卢比替康片Ⅰ期临床耐受性研究

目的:观察卢比替康片在人体的安全性,确定卢比替康片口服给药对肿瘤患者的最大耐受剂量(MTD)及剂量限制性毒性(DLT),为Ⅱ期临床研究提供安全有效的给药剂量及方案。另外初步观察卢比替康的抗肿瘤疗效。方法:共纳入23例晚期恶性肿瘤患者。研究分为单次给药和连续给药两部分。19例患者,分5个剂量组(0.75,1.5,2.5,3.75,5.0 mg.m-2)单次口服卢比替康片,待清除期(7 d)后,患者再接受每日1次,每周连续5 d,停2 d的连续给药方案,所对应接受的连续给药剂量为:0.5,1.0,1.3,1.5和1.8mg.m-2.d-1。其余4例患者仅进行连续给药研究,给药剂量为2.0 mg.m-2.d-1。结果:卢比替康片经口服后患者主要不良反应为消化道反应(表现为恶心、呕吐和食欲减退)、乏力、骨髓抑制,另外观察到的不良反应还包括:腹泻、发热、头晕、肝功能异常和尿常规异常。单次给药研究中,共19例患者单次服药后均未出现DLT,但因考虑到单次给药方式并非今后临床治疗的给药方式,因此未再继续进行。在连续给药第6剂量组(2.0 mg.m-2.d-1)出现DLT,MTD为1.8 mg.m-2.d-1。本研究共20例患...     

酪丝亮肽注射液Ⅰ期临床耐受性研究

目的:评价抗癌新药酪丝亮肽的人体安全性,确定推荐Ⅱ期临床研究的剂量。方法:分为连续3 d和30 d给药两部分。共入选21例健康受试者和18例恶性肿瘤患者,每剂量组3例,3 d给药试验共设7个剂量组(0.15,0.3,0.6,1.2,2.4,3.6,4.8 mg.m-2.d-1),连续静脉给药3 d;30 d给药试验共设6个剂量组(0.3,0.6,1.2,2.4,3.6,4.8 mg.m-2.d-1),连续静脉给药30 d。结果:21例健康受试者和18例恶性肿瘤患者连续给药均无不良事件发生,没有出现剂量限制性毒性。未观察到骨髓抑制、肝肾功能损害、消化道及心血管系统毒性。结论:酪丝亮肽无明显毒副作用,人体耐受性好。推荐Ⅱ期临床使用剂量及方法为:酪丝亮肽注射液1.2~2.4 mg.m-2.d-1,静脉给药,连用30 d。     

熊果酸纳米脂质体Ⅰ期临床单次耐受性试验研究

目的:观察注射用熊果酸纳米脂质体在肿瘤患者及健康受试者中单次静脉给药的安全性和耐受性,获得其单次给药的最大耐受剂量和剂量限制性毒性。方法:采用先低剂量后高剂量的逐渐递增的探索性研究方法,依次给予11,22,37,56,74,98,130 mg.m-2熊果酸纳米脂质体。给药后第1,2,4,6,8,12,24及72 h观察生命体征和临床症状,24和72 h进行各项理化检查。结果:受试者单次静脉应用熊果酸纳米脂质体的最高剂量为130 mg.m-2,剂量限制性毒性为肝脏毒性、腹泻,其他不良反应包括腹胀、恶心、血脂异常、血钠升高、镜下血尿、皮肤过敏反应和血管刺激性。结论:本研究中注射用熊果酸纳米脂质体单次静脉给药的最大耐受剂量为98 mg.m-2,剂量限制性毒性为肝脏毒性、腹泻。     

枸橼酸爱地那非片Ⅰ期临床耐受性研究

目的:观察构橼酸爱地那非片在健康人体的安全性和耐受性.方法:单次给药试验共入选28例健康男性志愿者,随机分为4个剂量组.由初始剂量30 mg开始,在耐受性较好的情况下,逐渐增加至60,90,120 mg.连续给药试验在单次给药试验结束后进行,共入选36例健康男性志愿者,随机分为3个剂量组,递增剂量分别为30,45,60 mg,qd,连续3 d.观察临床症状体征并严密观察记录试验期间发生的不良事件.结果:单次给药试验与研究药物有关的不良事件主要为视觉异常(发生率35.7%),面色潮红(发生率21.4%),头痛或头晕(发生率17.9%)等;连续给药试验与研究药物有关的不良事件为面色潮红(发生率7.4%),头痛或头晕(发生率7.4%).试验中未发生严重不良事件,所有不良事件的程度均为轻度,均未经处理均自行消失.给药后生命体征、实验室检查和眼科检查均未见有临床意义的改变.结论:中国男性健康受试者单次口服30～120 mg的构橼酸爱地那非片和连续3 d,30～60 mg qd的枸橼酸爱地那非片安全耐受.     

重组人血管内皮抑制素Ⅰ期临床研究

目的:确定重组人血管内皮抑制素(rh-endostatin,YH-16)的最大耐受剂量(MTD)并进行药动学研究.方法:将12例健康受试者分为4组,每组3例,分别单次静脉(滴注)YH-16 30,60,120和210mg·m;10例晚期肿瘤患者分为3组,各组分别为4,3,3例,分别静脉滴注7.5,15和30mg·m-2·d-1,连续28d.22例受试者均用ELISA法测定血清YH-16浓度,进行药动学研究.结果:剂量限制性毒性(DLT)为各种心脏不良反应,包括窦性心律不齐、阵发性室上性心动过速、室性期前收缩及心电图表现T波改变.其他不良反应有发热、皮疹、轻度头晕、头痛、疲劳、心悸、胸闷、腹泻,但均很轻微.1例恶性黑色素瘤患者病变好转(MR),5例病变稳定(SD).健康受试者中药动学呈近似线性,肿瘤患者个体间药物浓度-时间曲线差异很大.结论:人体对YH-16耐受性良好,健康受试者单次给药的MTD为120mg·m-2,晚期肿瘤患者连续给药MTD为15mg·m-2·d-1.初步观察治疗肿瘤有一定疗效.推荐Ⅱ期临床给药剂量为每天12mg·m-2·d-1,连续28d.     

阿米卡星日剂量单次与分两次给药方案的体内药效及毒性比较

目的探讨日剂量单次与分两次给药方案对阿米卡星体内抗菌作用及耳、肾毒性的影响.方法1.药效学实验健康雄性豚鼠,以临床分离的铜绿假单胞菌经气管注入建立肺炎模型,随机分成日剂量单次给药组(OD)、日剂量分两次给药组(BID)(给予阿米卡星100mg/kg/d肌注)和对照组(C)(给予等量生理盐水肌注qd),共72h.观测体温、体重变化,查WBC和CRP,取感染豚鼠肺组织制成匀浆,定量培养后进行活菌计数.2.毒性实验健康雄性豚鼠,随机分成OD、BID和C组,给予阿米卡星200mg/kg/d肌注,共4w.测定血BUN、Cr、尿NAG酶并计算Ccr,制备肾组织HE染色的病理切片及电镜标本综合评定肾毒性;测定听性脑干反应阈值,结合琥珀酶杂色的耳锅铺片和扫描电镜观察耳蜗形态学变化,综合评价耳毒性.结果1.药效学实验治疗72h后OD和BID组的体温、体重减少量、WBC、CRP及肺组织匀浆活菌计数均显著低于C组(P＜0.05),但OD和BID两组间差异无统计学意义(P＞0.05).2.毒性实验OD组2周时的尿NAG酶和4周时的血BUD显著低于BID组(P＜0.05),4周时的Ccr显著高于BID组(P＜0.05),耳蜗外毛细胞缺失数显著少于BID组(P＜0.05).结论阿米卡星日剂量单次和分两次给药方案的体内抗菌作用相当,与日剂量分两次给药相比单次给药可降低耳、肾毒性.     

夫马吉欣(TNP-470)I期临床研究

目的:确定晚期肿瘤患者对夫马吉欣(O-(氯乙酰-氨甲酰基)烟曲霉素醇,0-(chloroacetyl-carbamoyl)fumagillol,TNP-470)的最大耐受剂量(MTD)、TNP-470的剂量限制性毒性(DLT)以及药动学特征,确定Ⅱ期临床推荐剂量.方法:27例晚期肿瘤患者入组,初始剂量为10 mg·m-2,依次递增为20,35,40,45,54 mg·m-2.每组患者例数依次为3,3,3,4,9,5例.夫马吉欣注射液每日给药1次,静脉点滴1 h,d 1～5,d 8～12及d 15～19用药,28 d为一治疗周期.给药前(0时)和开始滴注后10,25,40,55,65,75,85,95,105,120和150 min取血并分离血浆供药动学研究.并于治疗结束后评价疗效.结果:27例晚期肿瘤患者均可评价毒性.DLT为呼吸困难,发生率10/27,其中Ⅲ度毒性4例(20 mg组1例,45 mg组1例,54 mg组2例),停药后缓解.主要不良反应为失眠,使用安眠药可部分改善症状,停药后缓解.其他不良反应有头痛、头晕、恶心、呕吐、食欲减退、乏力,均较轻微.尚有皮疹(1例)、心悸(1例)、腹痛(1例)等少见不良反应发生,程度轻微,未予处理自行缓解.未见明显的血液毒性及肝肾损害毒性.22例可评价疗效,无CR和PR病例,2例达MR,分别为肾上腺皮质癌和上颌窦癌患者,有效部位均为肺转移灶;SD 9例,PD 11例.药动学呈二室模型,平均半衰期(7.57±3.26)min.MTD为45 mg·m-2.结论:晚期肿瘤患者对夫马吉欣耐受性良好,MTD为45 mg·m-2.推荐Ⅱ期临床的剂量为40mg·m-2,每周5 d给药,连续3周,休患1周为1个治疗周期.     

紫杉醇与环磷酰胺分别联合铂类药治疗卵巢癌的对比研究

目的 :比较紫杉醇联合铂类药物 (TP方案 )与环磷酰胺加铂类药物 (CP方案 )治疗Ⅲ、Ⅳ期卵巢上皮癌的疗效。方法 :化疗方案每一疗程采用 2d疗法 ,每种药物d 1或d 2给药 ,采用大剂量单次给药。对 2 4例Ⅲ、Ⅳ期卵巢上皮癌给予TP方案化疗 :紫杉醇剂量为 135mg·m-2 ,溶于 5 %GS 5 0 0ml中 ,静滴 ,3h ,d 1;顺铂 (DDP) 75mg·m-2 ,d 2 (或卡铂按AUC =5计算所得的剂量 ) ,前 3～ 4个疗程采用腹腔给药 ,以后均静脉给药。 30例对照组病人采用环磷酰胺加铂类药为主的CP方案。环磷酰胺 (CTX )6 0 0mg·m-2 ,静注 ,d 1;阿霉素 (ADM ) 4 0～6 0mg·m-2 ,静注 ,d 1;长春新碱 (VCR) 2mg ,静注 ,d 1;DDP 6 0～ 80mg·m-2 (或卡铂 ,剂量按AUC =5计算 )。铂类药物用药时间、途径及水化均与TP方案相同。结果 :TP方案化疗组CR为 8例 ,PR为 10例 ,总有效率为 75 % ;CP方案对照组CR 4例 ,PR 8例 ,总有效率为 4 0 % ,TP方案化疗组有效率显著高于CP方案化疗组 (P <0 .0 5 )。TP治疗组中位生存期为 4 1.5个月 ,高于CP对照组的 32 .6个月 (P <0 .0 1)。结论 :TP方案治疗Ⅲ、Ⅳ期卵巢上皮癌疗效显著优于CP方案。     

重组人促黄体激素释放激素-绿脓杆菌外毒素A融合蛋白Ⅰ期人体耐受性临床研究

目的:考察人体对冻干重组人促黄体激素释放激素-绿脓杆菌外毒素A融合蛋白(lyophilizedrecombinant human luteinizing hormone releasing hormone-exotoxin of pseudomonas aeruginosa fusion protein,简称LHRH-PE40)的耐受性、最大耐受剂量(MTD)和药代动力学特点,以及人体对LHRH-PE40产生抗体的规律,并初步观察LHRH-PE40的抗肿瘤活性。方法:LHRH-PE40经静脉输注给药。单次给药试验共10例患者接受单剂LHRH-PE40治疗,剂量范围为220～1 110μg.m-2。每日给药试验14例患者接受LHRH-PE40输注每日1次,连用14 d,剂量范围120～600μg.m-2;隔日给药试验共7例患者接受LHRH-PE40输注隔日1次,共14次,剂量为600和700μg.m-2。结果:每日给药方法的MTD为400μg.m-2,剂量限制性毒性为乏力、食欲下降和肾功能损害。肾功能损害为一过性和可逆的。隔日给药方法的MTD为600μg.m-2。在MTD剂量时,LHRH-PE40的一般不良反应...     

盐酸洛拉曲克治疗恶性肿瘤的Ⅰ期临床试验

目的:观察盐酸洛拉曲克治疗恶性肿瘤的安全性,不良反应与剂量的关系,确定推荐Ⅱ期临床研究的剂量.方法:共入选18例患者,盐酸洛拉曲克剂量分为6级,由初始剂量100mg·m-2·d-1开始逐级增加至200,340,570,740,920mg·m-2·d-1,加入5d输液泵持续静脉点滴,21d为一周期,每剂量水平3例.观察药物对机体各系统的影响和毒性反应.结果:盐酸洛拉曲克主要毒性反应为骨髓抑制(白细胞、中性粒细胞和血小板降低)、消化道反应(恶心、呕吐、腹泻)和口腔黏膜炎,毒性反应恢复较快,无药物相关性死亡病例.毒性反应与剂量相关,740mg·m-2·d-1以下的剂量组主要是Ⅰ/Ⅱ度毒性反应,920mg·m-2·d-1剂量组均出现Ⅲ或Ⅳ度毒性反应.洛拉曲克的剂量限制性毒性(DLT)为骨髓抑制(白细胞、中性粒细胞和血小板降低)、腹泻、口腔黏膜炎.最大耐受剂量(MTD)为920mg·m-2·d-1.结论:盐酸洛拉曲克对消化道恶性肿瘤患者的耐受性良好,建议Ⅱ期临床研究推荐剂量为740mug·m-2·d-1×5d,21d为一周期.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.