Ultrasound-Induced Mild Hyperthermia as a Novel Approach to Increase Drug Uptake in Brain Microvessel Endothelial Cells

Purpose. Drug delivery to the central nervous system (CNS) is limited by the blood-brain barrier (BBB). Thus, a noninvasive and reversible method to enhance BBB permeation of drugs is highly desirable. In the present work, we studied if ultrasound-induced mild hyperthermia (USHT, 0.4 watts (W)/cm² at 41°C) can enhance drug absorption in BBB endothelial cells, and we elucidated the mechanism of USHT on cellular accumulation. Methods. To accomplish these aims, we studied the effects of hyperthermia (41°C), USHT, P-glycoprotein (P-gp) modulator (PSC 833), and combination of USHT and PSC 833 on accumulation of P-gp substrate (R123) and non-P-gp substrates (sucrose, 2-deoxyglucose, and antipyrine) in monolayers of primary bovine brain microvessel endothelial cells (BBMEC). Results. USHT, through its thermal effect, produces a significant (relative to controls; no USHT) and comparable increase in R123 accumulation with PSC 833. We also demonstrate that USHT increases permeability of hydrophobic (R123 and [¹⁴C]-antipyrine) and not hydrophilic molecules ([¹⁴C]-sucrose and 2-[³H]-deoxy-d-glucose). The enhanced permeability is reversible and size dependent, as USHT produces a much larger effect on cellular accumulation of [¹⁴C]-antitpyrine (molecular weight of 188 D) than that of R123 (molecular weight of 380.8 D). Although USHT increases membrane permeability, it did not affect P-gp activity or the activity of glucose transporters. Conclusions. Our results point to the potential use of USHT as a reversible and noninvasive approach to increase BBB permeation of hydrophobic drugs, including P-gp-recognized substrates.     

GABA(A)-benzodiazepine receptor complex sensitivity in 5-HT(1A) receptor knockout mice on a 129/Sv background

Previous studies in 5-HT(1A) receptor knockout (1AKO) mice on a mixed Swiss Websterx129/Sv (SWx129/Sv) and a pure 129/Sv genetic background suggest a differential gamma-aminobutyric acid (GABA(A))-benzodiazepine receptor complex sensitivity in both strains, independent from the anxious phenotype. To further investigate these discrepancies, various GABA(A)-benzodiazepine receptor ligands were tested in different behavioral paradigms in 1AKO and wild type (WT) mice on a 129/Sv background. 1AKO and WT mice responded comparably to alprazolam, flumazenil, alcohol and pentylenetetrazol as measured in the stress-induced hyperthermia paradigm. In addition, sedative-anesthetic effects of pentobarbital measured via the righting reflex were similar and a selected dose of diazepam exerted similar anxiolytic effects in both genotypes in the elevated plus maze. In conclusion, 1AKO mice on a 129/Sv background have undisturbed GABA(A)-benzodiazepine receptor sensitivity in contrast to those described on a mixed Swiss Websterx129/Sv background. The anxious phenotype of 1AKO mice seems to occur independent of the GABA(A)-benzodiazepine receptor complex functioning.     

Intraoperative hyperthermia and chemoradiotherapy for inoperable pancreatic carcinoma

The aim of this study was to evaluate the tolerability and the possible clinical benefit of intraoperative hyperthermia combined with multischedule chemotherapy and bypass surgery for the palliative treatment of inoperable pancreatic cancer. Ten patients with unresectable adenocarcinoma of the pancreas received preoperative chemotherapy [5-fluorouracil (5-FU)], bypass surgery and postoperative chemotherapy (5-FU, doxorubicin and cisplatin) plus sandostatin and radiotherapy (45 Gy, 25 fractions, 5 days a week). A single session of intraoperative hyperthermia was performed, by using a waveguide-type applicator (433 MHz). The tumour region was heated to 43-45 degrees C for up to 60 min, while 500 mg 5-FU was infused simultaneously through the gastroduodenal into the splenic artery. Postoperative recovery was uneventful for all patients. A brief instrument was developed for evaluating patients' quality of life. Chemotherapy-related toxicity included myelosuppression, vomiting, alopecia and increase in blood urea nitrogen (BUN), creatinine, SGOT and SGPT. Glucose and amylase determinations remained within normal limits throughout the whole treatment. There was a significant improvement before and 1 month after combined treatment in Eastern Cooperative Oncology Group (ECOG) status (1.8 +/- 0.4), Scott-Huskinsson pain scale (3.2 +/- 0.8) and quality of life score (30.5 +/- 6.7). No progressive disease was noticed and the median overall survival was 11 (SE = 2.4) months. There was also a significant (P = 0.002, Wilcoxon test) decrease in values of both serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9), from 7.6 +/- 1.3 ng/mL and 875.7 +/- 104.8 U/mL to 3.5 +/- 0.7 ng/mL and 65.3 +/- 14.1 U/mL respectively. The first clinical results suggest a potential advantage of using combined intraoperative hyperthermia, chemotherapy and postoperative radiotherapy in the palliative treatment of the adenocarcinoma of the pancreas. The whole procedure seems to be free of perioperative morbidity, while the chemotherapy toxicity was rather moderate. However, the preliminary nature limits the general applicability of our results.     

Intraoperative magnetic resonance: the future of surgery

Intraoperative magnetic resonance imaging (iMRI) is a new development in medicine that bridges the specialties of surgery and radiology. Deficiencies in the visualization of anatomical architecture and the perception of tumour boundaries in conventional open surgery have led to the integration of imaging within surgery. The superior soft tissue and multiplanar imaging features of magnetic resonance (MR) make this imaging modality superior to that of alternatives. The unique properties of MR to detect heat change and perfusion, and diffusion characteristics of tissue enhance the usefulness of this medium. Concurrent developments in computer aided image guidance and thermoablative technology, herald the era of minimally invasive tumour ablation. Applications have been developed for areas such as neurosurgery, general surgery, gynaecology and urology.     

腔内灌注化疗联合全身热疗治疗恶性胸腹腔积液临床研究

目的探讨腔内化疗联合全身热疗对恶性腔内积液的疗效及毒副作用。方法回顾分析64例胸腹水患者。分为A、B两组,A组34例为单纯腔内化疗组,行腔内中心静脉置管抽液后注入化疗药物,B组30例为热化疗组,行腔内置管抽液化疗联合全身热疗。两组均为每周1次共4次,评价两组患者的近期疗效及毒副作用。结果A组患者CR为29.41%(10/34),PR为32.35%(11/34),有效率(CR PR)为61.76%,B组患者CR为46.67%(14/30),PR为40%(12/30),有效率(CR PR)为86.67%,两组间比较差异有显著性(P=0.045)。毒副作用方面,消化道反应(I° II°)与血液学毒性(I° II°)两组间均无明显差异(P=1.000)。结论腔内灌注化疗联合全身热疗治疗恶性胸腹腔积液较单纯腔内化疗疗效高,耐受性良好。     

温热与顺铂以不同的时序性联合对人肺巨细胞癌细胞抑制作用的实验研究

目的探讨42℃热疗与化疗药物顺铂联合作用于肺癌细胞时,在进行化疗的同时何时进行热疗疗效最好,从而为临床治疗提供实验依据。方法利用MTT法测定单纯42℃热疗组、单纯化疗组以及不同时间结合点的热化疗组对人肺巨细胞癌细胞(PLA801D)的抑制率。结果42℃热疗与化疗药物顺铂(DDP)同时作用时,对肺癌细胞的抑制率最强(55.73%),不仅优于单纯热疗组(3.13%)、单纯化疗组,也优于先化疗后热疗组和先热疗后化疗组(P均<0.000)。结论顺铂与42℃热疗同时作用较其他结合方式对肺癌细胞的毒性作用更强。     

ET-SPACETM全身热疗系统的治疗温度与测控

ET-SPACE^TM全身热疗系统是利用红外线体表照射对人体进行全身加温的，可以确保人体各部位均匀加热。我科采用的治疗温度是41．8℃，升温时间约需3h，恒温期治疗时间为1h，降温时间约需1h。其测温系统可以同时实时显示各路测温探测器的温度变化曲线；其控温系统对人体的绝对控温精度达到0．1℃，显示分辨率达到0．01℃。     

晚期恶性肿瘤患者全身热疗期的输液策略与肺水肿并发症

目的探讨晚期恶性肿瘤患者全身热疗期的输液策略及肺水肿情况。方法选择ASAⅡ~Ⅲ级、心肺功能良好的晚期恶性肿瘤患者23例,用红外线辐射体表加热技术,在静脉全麻下实施全身热疗26人次。连续监测有创血流动力学、气道压、尿量,定期进行动脉、混合静脉血血气分析和血糖监测,并以此调节输液量和成分。记录热疗各时段输液和肺水肿情况。结果热疗期输液:升温早期为(23.6±3.2)ml/(kg.h),恒温期(19.1±2.9)ml/(kg.h),降温期(9.3±3.6)ml/(kg.h);输液总量:晶体液(5168±578)ml,胶体液(1890±391)ml;热疗期体液呈正平衡约5000 ml;热疗期肺水肿发生率为15.4%,热疗后24 h内有53.8%的患者出现轻度肺水肿,热疗中发生肺水肿者,气道峰压持续升高(>30 cm H2O,1 cm H2O=0.098 kPa),肺氧合各指标明显下降,其输液速率和总量均高于无肺水肿者(P<0.01)。结论热疗期应分时段输液管理,升温期较快、恒温期减慢、降温期控制输液;热疗期肺水肿发生率高,输液过快和过量可能会增加肺水肿的发生,热疗期呼吸力学和肺氧合等监测,对肺水肿的诊断和治疗有重要意义。     

外照射、热疗及超激光对荷VX2瘤兔TNF、IGF、CA-50的影响

目的:观察外照射(teletherapy)、局部热疗(hyperthermia)、超激光(super lizer,SL)对荷VX2瘤兔的治疗作用,及其细胞因子的改变情况。方法:将健康雄性3年的新西兰大白兔80只,分成4组,外照射组(外放组)、体外高频热疗组(热疗组)、超激光治疗组(激光组)和对照组,各20只。观察肿瘤直径,生存期、同时检测肿瘤坏死因子(TNF)、胰岛素样生长因子(IGF)、血型类肿瘤抗原标志物CA-50,在VX2瘤移植前后、和治疗1、3、4周后的变化。结果:经治疗肿瘤直径从大到小和生存期从长至短依次为激光组、对照组、热疗组、外放组;VX2瘤移植成功后细胞因子的变化为TNF、IGF、CA-50逐渐增高,治疗4周后TNF、IGF、CA-50逐渐增高。激光组各细胞因子与对照组差异无显著性(P>0.05),但激光组和对照组与外放组和热疗组比较有显著性差异。结论:VX2种植成功后对宿主细胞免疫产生明显的抑制作用。外照射对其疗效明显好于热疗,且较明显地改变其免疫过程。超激光治疗对VX2瘤治疗无效。