The effects of mirtazapine and fluoxetine on hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats

The use of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") as a recreational drug has spread worldwide. Fatal hyperthermia is a likely side effect of using MDMA in combination with monoamine oxidase inhibitors. However, most antidepressants do not pose a high risk of developing hyperthermia when used in conjunction with MDMA. Mirtazapine is a novel antidepressant and a potent 5-HT(2A) receptor antagonist. It remains to be elucidated whether mirtazapine is unlikely to have life-threatening implications in combination with MDMA. In the present study, we evaluated whether mirtazapine and fluoxetine influence MDMA-induced hyperthermia in rats. The rectal temperature of the rats increased to above 41°C following an injection of MDMA (10mg/kg). Pre- and post-treatment administration of mirtazapine (5mg/kg) significantly attenuated MDMA-induced hyperthermia. Administration of WAY100635 (1mg/kg), a 5-HT(1A) receptor antagonist, did not influence the ability of mirtazapine to decrease hyperthermia induced by MDMA. Although pretreatment administration of fluoxetine (10mg/kg) significantly attenuated MDMA-induced hyperthermia, post-treatment administration of the same drug had no effect. The differences in body temperature between the groups post-treated mirtazapine and the groups post-treated fluoxetine may be due to differing mechanisms of action of the two antidepressants. The present study indicates that mirtazapine is unlikely to induce fatal hyperthermia when used with MDMA, and it may be rather effective against MDMA-induced hyperthermia. Considering our previous study demonstrating that potent 5-HT(2A) antagonists completely inhibit MDMA-induced hyperthermia, the findings of the present study suggest that mirtazapine inhibits MDMA-induced hyperthermia mainly by blocking the activation of 5-HT(2A) receptors.     

Immunohistochemical localization of AMPA-type glutamate receptor subunits in the nucleus of the Edinger-Westphal in embryonic chick

The ischemic damage in the hippocampal CA1 region following transient forebrain ischemia, delayed neuronal death, is a typical apoptotic response, but the underlying mechanisms are not fully understood. We have reported that mild hyperthermia (38 °C) accelerates DNA fragmentation of the gerbil CA1 pyramidal neurons following transient forebrain ischemia. Recently, we reported that galectin-3, a β-galactosidase-binding lectin, is spatio-temporally expressed only by activated microglial cells located within CA1 region following transient forebrain ischemia in gerbils. Furthermore, expression of galectin-3 and Iba-1 (a specific microglial cell marker) are strongly reduced by hypothermia during ischemic insult. To further elucidate the effect of hyperthermia on the expression of galectin-3 by micloglia in delayed neuronal death, we examined immunohistochemical expression of galectin-3 and Iba-1, in situ terminal dUTP-biotin nick end labeling of DNA fragmentation (for determination of cell death) and hematoxylin and eosin staining (for morphological observation). We observed that between 37 °C and 39 °C, there was a temperature-dependent enhancement of galectin-3 expression in microglial cells in the CA1 region following transient ischemia. Apoptotic DNA fragmentation, detected by TUNEL staining, was observed in CA1 region in normothermia. This TUNEL staining was enhanced by hyperthermia at 37.5 °C and 38 °C, but not at 39 °C. Ischemia-induced neuronal degeneration in CA1 region in gerbil hippocampus subjected to hyperthermia (37.5 °C, 38 °C and 39 °C) observed by HE staining is similar to that in normothermic gerbils. These findings imply that galectin-3 expression in microglia may influence the survival of CA1 pyramidal neurons in cases such as hyperthermia-related neuronal injury.     

Hyperthermia-triggered intracellular delivery of anticancer agent to HER2 cells by HER2-specific affibody (ZHER2-GS-Cys)-conjugated thermosensitive liposomes (HER2 affisomes)

We previously reported the formulation and physical properties of HER2 (human epidermal growth factor receptor 2)-specific affibody (ZHER2:342-Cys) conjugated thermosensitive liposomes (HER2⁺affisomes). Here we examined localized delivery potential of these affisomes by monitoring cellular interactions, intracellular uptake, and hyperthermia-induced effects on drug delivery. We modified ZHER2:342-Cys by introducing a glycine-serine spacer before the C-terminus cysteine (called ZHER2-GS-Cys) to achieve accessibility to cell surface expressed HER2. This modification did not affect HER2-specific binding and ZHER2-GS-Cys retained its ability to conjugate to the liposomes containing dipalmitoyl phosphatidyl choline: DSPE-PEG2000-Malemide, 96:04 mole ratios (HER2⁺affisomes). HER2⁺affisomes were either (i) fluorescently labeled with rhodamine-PE and calcein or (ii) loaded with an anticancer drug doxorubicin (DOX). Fluorescently labeled HER2⁺ affisomes showed at least 10-fold increase in binding to HER2⁺ cells (SK-BR-3) when compared to HER2⁻ cells (MDA-MB-468) at 37 °C. A competition experiment using free ZHER2-GS-Cys blocked HER2⁺ affisome-SK-BR-3 cell associations. Imaging with confocal microscopy showed that HER2⁺ affisomes accumulated in the cytosol of SK-BR-3 cells at 37 °C. Hyperthermia-induced intracellular release experiments showed that the treatment of HER2⁺ affisome/SK-BR-3 cell complexes with a 45 °C (± 1 °C) pre-equilibrated buffer resulted in cytosolic delivery of calcein. Substantial calcein release was observed within 20 min at 45 °C, with no effect on cell viability under these conditions. Similarly, DOX-loaded HER2⁺affisomes showed at least 2- to 3-fold higher accumulation of DOX in SK-BR-3 cells as compared to control liposomes. DOX-mediated cytotoxicity was more pronounced in SK-BR-3 cells especially at lower doses of HER2⁺affisomes. Brief exposure of liposome-cell complexes at 45 °C prior to the onset of incubations for cell killing assays resulted in enhanced cytotoxicity for affisomes and control liposomes. However, Doxil (a commercially available liposome formulation) showed significantly lower toxicity under identical conditions. Therefore, our data demonstrate that HER2⁺affisomes encompass both targeting and triggering potential and hence may prove to be viable nanodrug delivery carriers for breast cancer treatment.     

二巯基丁二酸修饰的Fe3O4纳米磁液联合碘油动脉栓塞热疗治疗兔VX2肝癌

目的评估二巯基丁二酸修饰的Fe3O4(DSMA-Fe3O4)纳米磁液联合碘油动脉栓塞热疗治疗兔VX2肝癌的疗效。方法 25只开腹肝左叶种植VX2瘤的实验兔,随机等分为五组:对照组(A组)、碘油栓塞组(B组)、DSMA-Fe3O4纳米磁液+碘油栓塞组(C组)、DSMA-Fe3O4纳米磁液+热疗组(D组)、DSMA-Fe3O4纳米磁液+碘油栓塞+热疗组(E组)。成瘤2周后各组行CT扫描并测量,随后行肝动脉栓塞,D、E组栓塞后诱导热疗。分别在术后7、14d行CT检查,计算肿瘤生长比率、肿瘤增长体积。14dCT扫描结束后每组处死部分实验兔,取完整的肝、肾、脾及肺作病理检查。各组分别在术前1d,术后1、3、7d经兔耳缘静脉采血测ALT和AST。结果所有肝癌模型均建立成功。五组术前肿瘤体积、术前1d、术后7dALT、AST水平均无统计学差异(P>0.05)。术后14d,E组肿瘤体积平均缩小26.7%,而B、C、D三组肿瘤体积分别平均增大了200.7%、209.4%和422.5%。结论 DSMA-Fe3O4纳米磁液联合碘油动脉栓塞热疗兔VX2肝癌有效、安全。     

胸部聚束微波热化疗对肿瘤患者心电图的影响

目的探讨胸部高能聚束微波热化疗对肿瘤患者心电图的影响。方法47例患者分别采用AB模式或BA模式。AB模式：第1周期采用高能聚束微波热疗＋化疗,第2周期予单纯化疗;BA模式：第1周期采用单纯化疗,第2周期予高能聚束微波热疗＋化疗。治疗中予心电监护和每周期治疗前后进行心电图检查,分析评估热化疗周期和单纯化疗周期患者的心电图变化情况。结果心电监护发现热化疗周期患者的窦性心动过速的发生率明显高于单纯化疗周期患者（P〈0．05）,其他心电异常的发生率周期比较,差异无统计学意义（P〉0．05）;两组治疗前后的异常心电图的发生率比较,差异无统计学意义（P〉0．05）。结论热化疗周期患者治疗过程中的窦性心动过速的发生率较化疗周期明显增高为机体对体温增高的生理反应;胸部高能聚束微波热疗与化疗联合治疗恶性肿瘤对化疗患者的心电图改变无明显影响。     

Pronounced increase in breathing rate in the "hair dryer model" of experimental febrile seizures

In a study using a heated chamber for induction of experimental febrile seizures (eFS) in rat pups, ictal activity was shown to be precipitated by a respiratory alkalosis (Schuchmann et al., 2006). In sharp contrast to this, in a recent review Dubé et al., (2007) suggest that the respiratory alkalosis is model specific, and that no increase in respiratory rate is observed in the widely used "hair dryer model" of eFS. The data in the present work, based on well-established techniques for measuring respiratory rates in rat pups, show a pronounced increase in the "hair dryer model" with values that are slightly higher than those recorded in the heated chamber model. Hence, a temperature-evoked increase in respiration is a common feature of these two models of eFS.     

热疗对人肝癌细胞株HepG2生长影响的体外研究

目的:探讨热疗对人肝癌细胞株HepG2生长的影响.方法:人肝癌细胞株HepG2细胞常规方法培养,采用水浴加热法(43.0℃)分别加热0.5h、1h和1.5h.处理后继续培养48h、72h、96h、120h和144h,绘制生长曲线;处理后分别培养0h、3h、6h、12h和24h,倒置显微镜观察细胞的形态变化.结果:随着加热时间的延长HepG2细胞数明显减少(P＜0.05,P＜0.01),细胞的形态也发生明显病理变化.结论:热疗对人肝癌细胞株具有细胞毒性作用,加热时间对癌细胞的生长有重要影响,热疗作为治疗肝癌的一种辅助疗法,值得进一步研究.     

The design and characterization of an ultrasound phased array suitable for deep tissue hyperthermia

In this paper we describe the design and evaluation of a planar phased-array ultrasound transducer suitable for producing localized hyperthermia in solid tumors deep within the body. Simulation using a customized version of Ultrasim has been used to determine the relationship between the size and position of the focus and parameters of the array. These parameters include the overall size of the array and the size, shape and distribution of the individual elements. A 15-element prototype array has been constructed using the results of the simulation. Beam profile measurements on this transducer made in an acoustic tank were compared with the beam profile predicted by simulation. The results showed good agreement in the shape of the focal region, but with the focus closer to the surface of the physical transducer when compared with the simulation and with small high-intensity areas between the surface of the transducer and the focus in the measured profile. A sensitivity analysis using a simulated factorial experiment indicated that the presence of a secondary vibrational mode within the elements of the array was the principal cause for both the shift in the position of the focus and for the unwanted maxima close to the surface of the array. The results also showed that the array was tolerant of a large variation in output intensity of the individual elements in the array in producing a focal region. Extrapolation of the results obtained in this study indicate that an array of 60 elements, based on the design described, driven by 550 V peak-to-peak pulses would be capable of producing a peak focal intensity of 50 Wcm(-2) at a depth of 60 mm in tissue, which would be appropriate for hyperthermia used as an adjunct to radiotherapy or chemotherapy.     

Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans

The vanilloid receptor TRPV1 has been identified as a molecular target for the treatment of pain associated with inflammatory diseases and cancer. Hence, TRPV1 antagonists have been considered for therapeutic evaluation in such diseases. During Phase I clinical trials with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicited marked, but reversible, and generally plasma concentration-dependent hyperthermia. Similar to what was observed in rats, dogs, and monkeys, hyperthermia was attenuated after repeated dosing of AMG 517 (at the highest dose tested) in humans during a second Phase I trial. However, AMG 517 administered after molar extraction (a surgical cause of acute pain) elicited long-lasting hyperthermia with maximal body temperature surpassing 40 °C, suggesting that TRPV1 blockade elicits undesirable hyperthermia in susceptible individuals. Mechanisms of AMG 517-induced hyperthermia were then studied in rats. AMG 517 caused hyperthermia by inducing tail skin vasoconstriction and increasing thermogenesis, which suggests that TRPV1 regulates vasomotor tone and metabolic heat production. In conclusion, these results demonstrate that: (a) TRPV1-selective antagonists like AMG 517 cannot be developed for systemic use as stand alone agents for treatment of pain and other diseases, (b) individual susceptibility influences magnitude of hyperthermia observed after TRPV1 blockade, and (c) TRPV1 plays a pivotal role as a molecular regulator for body temperature in humans.     

恩度、顺铂及重组人白介素-2联合热疗治疗恶性腹腔积液的临床观察

目的 研究腹腔内注射恩度、顺铂、重组人白介素-2联合热疗治疗恶性肿瘤引起的恶性腹腔积液的临床疗效。方法 选取2017年1月—2020年6月河北工程大学附属医院收治的60例恶性腹腔积液患者为研究对象,分为观察组和对照组,各30例。观察组腹腔注射恩度30 mg、顺铂60 mg、重组人白介素-2 200万IU联合微波热疗,对照组腹腔注射顺铂60 mg、重组人白介素-2 200万IU联合微波热疗,比较两组患者的临床疗效及副反应。结果 观察组总有效率（90.0%）显著高于对照组（73.3%）（P=0.03）,生活质量改善率（80%）显著高于对照组（60%）（P=0.043）;两组患者出现的副反应主要为发热、恶心呕吐、食欲下降、乏力、血小板减少、贫血,发生率的差异无统计学意义（P=0.55）。结论 腹腔内注射恩度、顺铂、重组人白介素-2联合热疗治疗恶性腹腔积液安全有效,可明显减轻患者痛苦,改善生活质量,副反应轻且可控制,值得临床推广应用。