量     

黄山药总皂苷和薯蓣皂苷元抗高脂血症及体外抗血小板聚集的比较

目的 :比较黄山药总苷 (DX)和薯蓣皂苷元 (Dio)抗实验性高脂血症及体外抗血小板聚集作用强度。方法 :给小鼠和大鼠喂饲高胆固醇饲料造成高脂血症模型 ,之后灌胃或腹腔注射给予DX和Dio ,测定血清胆固醇含量。结果 :给小鼠灌胃DX( 4 0 0和 2 0 0mg·kg-1)和Dio( 160和 80mg·kg-1)时 ,Dio对小鼠高胆固醇血症有明显预防和治疗作用 ,而DX只有大剂量时才有一定预防作用。腹腔注射给药时 ,Dio( 4 0和 2 0mg·kg-1)仍然有效 ,但DX无效。给大鼠灌胃DX( 4 0 0和 2 0 0mg·kg-1)和Dio( 2 0 0和 10 0mg·kg-1) ,均能明显降低血中总胆固醇含量 ,但在上述剂量 ,Dio的预防效果明显优于DX。DX( 60～ 2 4 0 μg·ml-1)和Dio( 3 0～ 12 0 μg·ml-1)体外有明显的抗血小板聚集活性 ,但Dio的抑制率明显高于DX。结论 :Dio抗高脂血症及抗血小板聚集作用明显优于DX。     

丹酚酸胶囊Ⅰ期临床耐受性研究

目的 :观察和评价丹酚酸胶囊单次及连续给药对人体的安全性 ,推荐临床安全、有效的用药剂量。方法 :将 32名健康志愿者随机分为 4 0 0、6 0 0、80 0和 10 0 0mg单次给药组 (n =6 )及连续给药组 (2 0 0mg ,tid× 7d ,n =8)。各组观察指标为一般情况、生命体征 (心率、呼吸、血压 ) ;血尿常规、肝肾功能等实验室检查 ;监测心电图 ;试验过程中观察不良反应。结果 :单次给药后 1、2 4、72h ,受试者的生命体征及实验室结果与给药前相比均未发现异常变化。连续给药耐受性试验结果显示 ,服药后第 4及第 8天 (停药后 1天 )受试者的生命体征和实验室检查结果与给药前相比均在正常值范围内。结论 :健康志愿者对丹酚酸胶囊单次及连续给药均有很好的耐受性。本次耐受性试验最大给药剂量为 10 0 0mg,安全性好 ,临床推荐剂量为2 0 0mg ,tid。     

菝葜活血化瘀药理作用

目的 :研究菝葜的活血化瘀药理作用。方法 :菝葜水煎液 (Ⅰ )高 (10 0g·kg- 1 )、低 (5 0g·kg- 1 )剂量对小白鼠灌胃给药 7d后 ,眼眶取血 ,采用凝固比浊法对APTT、PT进行测定 ,用Derive法测定FIB ;全自动血细胞计数仪测定血小板数 ,采用比浊法体外测定Ⅰ对人血小板的聚集功能Ma、M 1、V1的影响。结果 :Ⅰ的 10 0 g·kg- 1 剂量能显著延长APTT(P <0 .0 5 ) ,稀释8倍后的Ⅰ能抑制体外的血小板聚集功能 ,特别是对V1的影响更显著 (P <0 .0 1) ,但对FIB和血小板数无明显影响。结论 :菝葜具有活血化瘀的药理作用 ,表现在抑制血小板聚集和延长内源性凝血时间。     

国产重组人白细胞介素11的Ⅰ期临床试验

目的 :观察国产重组人白细胞介素 11(rhIL 11)的临床不良反应 ;初步观察rhIL 11对化疗引起的血小板减少症的疗效 ;确定Ⅱ期临床试验rhIL 11的推荐剂量。方法 :对于上一个化疗周期中血小板计数最低点≤ 75× 10 9·L- 1的病人 ,于此周期化疗给药后的 2 4～ 36h皮下注射rhIL 11,qd×14d ,或血小板计数 >30 0× 10 9·L- 1后停药。rhIL 11分为 12 .5 ,2 5 ,5 0和 75 μg·kg- 1·d- 14个剂量组 ,剂量依次逐渐递增 ,每组应完成病例 3～ 5例 ,每完成一个剂量组试验后方可进行下一个剂量组试验。结果 :5 0 μg·kg- 1·d- 1剂量组有 2例病人分别出现了 3度关节肌肉疼痛和心律失常。其他不良反应均为Ⅰ～Ⅱ度 ,有发热、结膜充血、水肿、心悸、感冒样症状、恶心、呕吐、贫血、凝血因子Ⅰ升高等。 14例病人可评价疗效 ,6例 (43% )病人整个疗程中无血小板减少 ,8例有血小板减少的病人血小板最低点中位数为 80× 10 9·L- 1,从血小板最低点到恢复正常的中位时间为 4d。所有病人均不需输注血小板。结论 :rhIL 11的临床不良反应可以耐受 ,初步显示了对化疗引起的血小板减少症的疗效。Ⅱ期临床试验rhIL 11的推荐剂量为 5 0 μg·kg- 1·d- 1。     

复方四季青提取物雾化吸入给药的药效学研究

目的:进行复方四季青提取物雾化吸入给药的药效学研究。方法:小鼠随机分为空白对照组,阳性药物对照组,复方四季青提取物口服给药高剂量组(2．79 g·kg-1)、中剂量组(1．86 g·kg-1)、低剂量组(0．93 g· kg-1),雾化吸入给药高剂量组(2．79 g·kg-1)、中剂量组(1．86 g·kg-1)、低剂量组(0．93 g·kg-1),采用酚红祛痰法观察祛痰作用和体内抗菌法观察对肺炎双球菌感染小鼠的保护作用。结果:复方四季青提取物高剂量口服给药,高剂量雾化吸入、中剂量雾化吸入能使小鼠气管酚红排泌量明显增加,排泌量分别为(0．052±0．009), (0．055±0．009),(0．052±0．009)mg·L-1,有显著的祛痰作用,与空白对照组相比有显著差异(P<0．05)。雾化吸入给药及高剂量口服给药对腹腔感染肺炎双球菌小鼠的死亡率均有明显的抑制作用,72 h死亡率分别为 40％,40％,45％,55％,1 wk死亡率分别为40％,50％,55％,60％。与空白对照组相比有显著差异(P< 0．05)。结论:复方四季青提取物雾化吸入给药是提高疗效的有效途径之一。     

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.