亚微米级超声微泡造影剂的制备及体外基因转染效率的实验研究

目的 探索制备亚微米级超声微泡造影剂的方法 ,以GFP作为目的 基因验证其作为一种新型基因载体的可行性.方法 以高剪切分散法制备超声微泡造影剂,透射电镜及激光粒度分析仪检测其形态及粒径;将超声微泡造影剂与不同剂量的绿色荧光蛋白质粒PShuttle-IRES-hrGFP-1结合后转染HepG2细胞,利用荧光显微镜观察并检测其基因转染效率.结果 自制超声微泡造影剂为均匀分散的圆泡,粒径分布在282.2～415.7 nm之间,平均值为(335±5)nm,达到亚微米级;该微泡能将GFP基因成功转运到HepG2细胞内并高效表达,转染效率达32.61%±3.42%.结论 自制亚微米级超声微泡造影剂粒径小、分散均匀,并能成功转运外源DNA进入细胞内,可作为一种新型基因载体.     

自制脂膜氟碳声学造影剂对肾髓质血流灌注的评价及潜在价值

目的 探讨自制脂膜氟碳声学造影剂“脂氟显”评价肾髓质血流灌注的可行性及潜在价值。方法 10只健康家兔经耳缘静脉团注0．0lml／kg的脂氟显，采用视觉评分和视频分析，观察肾髓质的二维灰阶增强效果，并与皮质比较。结果 脂氟显能明显增强肾髓质的灰阶显像，但与皮质(持续52′)比较，持续时间较短(约2′20″)。结论 脂氟显可评价肾髓质的血流灌注，具有潜在的诊断价值。     

机械振荡法制备脂膜超声造影剂的初步实验研究

目的探讨机械振荡法制备脂膜超声造影剂的可行性,初步评价其制备效果。方法机械振荡仪系胶囊式调合器改装而成,造影剂制备后,用光镜观察微泡大小、形态,血球计数板测定微泡浓度,激光粒度分析仪测定粒径及分布、表面电位、pH值,在体实验观察造影剂对兔正常肝脏的增强效果。结果造影剂微泡的粒径均小于8μm,平均粒径为(1.67±0.11)μm,平均浓度为(2.56±0.15)×1010/ml,表面电位为(-37.5±0.3)mV,pH值为6.46±0.21,其对肝实质的增强持续时间达60min,而且重复性好。结论机械振荡法是制备脂膜超声造影剂的一种很有效的方法。     

Acoustic Sizing of an Ultrasound Contrast Agent

Because the properties of ultrasound contrast agent populations after administration to patients are largely unknown, methods able to study them noninvasively are required. In this study, we acoustically performed a size distribution measurement of the ultrasound contrast agent Definity^®. Single lipid-shelled microbubbles were insonified at 25 MHz, which is considerably higher than their resonance frequency, so that their acoustic responses depended on their geometrical cross sections only. We calculated the size of each microbubble from their measured backscattered pressures. The acoustic size measurements were compared with optical reference size measurements to test their accuracy. Our acoustic sizing method was applied to 88 individual Definity^® bubbles to derive a size distribution of this agent. The size distribution obtained acoustically showed a mean diameter (2.5 μm) and a standard deviation (0.9 μm) in agreement within 8% with the optical reference measurement. At 25 MHz, this method can be applied to bubble sizes larger than 1.2 μm in diameter. It was observed that similar sized bubbles can give different responses (up to a factor 1.5), probably because of shell differences. These limitations should be taken into account when implementing the method in vivo. This acoustic sizing method has potential for estimating the size distribution of an ultrasound contrast agent noninvasively. (E-mail: d.maresca@erasmusmc.nl)     

新型口服磁共振造影剂——D98A的基础和动物试验研究

目的 报道一种新近由复合铁磁性原料研制成功的口服磁共振胃肠造影剂-D98A。方法 按照新药研究的方法,进行了毒理、代谢、动力学、体外试管及动物体内磁共振成像试验。并对其进行了效果分析。结果和结论 这种对比剂易于接受,安全性好,成像浓度范围宽,性能稳定,成本低,有优良超顺磁性的阴性对比效果。为临床试验提供了依据。     

The Delayed Onset of Subharmonic and Ultraharmonic Emissions from a Phospholipid-Shelled Microbubble Contrast Agent

Characterizing the non-linear response of microbubble contrast agents is important for their efficacious use in imaging and therapy. In this article, we report that the subharmonic and ultraharmonic response of lipid-shelled microbubble contrast agents exhibits a strong temporal dependence. We characterized non-linear emissions from Targestar-p microbubbles (Targeson Inc., San Diego, CA, USA) periodically for 60 min, at 10 MHz excitation frequency. The results revealed a considerable increase in the subharmonic and ultraharmonic response (nearly 12–15 and 5–8 dB) after 5–10 min of agent preparation. However, the fundamental and the harmonic response remained almost unchanged in this period. During the next 50 min, the subharmonic, fundamental, ultraharmonic, and harmonic responses decreased steadily by 2–5 dB. The temporal changes in the non-linear behavior of the agent appeared to be primarily mediated by gas-exchange through the microbubble shell; temperature and prior acoustic excitation based mechanisms were ruled out. Further, there was no measurable change in the agent size distribution by static diffusion. We envisage that these findings will help obtain reproducible measurements from agent characterization, non-linear imaging, and fluid-pressure sensing. These findings also suggest the possibility for improving non-linear imaging by careful design of ultrasound contrast agents.     

以趋化因子受体4为靶点的恶性肿瘤靶向特异性磁共振对比剂的构建及体外成像

  目的  构建以趋化因子受体4(C-X-C motif chemokine receptor 4, CXCR4)为靶点的磁共振靶向对比剂并通过体外恶性肿瘤细胞的靶向磁共振成像探讨磁共振信号变化与肿瘤细胞CXCR4表达量的相关性。  方法  用细胞免疫荧光法和流式细胞计数法分别观察和测定3种恶性肿瘤细胞株(胰腺癌PANC-1、乳腺癌MCF-7和肺癌A549)的CXCR4表达, 并验证新型多肽Pep12与3种恶性肿瘤细胞表面的CXCR4特异性结合的能力。化学合成超顺磁性纳米氧化铁颗粒(ultra-small paramagnetic iron oxide nanoparticle, USPIO-Np), 并与Pep12实现共轭联接。动态光散射法测定Pep12-USPIO的水和直径; 用MTS细胞增殖与毒性检测试剂盒测定其细胞毒性; 磁共振成像检测不同浓度Pep12-USPIO溶液的T2/T2^*信号变化。普鲁士蓝染色验证Pep12-USPIO与3种肿瘤细胞的特异性结合, 磁共振成像验证Pep12-USPIO所致磁共振信号变化与3种肿瘤细胞CXCR4表达量的相关性。  结果  3种恶性肿瘤细胞株均有不同水平的CXCR4表达, 流式细胞计数的CXCR4阳性细胞百分比分别为PANC-1:18.7%;A549:2.9%;MCF-7:1.7%。多肽Pep12与3种恶性肿瘤细胞均能特异性结合, 并且结合量与CXCR4表达量呈正相关性(r=0.999, P=0.027)。自行合成的Pep12-USPIO在室温下长时间保持稳定的胶体状态, 水和直径为(86.60±1.48)nm。Pep12-USPIO细胞毒性较低, 铁浓度低于25 μg/ml时, ΔR2值和ΔR2^*值与铁浓度呈现良好的线性正比关系(△R2:R²=0.996;△R2^*:R²=0.977)。普鲁士蓝染色证实Pep12-USPIO能够与3种恶性肿瘤细胞实现靶向结合, 磁共振成像证实Pep12-USPIO能够造成肿瘤细胞悬液磁共振T2/T2^*值降低(P < 0.01), 并且ΔR2/ΔR2^*值与肿瘤细胞CXCR4表达水平呈显著的正相关(ΔR2:r=0.997, P=0.050;ΔR2^*:r=1.000, P=0.019)。  结论  Pep12-USPIO物理性质稳定, 细胞毒性较低, 能够与不同恶性肿瘤细胞株上的CXCR4特异性结合并实现磁共振T2/T2^*信号的减低, 并且磁共振信号的变化与细胞株CXCR4的表达量呈正相关。     

湖南地区成人血清IgG亚类水平调查及影响因素分析

目的调查湖南地区成年人血清IgG亚类的浓度水平,探讨年龄、性别及生活方式等因素的影响。方法用免疫散射比浊法测定170例体检者血清中IgG_1、IgG_2、IgG_3、IgG_4和IgG浓度。结果血清IgG_1、IgG_2、IgG_3、IgG_4和IgG浓度分别为(7.53±0.14)g/L、3.99(3.13,5.02)g/L、0.49(0.30,0.70)g/L、0.53(0.26,0.93)g/L、12.2(10.5,14.1)g/L;血清IgG_1/IgG、IgG_2/IgG、IgG_3/IgG和IgG_4/IgG分别为(61.3±0.69)%、33.38(27.8,38.8)%、3.97(2.5,5.3)%和4.44(2.1,7.3)%。女性血清IgG_3浓度及IgG_3/IgG比值高于男性(P=0.005,0.014);不同性别间IgG_1、IgG_2、IgG_4及IgG_1/IgG、IgG_2/IgG、IgG_4/IgG的差异无统计学意义。31~40岁组血清IgG_3浓度显著高于41~50岁组(P=0.03),而年龄对血清IgG_1、IgG_2和IgG_4浓度的影响无统计学意义。重度吸烟组血清IgG_1的浓度比不吸烟组低,差异有统计学意义(P=0.023)。重度吸烟组IgG_4/IgG高于不吸烟组(P=0.018)。中/重度饮酒组血IgG_1、IgG_3浓度和IgG_3/IgG比值比不饮酒组低(P=0.05,0.004,0.015)。代谢综合征低风险组血清IgG_3和IgG_3/IgG高于高风险组(P=0.034,0.038)。结论性别和年龄对于血清IgG_3浓度的影响有显著意义。重度吸烟可能导致IgG_1的浓度降低和IgG_4/IgG比值的上升。血清IgG_1、IgG_3和IgG_3/IgG的降低与饮酒存在一定的关系。     

Determination of the Interfacial Rheological Properties of a Poly(DL-lactic acid)-Encapsulated Contrast Agent Using In Vitro Attenuation and Scattering

The stabilizing encapsulation of a microbubble-based ultrasound contrast agent (UCA) critically affects its acoustic properties. Polymers, which behave differently from materials commonly used (i.e., lipids or proteins) for monolayer encapsulation, have the potential for better stability and improved control of encapsulation properties. Air-filled microbubbles coated with poly(DL-lactic acid) (PLA) are characterized here using in vitro acoustic experiments and several models of encapsulation. The interfacial rheological properties of the encapsulation are determined according to each model using attenuation of ultrasound through a suspension of microbubbles. Then the model predictions are compared with scattered non-linear (sub- and second harmonic) responses. For this microbubble population (average diameter, 1.9 μm), the peak in attenuation measurement indicates a weighted-average resonance frequency of 2.5–3 MHz, which, in contrast to other encapsulated microbubbles, is lower than the resonance frequency of a free bubble of similar size (diameter, 1.9 μm). This apparently contradictory result stems from the extremely low surface dilational elasticity (around 0.01–0.07 N/m) and the reduced surface tension of the poly(DL-lactic acid) encapsulation, as well as the polydispersity of the bubble population. All models considered here are shown to behave similarly even in the non-linear regime because of the low surface dilational elasticity value. Pressure-dependent scattering measurements at two different excitation frequencies (2.25 and 3 MHz) revealed strongly non-linear behavior with 25–30 dB and 5–20 dB enhancements in fundamental and second-harmonic responses, respectively, for a contrast agent concentration of 1.33 μg/mL in the suspension. Sub-harmonic responses are registered above a relatively low generation threshold of 100–150 kPa, with up to 20 dB enhancement beyond that pressure. Numerical predictions from all models show good agreement with the experimentally measured fundamental response, but not with the experimental second-harmonic response. The characteristic features of sub-harmonic responses and the steady response beyond the threshold are matched well by model predictions. However, prediction of the threshold value depends on estimated properties and size distribution. The variation in size distribution from sample to sample leads to variation in estimates of encapsulation properties: the lowest estimated value for surface dilational viscosity better predicts the sub-harmonic threshold.     

Hydrogen peroxide ingestion associated with portal venousgas and treatment with hyperbaric oxygen: a case seriesand review of the literature

Introduction.?Ingestion of concentrated hydrogen peroxide (H₂O^₂) has been associated with venous and arterial gas embolic events, hemorrhagic gastritis, gastrointestinal bleeding, shock, and death. Although H^₂O^₂ is generally considered a benign ingestion in low concentrations, case reports have described serious toxicity following high concentration exposures. Hyperbaric oxygen (HBO) has been used with success in managing patients suffering from gas embolism with and without manifestations of ischemia.?Methods.?Poison center records were searched from July 1999 to January 2010 for patients with H^₂O^₂ exposure and HBO treatment. Cases were reviewed for the concentration of H₂O₂, symptoms, CT scan findings of portal gas embolism, HBO treatment, and outcome.?Results.?Eleven cases of portal gas embolism were found. Ages ranged from 4 to 89 years. All but one ingestion was accidental in nature. In 10 cases 35% H^₂O^₂ was ingested and in 1 case 12% H^₂O^₂ was ingested. All abdominal CT scans demonstrated portal venous gas embolism in all cases. Hyperbaric treatment was successful in completely resolving all portal venous gas bubbles in nine patients (80%) and nearly resolving them in two others. Ten patients were able to be discharged home within 1 day, and one patient had a 3.5-day length of stay.?Conclusions.?HBO was successful in resolving portal venous gas embolism from accidental concentrated H^₂O^₂ ingestions.     

Reestimation of the effects of inorganic phosphates on the equilibrium between oxygen and hemoglobin

In a previous paper, published in this journal, we showed that the data obtained in patients with severe ketoacidosis suggest that inorganic phosphates (K₂HPO₄) can increase their P 50 and therefore enhance tissue oxygenation without concomitant alteration of the 2,3 diphosphoglycerate (DPG) [1]. In order to test the hypothesis that K₂HPO₄ could influence the oxyhemoglobin dissociation curve (ODC) by a mecanism which was not DPG mediated we have measured the total ODC on whole blood with and without addition of 13–80 mmol/1 of inorganic phosphates. On average, the level of DPG remained unchanged when the P 50 with K₂HPO₄ was significantly higher (p>0.001) (P 50=29.9±3.7 mmHg) than when phosphates were not administered (P 50=25.5±2.8 mmHg). The relationship between P 50 (mmHg) and K₂HPO₄ (=X mmol/1) was P 50=–2.97 10^–3(X)²+0.26(X)–0.42 (r=0.78).Seeing that phosphates have an immediate action on the ODC, we calculated in our ketoacidosis patients, the relationship between the P 50, the inorganic phosphates (P_i in mg%) and the DPG in mol/gHb. Both factors exert a highly significant effect (p<0.001) on the P 50, according to the following equation: P 50=0.35 DPG+0.26 P_i+18.92 (r=0.73). Our data are important in two points. First it is useful to add inorganic phosphates to the treatment of patients with severe ketoacidosis in order to enhance their tissue oxygenation. Second they recall that the ODC is not only determined by the classical effects of temperature, pH and DPG byt also by inorganic anions, like phosphates as described by Benesh and Benesh in their pioneering work [2].This work was supported by a grant of the Fonds de la Recherche Scientifique Médicale, no 3450.29.90     

Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron

Objective  The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron. Materials and methods  In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort. Results  The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%). Conclusion  None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated. Presented as an invited lecture at the Supportive Care in Cancer MASCC/ISOO 2008 International Symposium in Houston, TX, USA on June 26–28, 2008 This work was sponsored by GlaxoSmithKline. R Stoltz received funding from GlaxoSmithKline to conduct this study. All other authors were employees of GlaxoSmithKline.     

Sephadex filtration of serum iodocompounds and protein-binding of iodotyrosines

Di-iodotyrosine binding to serum protein cannot be demonstrated either by electrophoresis on paper, cellulose acetate or acrylamide-agarose (using various buffers at different pHs) or by double diffusion in agar and immunoelectrophoresis. To the contrary, binding of DIT to serum protein can be estimated by Sephadex G-25 gel filtration and by adsorption on charcoal. Binding increases with pH between 6 and 10. It is almost negligible below pH 6. This property was used to propose a method of separation of all the known iodocompounds found in serum using a single serum sample and two consecutive filtrations on Sephadex G-25. The first filtration at pH 5.80 allows the separation of MIT from DIT and iodide and from PBI. The latter is resolved into T₄, T₃ and iodoprotein by refiltration in 0.01 N NaOH. Recoveries of the radioactive iodine-labeled iodocompounds are almost quantitative. Sephadex gel filtration is useful in estimating the iodotyrosine content of serum. Experiments on DIT clearance from the blood in man support the idea that iodotyrosines are not normal components of the blood of euthyroid humans. The usefulness of Sephadex G-25 gel filtration in 0.01 N NaOH for the quantitative estimation of serum total hormonal iodine is confirmed.     

Granisetron in the control of nausea and vomiting associated with bone marrow transplantation: a review of its efficacy and tolerability

Cancer patients undergoing bone marrow transplantation (BMT) experience severe nausea and vomiting associated with high-dose chemotherapy agents; these emetic symptoms are compounded by total body irradiation used in many conditioning regimens. This paper reviews clinical experience with the 5-HT₃ receptor antagonist granisetron, both as a single agent and in combination with other anti-emetics, in patients undergoing BMT and peripheral blood stem cell transplantation (PBSCT). Clinical studies demonstrate the efficacy (47–61% with no vomiting and no worse than mild nausea) and tolerability of granisetron. Its long half-life and duration of action may be responsible for its effective 24 h control of nausea and vomiting in BMT patients.     

Granisetron in the control of radiotherapy-induced nausea and vomiting: a comparison with other antiemetic therapies

Radiotherapy-induced nausea and vomiting (RINV) can be one of the most distressing symptoms of radiotherapy treatment, which if incompletely controlled may last for several weeks with fractionated radiotherapy and prevent completion of the planned treatment course. Current treatment guidelines recommend the use of 5-HT₃ receptor antagonists with or without corticosteroids for highly and moderately emetogenic radiotherapy, though only granisetron and ondansetron are currently indicated for RINV in most countries. Granisetron is a potent and highly selective 5-HT₃ receptor antagonist, with demonstrated efficacy in RINV in both placebo-controlled and comparative studies. In this paper the clinical experience with granisetron in RINV is reviewed, and its efficacy and safety compared with other antiemetic therapies.     

Evaluation of the Integrity of the Dopamine System in a Rodent Model of Parkinson’s Disease: Small Animal Positron Emission Tomography Compared to Behavioral Assessment and Autoradiography

Purpose In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), it is important to determine lesion severity. This evaluation can be performed in vivo, through evaluation of dopamine (DA)-dependent motor function or with small animal positron emission tomography (microPET), or at postmortem, by examining markers for DA neurons.Procedures Rats were given mild or severe unilateral 6-OHDA lesions, scanned with the tracer [¹¹C](±)dihydrotetrabenazine ([¹¹C]DTBZ), and tested on a tapered/ledged beam-walking task. At postmortem, autoradiography was performed with [¹¹C]DTBZ.Results Autoradiography was significantly correlated with microPET and behavioral scores, whereas the microPET and behavioral data were not significantly correlated.Conclusions This study shows that behavioral analysis, microPET, and autoradiography are all good tools for measuring the integrity of the DA system, and demonstrates the utility of the tapered/ledged beam-walking test to screen for lesion severity, as well as the importance of including postmortem analysis after in vivo imaging studies.     

Comparison of the Pharmacokinetics,Safety, and Tolerability of Vitamin D3 in DP-R206 (150-mg Ibandronate/24,000-IU Vitamin D3 Tablet) and as Monotherapy (24,000 IU) in Healthy Male Korean Adults

Background

Combined treatment with a bisphosphonate and vitamin D has been proposed for postmenopausal osteoporosis. A new, fixed-dose combination tablet of ibandronate plus vitamin D₃ has been developed for monthly administration to treat postmenopausal osteoporosis.

Objectives

The main objective of the present study was to compare the pharmacokinetics of vitamin D₃ administered in 2 forms: a newly developed ibandronate 150-mg/vitamin D₃ 24,000-IU tablet (DP-R206, test drug) and a stand-alone vitamin D₃ 24,000-IU tablet (reference drug). A secondary objective was to evaluate the safety and tolerability of DP-R206 in healthy adult male Korean volunteers.

Methods

This study was a single-dose, open-label, randomized-sequence, 2-treatment, 2-way crossover trial. Blood samples were collected from 24 hours’ predose to 120 hours’ postdose. The plasma concentrations of vitamin D₃ were analyzed by using a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated, and the 90% CIs of the ratios of the geometric means of the parameters were determined from the logarithmically transformed data by using ANOVA.

Results

Thirty-sex healthy adult male Korean volunteers with a mean (SD) age of 25.8 (2.7) years, a mean height of 174.0 (5.9) cm, and a mean weight of 69.1 (6.2) kg were enrolled; 29 participants completed the study. The 90% CIs of the ratios of the geometric means (test drug/reference drug) of the baseline-corrected C_max, AUC_0–last, and AUC_0–∞ values were 0.93 to 1.24, 0.89 to 1.19, and 0.87 to 1.18, respectively. The 90% CIs of the ratios of the geometric means (test drug/reference drug) of the baseline-uncorrected C_max, AUC_0–last, and AUC_0–∞ values were 0.93 to 1.24, 0.88 to 1.19, and 0.87 to 1.18, respectively. Eighty-four adverse events (AEs) were reported in 24 of 32 subjects receiving DP-R206, and 14 AEs were reported in 8 of 29 subjects receiving the vitamin D₃ 24,000-IU tablet. All of the subjects who experienced AEs recovered without sequelae, and no serious AEs were observed.

Conclusions

The vitamin D₃ pharmacokinetics were similar for DP-R206 and the 24,000-IU vitamin D₃ tablet. DP-R206 was well tolerated. ClinicalTrials.gov identifier: NCT01577849.     

Nucleotides control the excitability of sensory neurons via two P2Y receptors and a bifurcated signaling cascade

Nucleotides contribute to the sensation of acute and chronic pain, but it remained enigmatic which G protein-coupled nucleotide (P2Y) receptors and associated signaling cascades are involved. To resolve this issue, nucleotides were applied to dorsal root ganglion neurons under current- and voltage-clamp. Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and uridine triphosphate (UTP), but not uridine diphosphate (UDP), depolarized the neurons and enhanced action potential firing in response to current injections. The P2Y₂ receptor preferring agonist 2-thio-UTP was equipotent to UTP in eliciting these effects. The selective P2Y₁ receptor antagonist MRS2179 largely attenuated the excitatory effects of ADP, but left those of 2-thio-UTP unaltered. Thus, the excitatory effects of the nucleotides were mediated by 2 different P2Y receptors, P2Y₁ and P2Y₂. Activation of each of these 2 receptors by either ADP or 2-thio-UTP inhibited currents through K_V7 channels, on one hand, and facilitated currents through TRPV₁ channels, on the other hand. Both effects were abolished by inhibitors of phospholipase C or Ca²⁺-ATPase and by chelation of intracellular Ca²⁺. The facilitation of TRPV₁, but not the inhibition K_V7 channels, was prevented by a protein kinase C inhibitor. Simultaneous blockage of K_V7 channels and of TRPV₁ channels prevented nucleotide-induced membrane depolarization and action potential firing. Thus, P2Y₁ and P2Y₂ receptors mediate an excitation of dorsal root ganglion neurons by nucleotides through the inhibition of K_V7 channels and the facilitation of TRPV₁ channels via a common bifurcated signaling pathway relying on an increase in intracellular Ca²⁺ and an activation of protein kinase C, respectively.     

The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel, comparative clinical trial

PURPOSE: This clinical trial was conducted to evaluate the efficacy and safety of Palonosetron in preventing chemotherapy-induced vomiting (CIV) among the Chinese cancer patients. PATIENTS AND METHODS: Two hundred and forty patients were scheduled to be enrolled and randomized to receive a single intravenous dose of palonosetron 0.25 mg, or granisetron 3 mg, 30 min before receiving highly emetogenic chemotherapy. The primary efficacy endpoint was the complete response (CR) rate for acute CIV (during the 0-24-h interval after chemotherapy). Secondary endpoints included the CR rates for delayed CIV (more than 24 h after chemotherapy). RESULTS: Two hundred and eight patients were accrued and received study medication. CR rates for acute CIV were 82.69% for palonosetron and 72.12% for granisetron, which demonstrated that palonosetron was not inferior to granisetron in preventing acute CIV. Comparisons of CR rates for delayed CIV yielded no statistical difference between palonosetron and granisetron groups and did not reveal non-inferiority of palonosetron to granisetron. Adverse events were mostly mild to moderate, with quite low rates among the two groups. CONCLUSIONS: A single dose (0.25 mg) of palonosetron is not inferior to a single dose (3 mg) of granisetron in preventing CIV and possesses an acceptable safety profile in the Chinese population.     

Single high-dose dexamethasone improves the effect of ondansetron on acute chemotherapy-induced nausea and vomiting but impairs the control of delayed symptoms

The introduction of serotonin receptor (5-HT₃) antagonists has improved the control of acute nausea and vomiting induced by cancer chemotherapy, but they seem to have little or no effect on delayed symptoms. Corticosteroids are known to reduce both acute and delayed nausea and vomiting. The aim of the present study was to test the hypothesis that a single high dose of dexamethasone (20 mg), a long-acting corticosteroid, given after cisplatin and in addition to ondansetron (8 mg three times a day), would enhance the control of both acute and delayed nausea and vomiting. A group of 104 chemotherapy-naive ovarian cancer patients, scheduled for at least three cycles of combination chemotherapy including cisplatin (50 mg/m₂), were randomly allocated to receive either dexamethasone or placebo in addition to ondansetron. Two-thirds of the patients received doxorubin and melphalan on the day before cisplatin and 1/3 received doxorubicin immediately before cisplatin. Unexpectedly we found, in all three chemotherapy cycles, that patients receiving dexamethasone suffered from more delayed nausea and vomiting than patients receiving placebo. In patients with no acute nausea or vomiting, the boomerang effect of dexamethasone could be seen on the first day after chemotherapy. In a follow-up study on 5 patients not included in the randomized trial, dexamethasone induced a pronounced reduction in urinary cortisol excretion on the day after chemotherapy with a return to normal excretion on day 2. It is concluded that a single high dose of dexamethasone does not seem appropriate for controlling delayed nausea and vomiting.