新型重组人肿瘤坏因子对恒河猴的长期毒性

AIM: To study the long-term toxicity of modified recombinant human tumor necrosis factor (rhTNF-NC) in Macaca mulatta compared with recombinant human tumor necrosis factor (rhTNF). METHODS: rhTNF-NC 93, 9.3 GU/m2, and rhTNF 62 GU/m2 were injected i.v. daily to 16 Macaca mulatta for 1 month and 10 d, respectively. Hematologic, chemical, urinalysis values, ECG, specific antibody, bone marrow, and pathologic profile of organs were measured. RESULTS: No more adverse effects of rhTNF-NC were found in spite of anorexia in 4 monkeys and palpebral edema in 2 monkeys of 93 GU/m2 group. Besides, in rhTNF group, the injury of liver and kidneys, the decrease of erythron, the phlebitis, and thrombosis at injection site occurred. Both drugs caused the production of specific antibody. CONCLUSION: No serious adverse effects of rhTNF-NC were found in Macaca mulatta. The toxicity of rhTNF-NC was much lower than that of rhTNF.     

硝基甲苯类化合物联合毒性的研究

研究结果表明,硝基甲苯类化合物的联合毒性主要表现为完全相加和部分相加,相互间不存在协同作用。为此建议,硝基甲苯类化合物在地面水中的混合物最高容许浓度可按相加特性制订。     

二硝基甲苯的毒性研究

二硝基甲苯 (ｄｉｎｉｔｒｏｔｏｌｕｅｎｅ ,ＤＮＴ)是制造三硝基甲苯(ＴＮＴ)的中间物和制造聚氨基甲酸酯泡沫塑料的重要原料。为了解ＤＮＴ对哺乳动物毒作用的危害 ,观察其毒效应的剂量水平 ,进行了此项研究。1　材料与方法1 1　材料　 80 / 2 0 (2 ,4 ＤＮＴ/ 2 ,6 ＤＮＴ)ＤＮＴ工业品 ,呈黄色蜡状物 ,纯度 99 6 % ,由某兵工厂提供。昆明小鼠、ＳＤ大鼠和新西兰兔 ,由第四军医大学实验动物研究中心提供。2　方法2 1　急性毒性实验　小鼠体重 2 4～ 2 8ｇ和大鼠体重 170～190 ｇ各 6 0只 ,按等比级数 1 37和 1 2 8随机分为 6组 ,每组1…     

PEG IFN α-1b重复给药对恒河猴的毒性实验

目的评价PEG IFN α-1b对恒河猴多次皮下注射给药的毒性作用,提供PEG IFN α-1b对恒河猴毒性反应的靶器官及其损害的性质,确定PEG IFN α-1b的无毒反应剂量,为制定临床用药方案提供参考资料。方法24只成年健康恒河猴(雌雄各半)分为溶剂对照、PEG IFN α-1b600、100和15μg/kg4组,每组雌、雄动物各3只。各组动物隔天一次分别皮下注射溶剂或不同浓度的PEG IFNα-1b各2ml,90d共注射45次。PEG IFN α-1b给药量分别相当于成人一次剂量的230、30和6倍。结果给药期间所有动物反应无异常,无死亡。动物的体重、体温、血压、呼吸、尿常规及凝血指标无异常。30项外周血象结果表明,给药期间各组动物外周血白细胞及中性粒细胞数减少,以大剂量组尤为明显,减少幅度约50%;单核细胞有升高,血小板数有降低的趋势,但各剂量组间无明显的量效关系。给药期间所有3个剂量PEG IFN α-1b组动物的16项血浆生化指标与同期溶剂对照组比较,差异无统计学意义。各组动物血清免疫球蛋白IgA、IgG、IgM和IgE检查结果与药前值比较,差异均无统计学意义。3个不同剂量PEG IFN α-1b给药后20d,血清中结合抗体滴度均开始明显升高,以大剂量组尤为明显。此后仍呈波动性升高的趋势,至停药后30d仍处峰值。PEG IFN α-1b皮下注射90d和停药后30d3个给药组均未查到中和抗体的产生。组织病理学检查结果显示大剂量PEG IFN α-1b给药组动物给药90d处死猴肾小球毛细血管减少,基底膜增厚,间质细胞增生;胸腺小叶蜕化,细胞数减少,胸腺脂肪化,停药后30d,上述病理变化消失,未见异常改变;肝中央静脉旁可见淋巴小结形成,肝细胞出现散在大片状水肿,胞体肿胀,但未见到肝细胞坏死现象,停药30d时可见个别动物仍有肝细胞广泛性水肿;骨髓细胞明显疏松,数量明显减少,可见多发性细胞坏死小灶,伴有明显地髓腔内出血。PEG IFN α-1b中、小剂量及溶剂对照组未见上述异常病理改变。结论PEG IFN α-1b100和15μg/kg隔天一次、连续90d皮下注射恒河猴给药期间除外周血白细胞、血小板数降低外,其他各项指标包括组织病理学检查均无明显异常改变。PEG IFN α-1b600μg/kg组动物给药期间外周血白细胞和血小板数降低至药前值的52%和80%,肾小球毛细血管减少,间质细胞增生;肝细胞胞体肿胀;骨髓细胞疏松,数量减少,可见有细胞坏死小灶。因此,在临床应用中,尤其是在大剂量、长期给药时,应密切观察肝、肾功能指标及外周血象。     

三硝基甲苯在小鼠体内代谢及对免疫功能影响

用油剂的三硝基甲苯（ＴＮＴ）剂量为１００，２００ｍｇ／ｋｇ给小鼠一次灌胃，小鼠血中ＴＮＴ及其代谢产物４Ａ－ＤＮＡＴ、２Ａ－ＤＮＡＴ在染毒后第２，９，１４天持续出现，但浓度较低。提示ＴＮＴ在体内有少量蓄积。染毒后第４，９天用ＳＲＢＣ免疫小鼠，对小鼠血清溶血素水平、迟发型变态反应均有抑制作用。ＡＮＡＥ阳性淋巴细胞百分率明显降低。随着染毒时间延长，Ｔ、Ｂ淋巴细胞抑制作用增强，差异显著。肝脏、肾脏重量无明显变化。提示进一步研究血液中ＴＮＴ及代谢产物ＤＮＡＴ浓度变化情况，应适当延长实验时间。把免疫功能检测作为对ＴＮＴ职业接触工人早期健康监护的生物学指标是有意义的。     

三硝基甲苯生物标志物的研究

三硝基甲苯生物标志物的研究刘玉瑛，姚明，方家龙，王雅文三硝基甲苯是我国常见五种工业毒物之一。工人接触后可产生眼白内障及肝脏损害。长期以来寻找特异性指标是生物监测及职业病临床所亟待解决的问题［１］。七五期间，我们从放射示踪入手观察到ＴＮＴ进入机体后，在...     

腺病毒载体疫苗在恒河猴体内的长期毒性试验

目的探讨以5型腺病毒为载体的人用疫苗Ad5-LMP2在恒河猴体内的药效学作用和安全性。方法恒河猴经im给予4.5×1011、1.5×1011和0.5×1011v.p·(kg·次)-1的Ad5-LMP2和等体积的磷酸盐缓冲液(对照组),每5d给药1次,共给药6次。在停药次日和停药15d时进行尿常规、血液、眼科、心电图、脏器重量和系数、大体观和病理组织学检查;给药前后定期采取猴血清并从剖检猴的脾脏分离淋巴细胞,用ELISA、病毒中和试验和ELISPOT检测腺病毒载体和目的基因蛋白产物LMP2诱导的体液和细胞免疫应答;通过PCR扩增各器官总DNA中的lmp2基因来检测Ad5-LMP2在体内的生物分布。结果在整个试验期间试验猴均未出现任何异常反应,也无动物死亡;给药组动物在整个给药期间的摄食、饮水和体重增长及上述各项常规毒理学检测中均未出现明显异常。受试物在试验猴体内诱发了较高水平的抗腺病毒中和抗体,但目的蛋白LMP2诱导的特异性细胞免疫应答未受抗腺病毒中和抗体的明显抑制;在猴的心、肝、脾、肺、肾、脑、睾丸(或卵巢)及给药部位均可检测到Ad5-LMP2并维持到停药后15d。结论在保证受试物药理学作用的前提下,恒河猴连续1mon肌肉注射相当人临床拟用剂量37.5倍的Ad5-LMP2,未见明显不良反应,中毒靶器官和中毒剂量未明显显示,其安全剂量大于4.5×1011v.p·(kg·次)-1。     

三硝基甲苯对雄性生殖毒性的研究

急性、亚急性和亚慢性TNT染毒大鼠睾丸铜锌含量和多种酶活性皆有所变化;睾丸和血清睾酮含量下降。大鼠辜丸游离间质细胞与TNT共同孵育时,睾酮形成量明显下降;间质细胞与TNT孵育后,活性氧与脂质过氧化阳性物质含量明显增加。补锌在一定程度上能拮抗TNT对大鼠的生殖毒性。横断面调查表明,TNT接触男工自觉性功能降低者增加,血清睾酮含量下降,精液常规检查有阳性所见。     

重组人脑钠素对恒河猴长期毒性研究

目的:研究重组人脑钠素(rhBNP)对恒河猴的长期毒性.方法:健康恒河猴分别按体重随机分为低、中、高剂量组和空白对照组.低、中、高剂量组给药量分别为0.03,0.09和0.3mg·kg-1.连续30d静滴给药.末次给药后处死一半动物做病理解剖,另一半停药后继续观察15d.观察症状和检测指标包括:①血压、尿量等一般症状.②心电图.③红细胞、白细胞等血液学指标.④血钾、钠、氯、醛固酮等血液生化指标.⑤尿液检查.⑥抗体测定.⑦骨髓检查.⑧注射部位、心脏等病理检查.结果:动物连续给药后,高剂量组猴静滴后血压明显下降,中剂量组给药后血压有下降趋势但无明显差异.血压变化在3h内恢复正常.高、中剂量组给药后2h内尿量明显增加,但24h总尿量无明显改变.低剂量组血压及尿量无明显变化.d30病理组织学检查发现高剂量组少数动物出现肝细胞坏死,d45未发现有上述病理变化.肾组织也发现有病理变化,但存在于各个组,可能非药物所致.结论:rhBNP对猴心血管、泌尿系统有一定的药理毒理作用,主要表现为降血压、利尿,对肝脏可能有轻度毒性作用,其作用均是可逆的.rhBNP对恒河猴的安全剂量为0.03mg·kg-1.     

恒河猴重复给药腺病毒载体疫苗毒性研究

目的 探讨以5型腺病毒为载体的人用疫苗Ad5 SARS-CoV-2(LW2006)经3次皮下重复给予恒河猴所产生的毒性反应,为其安全性评价实验和临床用药提供基础数据。方法 30例恒河猴,雌雄各半,按体重均衡随机分为对照组(生理盐水)、LW2006低剂量(0.5×10¹¹ VP)组和LW2006高剂量(2.0×10¹¹VP)组。通过皮下注射连续给药3周,每周给药1次,恢复期观察4周。于给药结束、恢复观察结束后,分别剖检18只和12只恒河猴。检测观察指标包括临床观察、体重、血液、生化、尿常规、淋巴细胞亚群、细胞因子、抗核抗体、脏器重量、脏器系数和病理学检查。结果 腺病毒疫苗可引起绝大部分动物给药部位皮肤皮下血管周围局灶性/多灶性炎细胞浸润。恢复期观察结束后,以上变化与给药结束后相比,皮下反应动物比例和程度均明显降低,其余检查脏器包括免疫器官胸腺、脾和淋巴结等均未见明显异常变化。结论 在本实验条件下,以5型腺病毒为载体的人用疫苗Ad5 SARS-CoV-2可引起恒河猴给药部位皮下局部轻度刺激性反应,恢复期可逆,无其他毒理学反应。     

反相高效液相色谱法测定恒河猴血浆中间尼索地平的浓度

目的:建立以反相高效液相色谱法测定恒河猴血浆中间尼索地平浓度的方法。方法:色谱柱为C18,流动相为甲醇-水(63∶37),柱温为30℃,流速为1.0ml/min,检测波长为236nm,灵敏度为0.05AUFS,内标为尼莫地平。结果:间尼索地平检测浓度在1.75～448μg/L范围内线性关系良好;平均提取回收率为84.1%(RSD=4.09%),平均方法回收率为98.7%(RSD=2.76%);处理后的血浆样品放置7d性质稳定,血浆样品反复冻融及低温保存性质稳定。结论:本方法灵敏度高、重现性好、操作简便,可用于恒河猴血浆中间尼索地平浓度的测定。     

Pharmacokinetics,cerebrospinal fluid penetration,and metabolism of piroxantrone in the Rhesus monkey

Summary Piroxantrone is an anthrapyrazole derivative with broad anti-tumor activityin vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantrone have not been determined. In this study we examined the pharmacokinetic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxantrone was isolated and its cytotoxicity evaluatedin vitro. The disappearance of piroxantrone from plasma after an intravenous dose of 150 mg/m² given over 60 minutes was biexponential with mean t_1/2 alpha of 1.0 minutes and a mean t_1/2 beta of 180 minutes. The mean area under the curve was 220 M·min and the clearance was 1420 ml/min/m². Piroxantrone was not detectable in the cerebrospinal fluid.Piroxantrone and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cytotoxicity against MOLT-4 cellsin vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detected in urine was determined to be a glucuronide conjugation product of the major metabolite.The results of this study may be useful in the interpretation of the activity and toxicity of piroxantrone in clinical trials.     

间苯二酚毒性研究

大鼠经口LD50为745.3mg/kg,小鼠经口LD50为286.9mg/kg。蓄积系数大于5.3,属弱蓄积级。对皮肤、眼结膜有刺激作用,无致敏作用。大鼠亚急性吸入染毒,高浓度组(229.8mg/m~3)的平均体重、肺灌流液巨噬细胞存活率和溶菌酶含量都显著低于对照组,而低浓度组(37.1mg/m~3)除肺巨噬细胞存活率明显低于对照组外,其余指标无明显改变。据此认为,慢性阈浓度为37.1mg/m~3。     

Prolonged Attenuation of the Reinforcing Strength of Cocaine by Chronic d-Amphetamine in Rhesus Monkeys

Chronic treatment with the indirect dopamine agonist d-amphetamine can reduce cocaine use in clinical trials and, in preclinical studies in laboratory animals, attenuates daily cocaine self-administration. The present study extended previous results to conditions designed to reflect a more clinically relevant experience of cocaine exposure and d-amphetamine treatment. Each morning, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio schedule of reinforcement. After determining a dose-response curve for cocaine (0.003–0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule of reinforcement in the evening, cocaine self-administration sessions were suspended and d-amphetamine (0.01–0.056 mg/kg/h, i.v.) was administered continuously for at least 24 days, except during cocaine self-administration sessions, which were conducted using the PR schedule once every 8 days. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was redetermined. Cocaine- and food-maintained responding were also examined after discontinuation of d-amphetamine. Although individual differences in sensitivity were observed, d-amphetamine produced selective, qualitatively similar decreases in the reinforcing strength of cocaine in all monkeys that persisted at least 4 weeks. Moreover, cocaine dose-effect curves were shifted downward and/or to the right. For 2 weeks following discontinuation of d-amphetamine treatment, the reinforcing strength of cocaine varied within and across individuals, however, on the whole no increased sensitivity was apparent. These data provide further support for the use of agonist medications for cocaine abuse, and extend the conditions under which such treatment is successful to those that incorporate clinically relevant patterns of cocaine use and drug treatment.     

One-Year Inhalation Toxicity Study of Chlorine in Rhesus Monkeys (Macaca mulatta)

Chlorine (Cl₂) gas is a potentially lung-damaging irritant whichis used in the chemical, plastics, and paper industries. Thereare no data published using experimental animals on the chronicinhalation toxicity of chlorine. The purpose of this study wasto investigate the chronic effects of Cl₂ inhalation in Rhesusmonkeys (Macaca mulatta). Rhesus monkeys were exposed to concentrationsof 0, 0.1, 0.5, or 2.3 ppm Cl₂ for 6 hr per day, 5 days perweek for 1 year. Pulmonary physiology (pulmonary diffusing capacityand distribution of ventilation), body weights, urinalysis,electrocardiographs, hematology, and clinical chemistry wereevaluated monthly during the study. Blood gas evaluations wereperformed at 3-month intervals during the study. Histopathologic,ophthalmologic, and neurologic parameters were evaluated afterthe 1-year exposure period. Monkeys exposed to 2.3 ppm Cl₂ exhibitedsigns of ocular irritation during the daily exposures and asuperficial conjunctival irritation was present in the 2.3 ppmgroup after the 1-year exposure regimen. Treatment-induced lesionsrevealed by histopathology were confined to the respiratorytract. Lesions associated with the nasal parasite Anatrichosomaspp. were present in the region of squamous epithelium of thenasal vestibule and did not interfere with interpretation ofCl₂ induced effects. Treatment-induced histopathologic changeswere found in the respiratory epithelium of the nasal passagesand trachea and were limited to focal, concentration-relatedepithe hal hyperplasia with loss of cilia and decreased numbersof goblet cells in affected areas. These changes in the noseand trachea were focal and mild in monkeys exposed to 2.3 ppmand were not found in all animals in these exposure groups.Tracheal lesions were confined to the 2.3 ppm group. The lesionsobserved at 2.3 ppm were not present in all animals. At thelower Cl₂ concentrations, similar though less prominent respiratoryepithelial lesions were observed. The latter changes were veryminimal and were confined to the nasal passages of some treatedmonkeys and one male control animal. The results of this studyindicate that 2.3 ppm chlorine acts as an upper respiratoryirritant in monkeys, while 0.5 and 0.1 ppm induce changes ofquestionableclinical significance. Furthermore, the monkey appears to beless sensitive than the rat to chlorine toxicity.     

Effects of Phendimetrazine Treatment on Cocaine vs Food Choice and Extended-Access Cocaine Consumption in Rhesus Monkeys

There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1–7: 0.32 mg/kg/h; days 8–21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).     

猕猴皮下注射重组人甲状旁腺激素的药代动力学研究

研究猕猴皮下注射重组人甲状旁腺激素[rhPTH（1-34）]后的药代动力学及生物利用度。猕猴皮下注射rhPTH（1-34）10，20和40ug/kg，静脉注射rhPTH（1-34）20ug/kg以及连续皮下注射rhPTH（1-34）40ug／kg（每天一次，连续14天），应用放免方法（IRMA）检测血浆样本中药物浓度，然后采用非房室模型计算药代动力学参数。IRMA方法检测血浆中rhPTH（1-34）的线性范围为0．027—2．22ng／mL。日内和日间精密度都小于15％，并且平均回收率约为93．0％±8．6％～116．5％±14．0％。猕猴皮下注射rhPTH（1—34）10，20和40ug／kg后，平均达峰时间Tmax分别为0．67，0．5和0．83h，峰浓度Cmax分别为1．85±0．05，3．23±0．25和7．15±1．19ng/mL,曲线下面积AUC（0-∞）分别为3．4±0．6，10．7±1．3和12．6±1．5ng／h／mL,末端相消除半衰期T1/2分别为0．72±0．10，1．15±0．10和1.03±0．06h。猕猴皮下注射mPTH（1-34）20ug／kg的绝对生物利用度为46．96％。连续注射猕猴rhPTH（1-34）后无药物蓄积。IRMA方法具有高灵敏度及专属性，适用于猕猴皮下注射mPTH（1-34）后的药物药代动力学研究。在给予剂量范围内，猕猴体内的rhPTH（1-34）药物代谢符合线性动力学特征。     

Pharmacokinetics,metabolism, excretion and plasma protein binding of 14C-levofloxacin after a single oral administration in the Rhesus monkey

Levofloxacin's metabolism, excretion, and in vitro plasma protein binding, together with its pharmacokinetics, were studied in the Rhesus monkey in support of an anthrax efficacy study in this species. Three males and three female Rhesus monkeys were dosed with a single oral dose of ¹⁴C-levofloxacin at 15?mg?kg^?1 (2?MBq?kg^?1). Following dose administration, blood samples were collected up to 48?h post-dose, and urine and faeces were quantitatively collected up to 168?h post-dose. Blood, plasma, urine, and faeces were analysed for total radioactivity. Metabolite profiling and identification was performed using radio-high-performance liquid chromatography (HPLC) and liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS). Additionally, the plasma protein binding of levofloxacin was determined in vitro by means of equilibrium dialysis. Peak plasma levels of total radioactivity and levofloxacin were rapidly reached after oral administration with a total radioactivity blood: plasma ratio close to unity. The elimination half-life of levofloxacin was estimated at about 2?h. Total radioactivity was mainly excreted in urine (about 57–86% of the dose) with faecal excretion accounting for only a minor fraction of the total amount of excreted radioactivity (about 7.4–14.7%). In the plasma, the majority of total radioactivity was accounted for by levofloxacin. In addition, two minor metabolites, i.e. levofloxacin n-oxide and presumably a glucuronide conjugate of levofloxacin, were detected. In the urine, five components were found, with levofloxacin being the major component. Minor metabolites included desmethyl levofloxacin, levofloxacin n-oxide, and a glucuronide conjugate of levofloxacin. In the faeces, the major analyte was a polar metabolite, tentatively identified as a levofloxacin glucuronide. The in vitro plasma protein binding was low (on average 11.2%) and independent of concentration (1.0–10.0?µg?ml^?1). No sex differences were noted in any of the investigations. The present data indicated that the metabolism and excretion pattern, and also the in vitro plasma protein binding of levofloxacin in the Rhesus monkey, were comparable with those previously reported in man, hereby supporting the use of this animal species in the efficacy evaluation of levofloxacin against inhalation anthrax. The shorter half-life of levofloxacin in the Rhesus monkey relative to man (2 versus 7?h) prompted the development of an alternative dosing strategy for use in the efficacy study.     

Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology,Behavior, and Dopamine System Development

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP_ND), an index of tracer-specific binding, and amphetamine-induced changes in BP_ND of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.     

Amelioration of the Cardiovascular Effects of Cocaine in Rhesus Monkeys by a Long-Acting Mutant Form of Cocaine Esterase

A long-acting mutant form of a naturally occurring bacterial cocaine esterase (T172R/G173Q CocE; double mutant CocE (DM CocE)) has previously been shown to antagonize the reinforcing, convulsant, and lethal effects of cocaine in rodents. However, the effectiveness and therapeutic characteristics of DM CocE in nonhuman primates, in a more clinically relevant context, are unknown. The current studies were aimed at (1) characterizing the cardiovascular effects of cocaine in freely moving rhesus monkeys, (2) evaluating the capacity of DM CocE to ameliorate these cocaine-induced cardiovascular effects when administered 10 min after cocaine, and (3) assessing the immunological responses of monkeys to DM CocE following repeated administration. Intravenous administration of cocaine produced dose-dependent increases in mean arterial pressure (MAP) and heart rate (HR) that persisted throughout the 2-h observation period following a dose of 3.2 mg/kg cocaine. Cocaine failed to produce reliable changes in electrocardiograph (ECG) parameters, body temperature, and locomotor activity. DM CocE produced a rapid and dose-dependent amelioration of the cardiovascular effects, with saline-like MAP measures restored within 5–10 min, and saline-like HR measures restored within 20–40 min of DM CocE administration. Although administration of DM CocE produced increases in anti-CocE antibodies, they did not appear to have a neutralizing effect on the capacity of DM CocE to reverse the cardiovascular effects of cocaine. In conclusion, these findings in monkeys provide strong evidence to suggest that highly efficient cocaine esterases, such as DM CocE, can provide a potential therapeutic option for treatment of acute cocaine intoxication in humans.