Treatment with Paclitaxel Orotate and Carboxyamidotriazole Orotate in SC-Implanted OVCAR-5 Human Ovarian Tumor Xenografts

Background: Paclitaxel (PTX) is approved for the treatment of refractory ovarian cancer and breast cancer, but is problematic due to severe, dose-dependent, potentially irreversible neurotoxicity. Alternative formulations using nanoparticles and liposomes have been developed to avoid solvent-related toxicity. These formulations allow improved delivery;however, toxicity, compensatory signaling, and drug resistance still pose challenges. Conversion of cytotoxic agents to their orotate compounds offers a potentially improved approach by increasing bioavailability and reducing toxicity. Orotate salts are neutral and acquire lipophilic properties, easing diffusion through lipid membranes. The orotate salt of PTX (PTXO) may yield an improved safety profile. Combination therapy with cytotoxic drugs, antiangiogenics and/or signal transduction pathway inhibitors has shown better efficacy than cytotoxic monotherapy. The combination of carboxyamidotriazole orotate (CTO, a calcium signal transduction pathway inhibitor) and PTX may be more effective than PTX alone at non-toxic doses. Materials and Methods: PTXO alone, and combinations of CTO with PTX and PTXO were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combinations. The tolerated combinations, PTX monotherapy, and PTXO monotherapy were then tested to evaluate their antitumor activity in female athymic NCr-nu/nu mice with subcutaneously implanted OVCAR-5 human ovarian tumor. Antitumor activity was measured by median time to doubling, median tumor growth delay, and mean percent body weight loss. Results: CTO, PTX, and PTXO showed significant inhibition of growth of the human OVCAR-5 ovarian tumor xenografts. The combination of low PTX and CTO, or high PTXO monotherapy, had significant efficacy and it was less toxic than high PTX as measured by body weight loss. Conclusions: Low-dose CTO is effective and has low toxicity, suggesting the potential for maintenance therapy for ovarian cancer. PTXO offers efficacy and a strategy for minimizing body weight loss, and may improve outcomes for patients who demonstrate toxicity to PTX.

Truth and the World： Why Davidson Is Right and Rorty Is Wrong

Richard Rorty thinks he has the same agenda as Donald Davidson. He is wrong. Though Rorty contends truth as only metaphor liberates us, he actually undercuts a rich interpretative ability. Davidson＇s agenda provides ways to explore this ability by elucidating the conditions that reside in the make up of successful communication and in which truth claims are made about the world. Thus, Davidson and Rorty have different agenda, and Davidson＇s offers more promise for philosophy to help explain what we seem to know-we can communicate truthfully about the world.

The Sign Test with Ties Included

The sign rank test is taught in virtually all introductory Statistics classes. When teaching the sign rank test the students are told to ignore the ties. Ignoring ties that support the null hypothesis is not logical. Why should valid data that support the null hypothesis be ignored? The approach taken here demonstrates a method for testing with ties included. A typical problem presentation in a text book would indicate that if you had ten ties in a sample of size fifty the tie scores would be excluded. However, the ten tie scores are a very valuable piece of statistical information which should not be ignored. The method demonstrated here shows that a different conclusion is reached in some cases when the ties are not excluded. Further many sign tests often will have ties because in some cases the data are not a cardinal number, but an ordinal number chosen from a set often results in ties. The alternative approach uses a one-tailed distribution and considers both +’s and -'s separated. A two-tailed test for equal variances is done with a one-tail of an F distribution. This alternate approach to the sign test allows the use of important statistical information which has been ignored with the traditional sign rank test.

An Investigation of the Effect of the Swamping Phenomenon on Several Block Procedures for Multiple Outliers in Univariate Samples

In its broadest sense, this paper reviews the general outlier problem, the means available for addressing the discordancy (or lack thereof) of an outlier (or outliers), and possible strategies for dealing with them. Two alternate approaches to the multiple outlier problem, consecutive and block testing, and their respective inherent weaknesses, masking and swamping, are discussed. In addition, the relative susceptibility of several tests for outliers in normal samples to the swamping phenomena is reported.

Comparative Response of SC CAKI-1 Renal Tumor to Treatment with Doxorubicin HCl and Doxorubicin Orotate

Background: Doxorubicin (DOX) is an effective treatment for many cancers across the age spectrum, but its therapeutic potential is limited because of dose-dependent relation to both progressive and irreversible cardiomyopathy leading to congestive heart failure. While decreases in cardiotoxicity have been reported with liposomal doxorubicin, the long-term cardiac effects are not known. Orotate salts of cytotoxic drugs have been shown to confer antitumor effects with a better safety profile than unconverted drug, and therefore may offer an improved approach to cancer treatment. Materials and Methods: Male, athymic NCr-nu/nu mice with subcutaneously implanted CAKI-1 human renal tumor xenografts were treated with DOX and its orotate salt (DOX-O) to evaluate antitumor activity, measured by median tumor mass doubling time and tumor weight. Nontumored male, athymic NCr-nu/nu mice were treated with DOX, DOX-O and liposomal doxorubicin formulations to determine DOX concentration in liver and heart;and to evaluate their effect on body weight. Non-tumored female, athymic NCr-nu/nu mice were treated with daunorubicin and daunorubicin orotate to evaluate tolerance. Results: DOX and DOX-O exhibited significant, similar levels of antitumor activity. Mice treated with DOX-O had a lower percentage body weight loss. In the animals treated with DOX, DOX-O, or liposomal doxorubicin, liposomal doxorubicin was associated with the lowest percentage of body weight loss, but the highest concentration of DOX in heart. In daunorubicin tolerance experiments, animals showed a better tolerance for daunorubicin orotate as measured by a smaller percentage change in body weight. Conclusions: DOX-O is effective as an antitumor therapy and may offer a less toxic alternative to DOX for maintaining therapy. The lower percentage of body weight loss in animals treated with DOX-O and daunorubicin orotate is a measure of improved tolerance and may translate into better patient outcomes.

Walking for health during pregnancy:A literature review and considerations for future research

Walking is the most commonly chosen type of physical activity(PA)during pregnancy and provides several health benefits to both mother and child.National initiatives have promoted the importance of walking in general,but little emphasis is directed toward pregnant women,the majority of whom are insufficiently active.Pregnant women face a variety of dynamic barriers to a physically active lifestyle,some of which are more commonly experienced during specific times throughout the pregnancy experience.Walking is unique in that it appears resistant to a number of these barriers that limit other types of PA participation,and it can be meaningfully integrated into some transportation and occupational activities when leisure-time options are unavailable.Preliminary intervention work suggests that walking programs can be effectively adopted into a typical pregnancy lifestyle.However,a great deal of work remains to administer successful pregnancy walking interventions,including developing and using validated methods of PA and walking assessment.This narrative review discusses the unique advantages of walking during pregnancy,provides recommendations for future intervention work,and outlines the need for pregnancy-focused community walking initiatives.Standard search procedures were followed to determine sources from the literature specific to walking during pregnancy for use in each section of this review.

Effect of Carboxyamidotriazole Orotate, a Modulator of Calcium-Dependent Signaling Pathways, on Advanced Solid Tumors

Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We determined the safety and tolerability, pharmacokinetic profile, maximum tolerated dose, and recommended Phase II dose of CTO monotherapy in patients with advanced solid tumors. In this first-in-human Phase I clinical trial, eligible patients with advanced solid tumors were enrolled to receive a once-daily dose of CTO following a standard 3 + 3 Phase I design (starting at 50 mg/m2/day) with dose escalations of 30% - 100%. Dose limiting toxicity (DLT) was defined in the first cycle of treatment. Measurable disease and response were defined by RECIST version 1.1. Forty-four patients were evaluable for safety. CTO-related grade 3 toxicities included diarrhea (2.5%), fatigue (5.0%), lymphopenia (2.5%) and transient creatine phosphokinase (CPK) elevation (2.5%). There were no grade 4 or 5 toxicities. Steady state plasma levels of CAI (CTO metabolite) were achieved by day 12 with a half life estimate of 55 hr. Although no objective response rates were observed, nine patients with rapidly progressive and treatment-refractory tumors achieved stable disease (SD) durable for up to 14 months. The maximum tolerated dose for CTO alone was 427 mg/m2/day. The dose-limiting toxicity was grade 3 fatigue. CTO is orally bioavailable, safe, well tolerated and produces disease stabilization in a broad range of heavily treated refractory tumors. Combination trials of CTO with other antineoplastic agents are ongoing.

美国住院药师培养模式及现状介绍

目的:通过了解美国住院药师培养项目,促进我国的住院药师培养制度的成熟和规范化。方法:参考美国医疗机构药师协会和美国临床药学学会发布的文件,结合在美国学习临床药学服务的经历。结果:美国住院药师培养模式以有组织、有导向性和经认证的毕业后项目为基础。2008年美国共有住院药师培养项目460个,提供约2000个培训岗位。结论:我国应将国内医院药学发展实际和美国的成功经验相结合,完善住院药师培养制度,培养临床药学人才。