Comparative studies of various antiemetic regimens

Since 1981, when highdose intravenous metoclopramide was demonstrated to be efficacious, slow but constant improvement in the prevention of chemotherapy-induced emesis has been achieved. Today, a combination of a serotonin receptor 3 (5-HT₃) antagonist plus dexamethasone can be considered the most efficacious treatment for the prevention of emesis induced by cisplatin and by moderately emetogenic chemotherapy. Which 5-HT3receptor antagonist should be used? Preclinical differences among 5-HT3receptor antagonists have been reported with regard to selectivity of receptor binding, potency, dose response, and duration of action. Twelve comparative studies among 5-HT₃receptor antagonists have been carried out. Unfortunately, all these trials have some important shortcomings (patient population not large enough to show small but clinically important differences; not blinded studies; no association with steroids to maximize treatment efficacy) and, therefore, no definitive conclusions can be drawn. Very recently three large, well-conducted double-blind comparative studies have been published. All three showed that 5-HT3receptor antagonists have almost identical antiemetic efficacy and tolerability. Therefore, the choice among the 5-HT₃receptor antagonists should be based only on the acquisition cost of the prescribed dose in each country for each compound.     

5水平冰冻混合人血清葡萄糖候选标准物质的制备研究

目的研制5水平冰冻混合人血清葡萄糖标准物质,为葡萄糖常规方法的准确度验证,提供稳定和互通性良好的真实值控制品。方法收集足量正常体检人群无肉眼溶血、脂血和黄疸的血清标本,依次采用Sartorius公司的0.8、0.45、0.2μm过滤微膜过滤除菌后分装于冻存管中。按《标准物质/标准样品生产者能力认可准则》[1]的要求,对冰冻混合人血清进行均匀性研究,短期稳定性(室温、4℃、-20℃)和长期稳定性(-80℃)研究,定值结果用"靶值±不确定度"表示,2家候选葡萄糖参考实验室测定结果均值作为靶值,不确定度包括测定变异和测定系统偏差、瓶间差及稳定性所带来的不确定度。并对冰冻混合人血清在6种进口配套检测系统中的互通性进行观察。结果共制备5水平冰冻混合人血清(C1、C2、C3、C4、C5)。C4水平血清瓶间标准偏差为0.018 mmol/L,其余4水平瓶间偏差为零,经单因素方差分析后P值全部大于0.05。稳定性研究经线性回归方差分析P值全部大于0.05。2家候选葡萄糖参考实验室测定结果的均值为3.08、5.92、13.60、9.311、8.71 mmol/L,不确定度相应为0.09、0.17、0.36、0.230、.55 mmol/L。5水平冰冻混合人血清的坐标点全部位于40份人血清标本的直线回归95%可信区间范围内,该5水平冰冻混合人血清与血清的反应性相同。结论 5水平冰冻混合人血清均匀性、稳定性、互通性良好,定值准确。     

Analytical performances of a glycated albumin assay that is traceable to standard reference materials and reference range determination

BackgroundGlycated albumin (GA) is an intermediate‐term marker for monitoring glycemic control (preceding 2–3 weeks) in patients with diabetes mellitus. We evaluated the performance of Lucica Glycated Albumin‐L, a new GA assay that is traceable to standard reference materials and determined the reference range in healthy subjects without diabetes.MethodsThe performance and reference range studies were conducted in accordance with Clinical and Laboratory Standards Institute (CLSI) Guidelines. The traceability was established using reference material recommended by the Japan Society of Clinical Chemistry (JSCC).ResultsThe coefficient of variation (CV) of overall repeatability, within‐laboratory precision, and overall reproducibility values of GA values were not more than 2.6%, 3.3%, and 1.6%, respectively, among laboratories. The GA values showed good linearity from 173 to 979 mmol/mol (9.4%–54.9%) across the assay range. The GA reference range in 262 healthy subjects was between 183 and 259 mmol/mol (9.9%–14.2%) while that of subjects with diabetes was 217–585 mmol/mol (11.8–32.6%). The reagent was stable for 2 months on the bench at room temperature. The limits of blank, detection, and qualification were 6.9, 7.9, and 9.7 μmol/L for GA concentration, and 3.8, 7.0, and 21.8 μmol/L for albumin concentration, respectively. Hemoglobin slightly affected the assay, while other classical interfering substances had no significant impact.ConclusionsThe present GA assay shows comparable performance to current clinical assays and could be used for intermediate‐term monitoring of glycemic control in diabetes patients.     

Study of the susceptibility of human colorectal tumor explants to lak-cell lysis: Comparison of various cytotoxicity tests

The susceptibility of tumor cells from cultures of 8 human colorectal tumor explants to a standard LAK preparation originating from a single healthy donor was assessed in 5 various cytotoxic tests. Target cells were suspended or attached (in three different ⁵¹Cr-release 4 hr tests), grown as a confluent monolayer (in a colorymetric 72 hr test) and grown as three-dimensional spheroids (in a ⁵¹Cr-release 24 hr assay). The susceptibility to lysis observed for one tumor in the 5 tests varied from 4 to 15 times and was a tumor attribute independent of the susceptibility to lymphocyte attack. There was no correlation of results between the 4 hr tests and a 72 hr test performed on monolayer, or the spheroid test taking into account the resistance of the three-dimensional structure to lymphocyte invasion. Our study excludes the possibility of quantitative interpolation of assessments of tumor cell susceptibility to lymphocytes received from various tests. It also refers to simple reductionist tests which may be compared, however, after ranking the qualitative categories. © 1993 Wiley-Liss, Inc.     

Comparative in vivo mucoadhesion studies of thiomer formulations using magnetic resonance imaging and fluorescence detection.

The aim of this study was to compare different oral delivery systems based on the thiolated polymer polycarbophil-cysteine (PCP-Cys) and to provide evidence for the validity of the hypothesis that unhydrated polymers provide better mucoadhesion in vivo. To achieve dry polymer application, a new, experimental dosage form named Eutex (made of Eudragit L100-55 and latex) capsule has been developed. Magnetic resonance imaging was used to localize the point of release of the thiolated polymer from the application forms via the positive magnetic resonance signal from a gadolinium complex (Gd-DTPA). In vivo mucoadhesion was determined by ascertaining the residence time of the fluorescence-tagged thiomer on intestinal mucosa after 3 h. Results showed that in comparison to conventional application forms the Eutex capsules led to 1.9-fold higher mucoadhesive properties of PCP-Cys when compared to application with a conventional enteric-coated capsule, and to 1.4-fold higher mucoadhesion when compared to administration with an enteric-coated tablet of the thiomer. The findings of this study should contribute to the understanding of mucoadhesion and mucoadhesion influencing parameters in vivo and should therefore be of considerable interest for the development of future mucoadhesive oral drug delivery dosage forms.     

Comparative study of secretin and Lundh tests.

Exocrine pancreatic function in 19 patients with pancreatic disease and in 14 of 16 controls was measured by secretin stimulation and by the Lundh test on two different occasions. Peak bicarbonate concentration in the Lundh test emerged as the most reliable parameters. No additional diagnostic value was obtained by measuring enzymes after secretin injection. In 6 patients with chronic and in 8 of 13 patients with acute pancreatitis, both tests gave results that agreed with each other. The remaining 5 patients showed either an abnormal secretin value or an abnormal Lundh test. This is consistent with the wide variation seen in acute pancreatitis. It is concluded that the Lundh test as well as the secretin test were of value in the assessment of chronic pancreatic disease. The secretin test may be slightly more sensitive to mild and acute pancreatic damage than is the Lundh test. However stimulation of the pancreas by a test meal is easier to perform and more economic.     

Designing image segmentation studies: Statistical power,sample size and reference standard quality

Segmentation algorithms are typically evaluated by comparison to an accepted reference standard. The cost of generating accurate reference standards for medical image segmentation can be substantial. Since the study cost and the likelihood of detecting a clinically meaningful difference in accuracy both depend on the size and on the quality of the study reference standard, balancing these trade-offs supports the efficient use of research resources.In this work, we derive a statistical power calculation that enables researchers to estimate the appropriate sample size to detect clinically meaningful differences in segmentation accuracy (i.e. the proportion of voxels matching the reference standard) between two algorithms. Furthermore, we derive a formula to relate reference standard errors to their effect on the sample sizes of studies using lower-quality (but potentially more affordable and practically available) reference standards.The accuracy of the derived sample size formula was estimated through Monte Carlo simulation, demonstrating, with 95% confidence, a predicted statistical power within 4% of simulated values across a range of model parameters. This corresponds to sample size errors of less than 4 subjects and errors in the detectable accuracy difference less than 0.6%. The applicability of the formula to real-world data was assessed using bootstrap resampling simulations for pairs of algorithms from the PROMISE12 prostate MR segmentation challenge data set. The model predicted the simulated power for the majority of algorithm pairs within 4% for simulated experiments using a high-quality reference standard and within 6% for simulated experiments using a low-quality reference standard. A case study, also based on the PROMISE12 data, illustrates using the formulae to evaluate whether to use a lower-quality reference standard in a prostate segmentation study.     

Renewable standard reference material for the detection of TP53 mutations.

BACKGROUND: Numerous DNA-based tests are currently in use or under development for the detection of mutations associated with disease. Most of the current methods use PCR amplification technologies and detection after separation or chromatography of the products. We have developed a panel of standard reference materials consisting of 12 plasmid clones containing a 2.0 kb region of the TP53 gene, including exons 5-9. Eleven of these clones contain a single mutation within the mutational hot spots of the TP53 gene, the twelfth is wild-type in this region of the gene. The mutations are amino acid (aa) 128: C to T; aa 175: G to A; aa 237: T to C; aa 245: G to A; aa 248: C to T; aa 248: G to A; aa 249: G to T; aa 273: C to T; aa 273: G to A; aa 282: C to T; and aa 328: T to C. These standard reference materials (SRMs), created by site-directed mutagenesis of wild-type TP53 from a human cell line, include the specific mutations most commonly found to be associated with cancer. Their use will improve disease detection by serving as validation materials to monitor errors in measurement methods, including PCR amplification, amplicon separation, and data analysis from different technology platforms. METHODS AND RESULTS: The single point mutations of the panel were validated by capillary electrophoresis single-strand conformational polymorphism analysis, denaturing gradient gel electrophoresis, and denaturing high-performance liquid chromatography, as well as full sequence analysis of both DNA strands of the cloned material. For both heteroduplex analysis methods, the presence of the mutations was resolved for each SRM. CONCLUSION: The generation of a standard TP53 reference panel and demonstration that the panel can successfully validate mutation detection across different mutation scanning technology platforms. Hence, this panel functions as an SRM to normalize results obtained from different laboratories using different techniques.     

A list of selected reference materials in clinical chemistry.

This is a compilation of reference materials suggested for scientists considering a laboratory reference collection in clinical chemistry, or for librarians seeking to develop or add to an up-t-o-date library collection. Nine areas are represented: general clinical chemistry; analytical methods, procedures, and techniques; calculations and statistics; the clinical laboratory; drugs and metabolism; enzymology; instrumentation, interpretation of data; and ready reference.     

In vitro and in vivo enhancement of ganciclovir-mediated bystander cytotoxicity with gemcitabine.

To improve bystander cell killing with HSV-TK/GCV, we have utilized dFdCyd to reduce endogenous dGTP, which competes with GCVTP for incorporation into DNA. In this study we demonstrate the ability of dFdCyd to enhance GCV-mediated bystander cytotoxicity in cultured SW620 human colon carcinoma cells as well as in a murine xenograft model. In vitro, dFdCyd reduced cellular dGTP levels and produced a fourfold increase in the GCVTP:dGTP ratio. This elevated GCVTP:dGTP ratio resulted in a twofold increase in GCVMP incorporation into DNA in bystander cells cocultured with HSV-TK-expressing cells. The combination of GCV and dFdCyd was determined to be synergistic by isobologram analysis of bystander cytotoxicity. Tumors in mice treated with GCV and dFdCyd exhibited a significant growth delay requiring 40 days to obtain approximately 10 times their initial size compared to tumors in PBS- or single-drug-treated animals, which grew rapidly, increasing to a similar size in just 19 to 24 days. In addition, complete tumor regression was observed only in animals treated with both drugs. Furthermore, dFdCyd alone or in combination with GCV produced no evidence of toxicity or significant weight loss. These data suggest that dFdCyd may improve the clinical efficacy of HSV-TK/GCV gene therapies.     

Tissue toxicity of local anesthetics. An in vivo trial

AIM: Local anesthetics are often administered intra-articularly after knee surgery. The aim of this study was to determine differences in irritancy of local anesthetics in an in vivo test performed on the chorioallantoic membrane of hen's eggs (HET-CAM test) to evaluate the specific irritation score. METHOD: After incubation for 9 days, the chorioallantoic membrane was prepared and then exposed to different local anesthetics (Naropin, Scandicain,Carbostesin,Xyloneural). RESULTS: We found no irritating values for the tested substances. No vascular injuries of the chorioallantoic membrane could be detected. Therefore, the irritation score was measured according to the standard protocol with an irritation score=0. CONCLUSION: Our results show that local anesthetics often used in clinics do not provoke severe vascular injuries as a sign of tissue toxicity. Therefore, the customary concentrations can be recommended for clinical use.