沙利度胺对鼠子宫内膜异位病灶血管生成作用的研究

目的:探讨沙利度胺(thalidomide)对子宫内膜异位症(endometriosis,EMs)病灶生长和血管生成的影响,为从抗血管途径治疗EMs提供依据.方法:将EMs患者在位子宫内膜种植于重度复合性免疫缺陷病(severe combined immunodeficiency disease, SCID)小鼠皮下,建立EMs鼠模型.接种后第3周给予治疗,治疗组(n=10)腹腔注射沙利度胺50mg/kg/d,对照组(n=10)腹腔注射等体积PBS,连用14d;每隔3d测量异位病灶体积一次;病灶组织采用免疫组化法测定病灶微血管密度(microvessel density,MVD)及血管内皮生长因子(VEGF)的表达.结果:SCID小鼠皮下种植内异症模型内膜存活率高且观察方便;治疗组病灶体积增长有缩小趋势,但与对照组相比差异无统计学意义(P＞0.05);治疗组MVD显著低于对照组(P＜0.05);治疗组和对照组VEGF的表达差异无统计学意义(P＞0.05).结论:沙利度胺对EMs异位病灶的血管生成有明显抑制作用;抑制VEGF的表达可能不是沙利度胺抑制EMs血管生成的主要原因.     

反应停治疗难治性多发性骨髓瘤6例

目的：探讨反应停治疗难治性多发性骨髓瘤(MM)的临床疗效。方法：对6例难治疗性多发性骨髓瘤应用反应停治疗后的临床资料进行分析，并结合文献复习，为该病的治疗提供一条思路。结果：1例患者达完全缓解；1例患者达部分缓解；1例进步，血清M蛋白减少35％、骨痛明显减轻、血沉降低40％、血红蛋白上升20g／L；2例无效；1例死亡。结论：反应停对多发性骨髓瘤有较好的疗效，不良反应可以耐受且不产生骨髓抑制：抗血管新生是其主要疗效机制。     

Thalidomide-induced neuropathy and genetic differences in drug metabolism

A pharmacogenetic predisposition to thalidomide-induced neuropathy has been investigated. Differences of drug metabolism were examined in 16 patients with severe orogenital ulceration, who were treated with thalidomide (200 mg/day) for 0.3–5.0 years. Eight had evidence of early peripheral neuropathy according to nerve conduction studies. Rates of C-hydroxylation, N-acetylation, and conjugation reactions with sulphate, glucuronide and glycine, were tested with the probe compounds debrisoquine, sulphadimidine, paracetamol and aspirin, respectively. Urinary drug metabolites were analysed by high pressure liquid chromatography. Results were compared with 16 healthy age- and sex-matched volunteers.Of the patients 6.25% and 13.3% of the controls had a poor Debrisoquine Hydroxylator Ratio (DMR); none of the patients with neuropathy had a poor DMR as compared to 12.5% without neuropathy. Of the patients 40.0% and 35.7% of the controls were slow acetylators; 28.6% with neuropathy were slow acetylators as opposed to 50% without neuropathy. Similarly, there were no significant differences in rates of conjugation between groups. All unaffected patients were active smokers, whereas only two of those with neuropathy smoked. Cumulative dose or duration of therapy were unrelated to risk of neuropathy.In conclusion, changes of nerve conductivity are a frequent and unpredictable adverse effect of thalidomide (200 mg/day), although smoking may have a protective action against their development. Nerve conduction studies are required before and during treatment, irrespective of the prescribed dose.     

沙利度胺治疗原发性骨髓纤维化临床疗效观察

目的探讨沙利度胺治疗原发性骨髓纤维化(IMF)的临床有效性。方法IMF患者10例,剂量150mg/d,同时羟基脲1.0~3.0mg/d仍维持治疗。根据治疗前后血液学指标白细胞计数、血红蛋白测定、血小板计数和肝脾大小测定的变化及腹胀和下肢浮肿的改善来评定疗效。结果10例脾大患者,9例明显缩小,其中7例巨脾患者5例缩小更显著;2例肝大患者2例恢复正常;5例白细胞升高患者,1例明显降低,2例恢复正常;6例轻中度贫血患者,1例有所上升,2例贫血纠正;4例血小板升高患者,1例明显降低,3例恢复正常。9例腹胀患者,4例好转,3例消失;7例双下肢浮肿患者,2例好转,4例消失。10例IMF患者中,仅2例出现轻度不良反应。结论沙利度胺治疗原发性骨髓纤维化有一定疗效。     

Positive and negative effects of thalidomide on refractory cutaneous lupus erythematosus

Background: Thalidomide is used in cutaneous lupus erythematosus (CLE) refractory to conventional therapies. Peripheral neuropathy (PN) is the most severe side effect, but the incidence of PN and its relation to thalidomide dose are still unclear.

Objective: To prospectively evaluate the efficacy as well as the occurrence of PN in CLE patients treated with thalidomide, and to assess whether PN, when occurs, correlates with thalidomide dose and/or length of treatment.

Methods: Fourteen female patients with CLE in low-dose thalidomide therapy were followed for up to 24 months. Prior to, and regularly during treatment patients underwent rheumatological, dermatological, neurological and electrophysiological evaluations. A decline in sural SNAP of 50% or more from baseline value was considered as criterion of sensory axonal PN.

Results: All patients showed a dramatic improvement of skin manifestations. Ten patients (71.4%) developed a sensory axonal PN. The median time free from this complication was 14 months. No correlations were found between age of the patients nor thalidomide cumulative dose and occurrence of PN (Mann-Whitney U Test; p>0.16). Other adverse effects were: tremor, paresthesias, somnolence, amenhorrea, constipation and thoracic pain.

Conclusions: Low does thalidomide is efficacious in treating CLE, but PN is a common complication whose occurrence does not seem to correlate with total thalidomide dose, whereas with the duration of therapy. A closer electrophysiological follow-up is therefore recommended in the long-term treatment.     

Embryo–fetal exposure and developmental outcome of thalidomide following oral and intravaginal administration to pregnant rabbits

Studies in pregnant rabbits were conducted to evaluate if there are any differences in the uptake of thalidomide into the intrauterine compartment and developmental toxicity risk following oral and intravaginal administration. Thalidomide concentrations in maternal plasma, yolk sac cavity (YSC) fluid and embryo following intravaginal administration were 2- to 7-fold lower than their respective levels after oral administration. Ratios of thalidomide concentration in YSC fluid to maternal plasma were similar between these two routes, indicating no difference in uptake into the intrauterine compartment. A rabbit embryo–fetal development study using oral and intravaginal thalidomide administration at 2 mg/kg/day (a dose >10,000-fold higher than the expected amount of thalidomide in human semen) did not result in any developmental abnormalities. These data demonstrated no preferential transfer mechanism of thalidomide from vagina to conceptus, and no additional embryo–fetal developmental toxicity risks with thalidomide exposure via the vaginal route.