Safety Pharmacology Society: 9th Annual Meeting

The keynote presentation of the Safety Pharmacology (SP) Society 9th Annual Meeting addressed the urgency, for pharmaceutical organizations, to implement strategies for effectively communicating drug risks to all concerned stakeholders and, in particular, the general public. The application of chronobiology to SP investigational protocols can improve the search of drug-induced adverse effects. The Distinguished Service Award Lecture reviewed a life-long journey through trials and tribulations in the quest of the ever-distant scientific truth. The revision process of Directive 86/609/EC for improving animal welfare should be conducted with the purpose of maintaining a fair balance among animal protection, human health and research imperatives in order to prevent the migration of pharmaceutical activities outside Europe. Additional topics of interest were the behavioral, metabolic and cardiovascular problems experienced by small animals housed at the standard laboratory temperature. A technology for the automated collection of blood and urine samples in rats implanted with telemetry sensors was presented. Non-clinical, clinical, regulatory and legal aspects of abuse liability were expertly reviewed. The ‘degradability’ of pharmaceuticals into environment-friendly chemicals should be an actively searched and optimized feature of future pharmaceuticals in order to prevent drug pollution of ecosystems. Transgenic and diseased animal models should be selected whenever they can facilitate the determination of drug-induced adverse effects. SP strategies to investigate the safety of drug combination products were exemplified and analyzed in depth. The future of SP was proposed to lie not in the performance of regulatory studies of pharmacodynamic nature but in developing and early applying an array of screening assays for clearing clinical candidates against known drug-induced organ function injuries. In conclusion, the 2009 SP Society annual meeting offered a wealth of thought-provoking material to attendees for improving SP investigation strategies.     

时辰化疗在结肠癌肝转移中的应用

目的目前,大量的临床及实验室资料证实,肿瘤患者的化疗效果受给药时间的影响。经过多年的研究,如今大部分的化疗药已经具备了部分时辰化疗方面的基础和临床研究数据。自1985年Hrushesky率先运用阿霉素和DDP进行卵巢癌时辰治疗以来,恶性肿瘤时辰化疗的基础与临床研究成为一个非常活跃的领域。目前,国内外相关资料显示时辰化疗已广泛应用于各种恶性肿瘤的化学治疗中,如胃癌、肠癌、鼻咽癌、肺癌、恶性淋巴瘤、肾癌、乳腺癌等恶性肿瘤,并且取得了可喜效果,其主要优势是时辰化疗的疗效显著高于常规化疗,且其毒副作用显著低于常规化疗,达到了减毒增效的目的 ,能改善患者生存质量,延长生存期。结肠癌肝转移方面尚未见大宗文献报道。本课题研究通过时辰化疗与常规化疗在结肠癌肝转移中的临床应用,以观察两种治疗方式的近期疗效及毒副作用。方法两组病例肝转移灶均初始无手术切除指征,行肝动脉置化疗泵术后,经肝动脉灌注化疗。所用药物及剂量均相同。L-OHP 50 mg,第1~3天,5-FU,第1~5天。CF 0.2,全身静脉给药,第1~5天。常规化疗组用药时间安排在正常上班的8 am~5 pm,时辰化疗组采用法国AGUETTANT公司提供的M elod ie多通道编程输液泵,以正弦曲线形式,5-FU与CF从10 pm到10 am连续12 h给药,4 am达给药高峰;L-OHP则从10 am到10pm连续给药,4 pm达给药高峰。患者化疗前均行CT检查,化疗3周期后复查CT,评价化疗的毒副反应及疗效。结果时辰化疗组总有效率为68.0%,常规辅助化疗组为29.1%,时辰化疗组近期客观疗效明显优于常规组,差异具有显著性(χ2=7.389,P0.01)。化疗后继行手术切除的患者,时辰化疗组为44%,常规辅助化疗组为12%,差异具有显著性(χ2=5.9535,P0.05)。毒副反应方面,时辰化疗组发生静脉炎、末梢神经炎明显少于常规组病人,发生率分别为4%、28%和70.8%、62.5%(P0.05),其它毒副反应两组间比较差异无统计学意义。结论 1时辰化疗组在治疗结肠癌肝转移中较常规化疗组能显著提高疗效及手术切除率。2时辰化疗组毒副反应较常规化疗组显著减轻,耐受增强。     

顺铂药效和毒性作用的依时特征

目的:探索顺铂药效和毒性依时特征.方法:通过监测S180实体瘤小鼠的瘤重、外周血尿素氮和LD50评价昼夜不同时间顺铂给药的反应.结果:顺铂凌晨2:00给药作用强、毒性大,晚上18:00给药毒性小,作用弱.结论:顺铂的药效和毒性反应同步运行,对于小鼠晚上给药不良反应小,提示顺铂临床用药应避开毒性反应最大的时间.     

Preclinical relevance of dosing time for the therapeutic index of gemcitabine-cisplatin

The relevance of gemcitabine timing for chronotherapeutic optimisation was investigated. Healthy mice received multiple doses of gemcitabine (120, 160 or 200 mg kg(-1) injection (inj)(-1)) at one of six circadian times (3, 7, 11, 15, 19 or 23 h after light onset--HALO) on days 1, 4, 7 and 10 or a single dose of gemcitabine (400 mg kg(-1)) at 11 or 23 HALO+/-cisplatin (5 mg kg(-1) at 1 min, 4 or 8 h later). Mice bearing Glasgow osteosarcoma received multiple doses of gemcitabine (200 mg kg(-1) inj(-1)) at 11 or 23 HALO+/-cisplatin (5 mg kg(-1) inj(-1) at 1 min or 4 h later) on days of 10, 13, 16 and 19 following tumour inoculation. A circadian rhythm in body weight loss was statistically validated, with 1030 HALO corresponding to the least toxic time (95% CL, 0800 to 1300). Gemcitabine dosing produced least body weight loss and least neutropenia after injection at 11 vs 23 HALO, whether the drug was given alone or with cisplatin (P=0.001). Gemcitabine-cisplatin tolerability was improved by dosing gemcitabine at 11 HALO and CDDP at 15 HALO (P<0.001). The administration of this schedule to tumour-bearing mice increased median survival three-fold as compared to treatments where both drugs were given simultaneously at 11 or 23 HALO (P=0.02). The optimal schedule would correspond to the delivery of gemcitabine upon awakening and cisplatin near mid-activity in cancer patients.     

时辰对普鲁卡因、丁卡因和布比卡因致惊厥作用半数有效量的影响

目的观察时辰对普鲁卡因、丁卡因和布比卡因惊厥半数有效量(ED50)的影响。方法180只小鼠随机分3组即普鲁卡因组、丁卡因组、布比卡因组,按不同时辰每组再随机分为4个亚组。分别于2∶00时、8∶00时、14∶00时和20∶00时腹腔注射普鲁卡因、丁卡因和布比卡因,以小鼠惊厥为观察指标,用序贯法测定各时间点的ED50。结果普鲁卡因在8∶00时的惊厥ED50明显低于2∶00时、14∶00时和20∶00时的ED50(P<0.05),其余各时辰之间的ED50比较,无显著性差异(P>0.05);丁卡因和布比卡因在14∶00的惊厥ED50均明显低于2∶00时、8∶00时和20∶00时的ED50(P<0.05),其余各时辰之间的ED50比较,无显著性差异(P>0.05)。结论普鲁卡因、丁卡因和布比卡因所致惊厥ED50作用具有时辰依赖性。     

Animal scale-up

Animal scale-up is discussed as a formal approach to drug distribution in the body which permits consideration of scale through the individual processes that occur. Some of these are physical, such as blood flows, tissue binding, and kidney clearances. Others are chemical, such as metabolic reactions. The physical processes often vary quite predictably among mammalian species, and much is known about these independent of any chemical reactions. Certain metabolic reactions vary greatly and unpredictably among species. The physical and chemical processes interact so that the relationship of the pharmacokinetics of any given drug between one species and another may be quite straightforward or it may be rather obscure unless the correct interaction is perceived. Methotrexate pharmacokinetics are reviewed in discussing the use of animal scale- up for a drug where only physical processes need be considered. Problems involving metabolism are illustrated for thiopental and cytosine arabinoside.Presented at the Conference on Pharmacology and Pharmacokinetics: Problems and Perspectives, October 30–November 1, 1972, at the Fogarty International Center, National Institutes of Health, Bethesda, Maryland. This paper, in a slightly different format, will be published in the Proceedings of the Conference by Plenum Press, New York.     

Circadian changes in the distribution and effects of haloperidol in the rat

Striking circadian changes in behavioral sensitivity to haloperidol were found by measurements of cataleptic responses in rats trained in a controlled lighting cycle (lights on, 7:00 a.m.–7:00 p.m.). Thus, catalepsy was maximal at about 4:00 p.m. and minimal at about 4:00 a.m., virtually the opposite of the circadian rhythm of spontaneous behavioral activity in drug-free rats. At a given dose of haloperidol, catalepsy scores differed 2- to 3-fold, and the ED₅₀ shifted left nearly 10-fold from a.m. to p.m. After fixed doses of haloperidol, tissue levels of the drug, as determined by a sensitive and selective radioreceptor assay, differed by 2- to 6-fold through the 24 hr cycle and brain levels closely followed the circadian changes in behavior. These results suggest a pharmacokinetic contribution to the circadian changes in behavioral response, although additional pharmacodynamic factors are also considered.     

Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.