Teratologic studies on the Himalayan rabbit: new aspects of thalidomide-induced teratogenesis

The aim of our study was to determine the period of maximum sensitivity for the induction of characteristic malformations with thalidomide (TH) in Himalayan rabbits. TH was administered orally in different doses (50, 100, 150 and 200 mg/kg) four times at 24-h intervals starting at 192 h of gestation. The malformations affected various organs: renal defects (dysplasia) and limb anomalies (dysmelia) — which had never occurred spontaneously in this strain — appeared as dose-dependent effects of the drug. By administering single doses of TH (200 and 300 mg/kg body wt) between hours 192 and 264 of gestation, we discovered the different periods of maximum sensitivity for induction of renal dysplasia (clearly prior to the 220th h of gestation) and dysmelia (between hours 230 and 240 of gestation). The types of limb malformations that we observed in the rabbit were identical to those produced in man following the intake of TH. Three doses of TH (300 mg/kg each) given between hours 222 and 228 of gestation produced characteristic limb malformations in 9 of 11 litters treated. These results make it possible to conduct in vivo experiments on a readily available laboratory animal with minor drug exposure of the gravid dam and under avoidance of toxic side effects.     

Chronic urticaria associated with autoreactivity to progesterone

Autoimmune progesterone dermatitis is a rarely recognized cutaneous disorder revealed by recurrent and cyclic skin eruption with variable morphology, during the luteal phase. We report the case of a 42-year-old woman with chronic urticaria since the age of 38 with premenstrual exacerbation. Intradermal progesterone tests revealed a strong reactivity against this hormone. Treatment with thalidomide was effective but induced a peripheral neuropathy. Oophorectomy was performed with clearing of the cutaneous lesions.     

Embryotoxic effects of thalidomide derivatives on the non-human primateCallithrix jacchus

The teratogenic potencies of the enantiomers of 2-(2,6-dioxopiperidine-3-yl)-phthalimidine (= EM 12), a teratogenic thalidomide analogue, were investigated inCallithrix jacchus, a primate very sensitive to the teratogenic action of this thalidomide analogue. The results indicate that the S-(–)-form of EM 12 is clearly more teratogenic than the R-(+)-form. The interpretation of the studies designed to evaluate stereo-selective differences in the teratogenicity of the enantiomers becomes difficult, since both enantiomers racemise in vivo with appreciable rates (Schmahl et al. 1988a, b). Therefore, it cannot be concluded as yet that the R-(+)-form lacks all teratogenic potential.Abbreviations EM 12 2-(2,6-dioxopiperidine-3-yl)-phthalimidine - S-EM 12 S-(–) enantiomer of EM 12 - R-EM 12 R-(+) enantiomer of EM 12     

Thalidomide does not interact with P-glycoprotein

Background: There is growing clinical interest in thalidomide for the treatment of various disorders due to its anti-inflammatory, immunomodulatory, and anti-angiogenic properties. In numerous clinical trials thalidomide is used as an adjunct to standard therapy. Therefore, clinicians should be aware of all possible drug–drug interactions that might occur with this drug. P-glycoprotein (P-gp), a drug efflux transporter that is expressed in many tissues, is the cause of several drug–drug interactions. P-gp induction or inhibition can lead to ineffective therapy or side-effects. In this study, we investigated thalidomide’s potential to cause drug–drug interactions on the level of P-gp. Methods: LS180 cells were incubated with thalidomide for 72 h in order to determine P-gp induction using real-time RT-PCR. A human leukaemia cell line over-expressing MDR1 (CCRF-CEM/MDR1) was used to measure uptake of rhodamine 123, a P-gp substrate, in the presence of thalidomide. Dose-dependent and bi-directional transport of thalidomide through Caco-2 cell monolayers was performed to assess site-directed permeability. Transport rates were determined using HPLC including chiral separation of the thalidomide enantiomers. Results: Thalidomide did not induce P-gp expression in LS180 cells. The uptake of rhodamine 123 in CCRF cells over-expressing MDR1 was not influenced by co-incubation with thalidomide. The transport through Caco-2 monolayers was linear and the permeability was similar for both directions. No differences between the thalidomide enantiomers were observed. Conclusions: Our study indicates that thalidomide is neither a substrate, nor an inhibitor or an inducer of P-gp. Therefore, P-gp-related drug–drug interactions with thalidomide are not likely.     

Anti-nociceptive effect of thalidomide on zymosan-induced experimental articular incapacitation

The anti-nociceptive effect of thalidomide on zymosan-induced articular knee joint incapacitation in rats was investigated. Thalidomide (5-45 mg/kg), given 30 min before but not 2 h after the intra-articular injection of zymosan, inhibited the nociceptive response in a dose-dependent manner. Furthermore, thalidomide pretreatment significantly reduced the concentration of tumor necrosis factor-alpha (TNF-alpha, -68.4%) in the exudate of zymosan-injected joints, but not those of interleukin-1beta, interleukin-6, CINC-1 or interleukin-10. The expression of TNF-alpha, determined by immunohistochemical staining, in synovial tissues obtained from articular joints injected with zymosan was also inhibited by thalidomide pretreatment. The anti-nociceptive effect of thalidomide was not reversed by the co-administration of an opioid receptor antagonist, naloxone, suggesting that endogenous opioids do not mediate the anti-nociceptive effect of thalidomide in this model. In conclusion, the anti-nociceptive activity of thalidomide in zymosan-induced articular incapacitation is associated with the inhibition of TNF-alpha by resident synovial cells.     

沙利度胺的临床应用新进展

沙利度胺是一种人工合成的谷氨酸衍生物,曾因罕见的"海豹肢症"事件,被作为一种毒性药物被迫退出国际市场。近来,沙利度胺已经被证实有镇静、抗炎、免疫调节、抗血管生成作用,被创新性应用于系统性红斑狼疮、伯克肉样瘤和移植物抗宿主病等疾病。总结沙利度胺临床上应用的新进展,必将为进一步探讨沙利度胺的临床疗效提供新的证据。     

Treatment of pediatric refractory Crohn's disease with thalidomide

AIM: To assess the efficacy and tolerability of thalidomide in pediatric Crohn’s disease (CD).METHODS: Six patients with refractory CD received thalidomide at an initial dose of 2 mg/kg per day for one month, then increased to 3 mg/kg per day or decreased to 1 mg/kg per day, and again further reduced to 0.5 mg/kg per day, according to the individual patient’s response to the drug.RESULTS: Remission was achieved within three months. Dramatic clinical improvement was demonstrated after thalidomide treatment. Endoscopic and pathological improvements were also observed after thalidomide treatment, which was well tolerated by all patients.CONCLUSION: Thalidomide is a useful drug for pediatric refractory CD.     

沙利度胺对人胰腺癌细胞株SW1990体外增殖及凋亡的影响

目的 观察沙利度胺(THD)体外抑制人胰腺癌细胞株SW1990增殖及诱导其凋亡的作用.方法 应用不同浓度的THD(3.125、6.25、12.5、25、50、100、200、400μg/ml)处理胰腺癌SW1990细胞24、48、72 h,用MTT法测定细胞的生长抑制率,流式细胞仪分析细胞周期,Annexin V/PI检测细胞凋亡率,蛋白质印迹法检测细胞Bcl-2、Bax蛋白的表达.结果 THD呈浓度和时间依赖性抑制胰腺癌细胞SW1990的生长.200μg/ml的THD干预使SW1990细胞G0/G1期比例从(41.15±2.23)％上升到(58.83 ±2.33)％;细胞凋亡率从2.6％增加到28.0％;细胞Bax蛋白表达量从0.17±0.03上调到0.33±0.04,Bcl-2蛋白表达量从0.35±0.02下调到0.17±0.01,Bcl-2/Bax比值从2.17±0.44下降到0.52±0.07.结论 THD可以抑制SW1990细胞增殖,其机制可能与上调Bax蛋白表达、下调Bcl-2蛋白表达,促进细胞凋亡,将细胞周期阻滞于G0/G1期有关.     

沙利度胺对人结肠癌细胞增殖及迁移的影响

目的：观察沙利度胺对人结肠癌细胞HCT116增殖和迁移的影响,并初步探讨其影响机制。方法：分别用不同浓度沙利度胺处理人结肠癌细胞HCT116,采用MTT法检测沙利度胺对人结肠癌细胞增殖的影响,平板克隆试验法检测沙利度胺对单个细胞克隆增殖的作用,流式细胞术检测细胞周期分布,Transwell细胞培养小室检测沙利度胺对细胞迁移的影响,蛋白免疫印迹检测沙利度胺对细胞P53、CXCR4蛋白的作用。结果：MTT检测显示不同浓度沙利度胺对HCT116细胞增殖无影响,平板克隆试验表明其对细胞克隆生长具有抑制作用,流式细胞检测显示100 mg/L沙利度胺处理组G2/M期细胞比例明显高于对照组（P〈0.05）,沙利度胺组HCT116细胞迁移数明显少于对照组,P53蛋白、CXCR4蛋白表达与对照组比较无明显变化。结论：沙利度胺抑制结肠癌细胞克隆增殖的作用,可能与其影响细胞周期有关;抑制结肠癌细胞迁移的作用,与CXCR4蛋白表达无关。     

沙利度胺干预核因子-κB活化对肝细胞癌变的影响

我们以2-乙酰氨基芴(2-FAA)诱发鼠肝癌发生,同时给予沙利度胺干预,观察核因子-κB(NF-κB)表达的动态变化及其对肝细胞癌变的影响.