The combined effect of pravastatin and aspirin on clinical cardiovascular events

The 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, can achieve significant reductions in plasma low-density lipoprotein (LDL)-cholesterol levels. Experimental and clinical evidence now shows that some statins interfere with formation of atherosclerotic lesions independent of their hypolipidemic properties. Vulnerable plaque rupture can result in thrombus formation and artery occlusion; this plaque deterioration is responsible for most acute coronary syndromes, including myocardial infarction (MI), unstable angina, and coronary death, as well as coronary heart diseaseequivalent non-hemorrhagic stroke. Inhibition of HMG-CoA reductase has potential pleiotropic effects other than lipid-lowering, as statins block mevalonic acid production, a precursor to cholesterol and numerous other metabolites. Statins' beneficial effects on clinical events may also thus involve nonlipid-related mechanisms that modify endothelial function, inflammatory responses, plaque stability, and thrombus formation. Aspirin, routinely prescribed to post-MI patients as adjunct therapy, may potentiate statins beneficial effects, as aspirin does not compete metabolically with statins but acts similarly on atherosclerotic lesions. Common functions of both medications include inhibition of platelet activity and aggregation, reduction in atherosclerotic plaque macrophage cell count, and prevention of atherosclerotic vessel endothelial dysfunction. The Cholesterol and Recurrent Events (CARE) trial provides an ideal population in which to examine the combined effects of pravastatin and aspirin. Lipid levels, intermediate outcomes, are examined by pravastatin and aspirin status, and differences between the two pravastatin groups are found. A modified Cox proportional-hazards model with aspirin as a time-dependent covariate was used to determine the effect of aspirin and pravastatin on the clinical cardiovascular composite endpoint of coronary heart disease death, recurrent MI or stroke. Among those assigned to pravastatin, use of aspirin reduced the composite primary endpoint by 35%; this result was similar by gender, race, and diabetic status. Older patients demonstrated a nonsignificant 21% reduction in the primary outcome, whereas the younger had a significant reduction of 43% in the composite primary outcome. Secondary outcomes examined include coronary artery bypass graft (38% reduction), nonsurgical bypass, peripheral vascular disease, and unstable angina. Pravastatin and aspirin in a post-MI population was found to be a beneficial combination that seems to work through lipid and nonlipid, anti-inflammatory mechanisms. ^

A BAYESIAN APPROACH TO DOSE-RESPONSE ASSESSMENT AND DRUG-DRUG INTERACTION ANALYSIS: APPLICATION TO IN VITRO STUDIES

The considerable search for synergistic agents in cancer research is motivated by the therapeutic benefits achieved by combining anti-cancer agents. Synergistic agents make it possible to reduce dosage while maintaining or enhancing a desired effect. Other favorable outcomes of synergistic agents include reduction in toxicity and minimizing or delaying drug resistance. Dose-response assessment and drug-drug interaction analysis play an important part in the drug discovery process, however analysis are often poorly done. This dissertation is an effort to notably improve dose-response assessment and drug-drug interaction analysis. The most commonly used method in published analysis is the Median-Effect Principle/Combination Index method (Chou and Talalay, 1984). The Median-Effect Principle/Combination Index method leads to inefficiency by ignoring important sources of variation inherent in dose-response data and discarding data points that do not fit the Median-Effect Principle. Previous work has shown that the conventional method yields a high rate of false positives (Boik, Boik, Newman, 2008; Hennessey, Rosner, Bast, Chen, 2010) and, in some cases, low power to detect synergy. There is a great need for improving the current methodology. We developed a Bayesian framework for dose-response modeling and drug-drug interaction analysis. First, we developed a hierarchical meta-regression dose-response model that accounts for various sources of variation and uncertainty and allows one to incorporate knowledge from prior studies into the current analysis, thus offering a more efficient and reliable inference. Second, in the case that parametric dose-response models do not fit the data, we developed a practical and flexible nonparametric regression method for meta-analysis of independently repeated dose-response experiments. Third, and lastly, we developed a method, based on Loewe additivity that allows one to quantitatively assess interaction between two agents combined at a fixed dose ratio. The proposed method makes a comprehensive and honest account of uncertainty within drug interaction assessment. Extensive simulation studies show that the novel methodology improves the screening process of effective/synergistic agents and reduces the incidence of type I error. We consider an ovarian cancer cell line study that investigates the combined effect of DNA methylation inhibitors and histone deacetylation inhibitors in human ovarian cancer cell lines. The hypothesis is that the combination of DNA methylation inhibitors and histone deacetylation inhibitors will enhance antiproliferative activity in human ovarian cancer cell lines compared to treatment with each inhibitor alone. By applying the proposed Bayesian methodology, in vitro synergy was declared for DNA methylation inhibitor, 5-AZA-2'-deoxycytidine combined with one histone deacetylation inhibitor, suberoylanilide hydroxamic acid or trichostatin A in the cell lines HEY and SKOV3. This suggests potential new epigenetic therapies in cell growth inhibition of ovarian cancer cells.

AN ANALYSIS OF THE RELATIVE INFLUENCE OF RACE, INCOME, EDUCATION, AND FOOD STAMP PROGRAM PARTICIPATION/NONPARTICIPATION ON THE FOOD AND NUTRIENT CONSUMPTION OF A NORTH FLORIDA URBAN CLINIC POPULATION IN CONJUNCTION WITH A SURVEY OF NUTRITION RELATED HABITS AND ATTITUDES

The relative influence of race, income, education, and Food Stamp Program participation/nonparticipation on the food and nutrient intake of 102 fecund women ages 18-45 years in a Florida urban clinic population was assessed using the technique of multiple regression analysis. Study subgroups were defined by race and Food Stamp Program participation status. Education was found to have the greatest influence on food and nutrient intake. Race was the next most influential factor followed in order by Food Stamp Program participation and income. The combined effect of the four independent variables explained no more than 19 percent of the variance for any of the food and nutrient intake variables. This would indicate that a more complex model of influences is needed if variations in food and nutrient intake are to be fully explained.^ A socioeconomic questionnaire was administered to investigate other factors of influence. The influence of the mother, frequency and type of restaurant dining, and perceptions of food intake and weight were found to be factors deserving further study.^ Dietary data were collected using the 24-hour recall and food frequency checklist. Descriptive dietary findings indicated that iron and calcium were nutrients where adequacy was of concern for all study subgroups. White Food Stamp Program participants had the greatest number of mean nutrient intake values falling below the 1980 Recommended Dietary Allowances (RDAs). When Food Stamp Program participants were contrasted to nonparticipants, mean intakes of six nutrients (kilocalories, calcium, iron, vitamin A, thiamin, and riboflavin) were below the 1980 RDA compared to five mean nutrient intakes (kilocalories, calcium, iron, thiamin and riboflavin) for the nonparticipants. Use of the Index of Nutritional Quality (INQ), however, revealed that the quality of the diet of Food Stamp Program participants per 1000 kilocalories was adequate with exception of calcium and iron. Intakes of these nutrients were also not adequate on a 1000 kilocalorie basis for the nonparticipant group. When mean nutrient intakes of the groups were compared using Student's t-test oleicacid intake was the only significant difference found. Being a nonparticipant in the Food Stamp Program was found to be associated with more frequent consumption of cookies, sweet rolls, doughnuts, and honey. The findings of this study contradict the negative image of the Food Stamp Program participant and emphasize the importance of education. ^

DEVELOPMENT AND IMPLEMENTATION OF A REMOTE AUDIT TOOL FOR HIGH DOSE RATE (HDR) 192IR BRACHYTHERAPY USING OPTICALLY STIMULATED LUMINESCENCE DOSIMETRY

This work aimed to create a mailable and OSLD-based phantom with accuracy suitable for RPC audits of HDR brachytherapy sources at institutions participating in NCI-funded cooperative clinical trials. An 8 × 8 × 10 cm3 prototype with two slots capable of holding nanoDot Al2O3:C OSL dosimeters (Landauer, Glenwood, IL) was designed and built. The phantom has a single channel capable of accepting all 192Ir HDR brachytherapy sources in current clinical use in the United States. Irradiations were performed with an 192Ir HDR source to determine correction factors for linearity with dose, dose rate, and the combined effect of irradiation energy and phantom construction. The uncertainties introduced by source positioning in the phantom and timer resolution limitations were also investigated. It was found that the linearity correction factor was where dose is in cGy, which differed from that determined by the RPC for the same batch of dosimeters under 60Co irradiation. There was no significant dose rate effect. Separate energy+block correction factors were determined for both models of 192Ir sources currently in clinical use and these vendor-specific correction factors differed by almost 2.6%. For Nucletron sources, this correction factor was 1.026±0.004 (99% Confidence Interval) and for Varian sources it was 1.000±0.007 (99% CI). Reasonable deviations in source positioning within the phantom and the limited resolution of the source timer had insignificant effects on the ability to measure dose. Overall measurement uncertainty of the system was estimated to be ±2.5% for both Nucletron and Varian source audits (95% CI). This uncertainty was sufficient to establish a ±5% acceptance criterion for source strength audits under a formal RPC audit program. Trial audits of eight participating institutions resulted in an average RPC-to-institution dose ratio of 1.000 with a standard deviation of 0.011.

Effects of Combined Bevacizumab and Paclitaxel on Tumor Interstitial Fluid Pressure in a Preclinical Breast Cancer Model

Effects of Combined Bevacizumab and Paclitaxel on Tumor Interstitial Fluid Pressure in a Preclinical Breast Cancer Model by Ricardo H. Alvarez Several mechanisms of cell resistance are often accountable for unsuccessful chemotherapy against cancer. Another reason, which has received increased attention, is the inefficient transport of anticancer drugs into tumor tissue. These impaired transports of chemotherapy into the tumor have been attributed to abnormal microvasculature and to pathologically increased tumor hypertension also called: interstitial fluid pressure (IFP). The pathophysiological processes leading to elevated tumor IFP are poorly understood. Here, in a preclinical breast cancer model, it is argued that a condition of raised IFP is a major factor in preventing optimal access of systemically administered chemotherapy agents. In our experimental model, we used a GILM2 human breast cancer in xenografts; mice were treated with different doses of paclitaxel –a widely used antimicrotubular agent, and bevacizumab –monoclonal antibody against vascular endothelial growth factor (VEGF). The proposed research project is designed to test the hypothesis that paclitaxel in combination with bevacizumab decreases the tumor IPF by restoring tumor permeability and increasing chemotherapy delivery. We demonstrated that the combination of paclitaxel and bevacizumab produced greater tumor control than either agent given alone and this combination reduced the IFP, producing an increment of 75% of apoptosis compared with the control arm. In addition, the intra-tumor paclitaxel quantification by liquid chromatography/Mass Spectrometry (LC/MS) demonstrated that lower dose of both agents showed a synergistic effect compared with high dose of treatment, where there is no significantly increase of paclitaxel into the tumor. These preclinical results are likely to have broad implications for the utility of anti-angiogenic therapies alone and in combination with chemotherapeutic agents.

Physician adoption of a practice guideline: Effect on the cost of medical care for adult patients with diabetes

In the demanding environment of healthcare reform, reduction of unwanted physician practice variation is promoted, often through evidence-based guidelines. Guidelines represent innovations that direct change(s) in physician practice; however, compliance has been disappointing. Numerous studies have analyzed guideline development and dissemination, while few have evaluated the consequences of guideline adoption. The primary purpose of this study was to explore and analyze the relationship between physician adoption of the glycated hemoglobin test guideline for management of adult patients with diabetes, and the cost of medical care. The study also examined six personal and organizational characteristics of physicians and their association with innovativeness, or adoption of the guideline. ^ Cost was represented by approved charges from a managed care claims database. Total cost, and diabetes and related complications cost, first were compared for all patients of adopter physicians with those of non-adopter physicians. Then, data were analyzed controlling for disease severity based on insulin dependency, and for high cost cases. There was no statistically significant difference in any of eight cost categories analyzed. This study represented a twelve-month period, and did not reflect cost associated with future complications known to result from inadequate management of glycemia. Guideline compliance did not increase annual cost, which, combined with the future benefit of glycemic control, lends support to the cost effectiveness of the guideline in the long term. Physician adoption of the guideline was recommended to reduce the future personal and economic burden of this chronic disease. ^ Only half of physicians studied had adopted the glycated hemoglobin test guideline for at least 75% of their diabetic patients. No statistically significant relationship was found between any physician characteristic and guideline adoption. Instead, it was likely that the innovation-decision process and guideline dissemination methods were most influential. ^ A multidisciplinary, multi-faceted approach, including interventions for each stage of the innovation-decision process, was proposed to diffuse practice guidelines more effectively. Further, it was recommended that Organized Delivery Systems expand existing administrative databases to include clinical information, decision support systems, and reminder mechanisms, to promote and support physician compliance with this and other evidence-based guidelines. ^

Breast cancer risk and heterocyclic amines and effect modification by NAT gene polymorphisms

Breast cancer is the most common cancer in women in the United States and is a leading cause of cancer-related deaths (1). Recently, dietary heterocyclic amines (HCAs) have been proposed to be a risk factor for breast cancer (2). This study uses the data collected for a case-control study conducted at the M.D. Anderson Cancer Center to assess the association between breast cancer risk and HCAs {2-amino-1-methyl-6-phenylimidazole [4,5-b] pyridine (PhIP), 2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo [4,5-f] quinoxaline (DiMeIQx) and mutagenicity of HCAs} and to examine if this association is modified by genetic polymorphisms of N-acetyl transferases (NAT1/NAT2). The NAT1/2 genotype was determined using Taqman technology. HCAs were estimated by using a meat preparation questionnaire on meat type, cooking method, and doneness, combined with a quantitative HCA database. Three hundred and fifty patients with breast cancer attending the Diagnostic Radiology Clinic at M. D. Anderson Cancer Center and fulfilling the eligibility criteria were compared to three hundred and fifty patients attending the same clinic for benign breast lesions to answer these questions. Logistic regression models were used to control for known risk factors and showed no statistically significant association between breast cancer versus benign breast cancer lesions and dietary intake of heterocyclic amines. There was no clear difference in their effect after subgroup analyses in different acetylator strata of NAT1/2 and no statistical interactions were found between NAT1/2 genotypes and HCAs, suggesting no effect modification by NAT1/2 acetylator status. These results suggest the need for further research to analyze if these null associations were because of the benign breast lesions sharing the risk factors with breast cancer or any other factors which haven't been explored yet.^

A new combined endpoint using U-statistic in analysis in clinical trials

Common endpoints can be divided into two categories. One is dichotomous endpoints which take only fixed values (most of the time two values). The other is continuous endpoints which can be any real number between two specified values. Choices of primary endpoints are critical in clinical trials. If we only use dichotomous endpoints, the power could be underestimated. If only continuous endpoints are chosen, we may not obtain expected sample size due to occurrence of some significant clinical events. Combined endpoints are used in clinical trials to give additional power. However, current combined endpoints or composite endpoints in cardiovascular disease clinical trials or most clinical trials are endpoints that combine either dichotomous endpoints (total mortality + total hospitalization), or continuous endpoints (risk score). Our present work applied U-statistic to combine one dichotomous endpoint and one continuous endpoint, which has three different assessments and to calculate the sample size and test the hypothesis to see if there is any treatment effect. It is especially useful when some patients cannot provide the most precise measurement due to medical contraindication or some personal reasons. Results show that this method has greater power then the analysis using continuous endpoints alone. ^

Retrospective cohort study to determine the effect of metformin on survival of diabetic patients with pancreatic adenocarcinoma

Background: Pancreatic cancer is the fourth most common cause of cancer death in the United States. Despite advances in cancer treatment, prognosis of pancreatic cancer remains extremely poor with survival rates of 24% and 5% in 1 and 5 years, respectively. Many patients with pancreatic cancer have a history of diabetes and are treated with various antidiabetic regimens including metformin. In multiple retrospective studies, metformin has been associated with decreased risk of cancer and cancer-related mortality. Metformin has also been reported to inhibit the growth of cancer cells, both in vitro and in vivo.^ Methods: We conducted a retrospective cohort study to examine the survival benefit of metformin in diabetic patients with pancreatic cancer at MD Anderson Cancer Center (MDACC). A dataset of 397 patients who carried the diagnosis of "Diabetes Mellitus" and "Pancreatic Cancer" at MD Anderson were screened for this study. ^ Results: Mean age of patients at diagnosis of cancer was 64.0 ± 8.7 years (range 37-84). The majority of the patients were male (65.6%) and of Caucasian race (78.5%). The most common antidiabetic regimen used were insulin and metformin (in 39.1% and 38.7%, respectively). Patients' cancer were staged as resectable in 34.1%, locally advanced unresectable in 29.1%, and disseminated disease in 36.7% of cases. Overall 1-year and 3-year survival rates for all stages combined were 51.8% and 7.6%, respectively. Earlier stage, metformin use, low CA19-9 level, better ECOG performance status, surgical intervention, negative surgical margins, and smaller tumor size were associated with longer survival. Metformin use was associated with a 33% decrease in risk of death (HR: 0.67; 95% CI: 0.51-0.88). Multivariate Cox proportional hazard regression showed hazard ratio of 1.77 (95% CI 1.49-2.10) for cancer stage, 0.65 (95% CI 0.49-0.86) for metformin use, and 1.68 (95% CI 1.26-2.23) for CA 19-9 level above population median. ^ Conclusion: Our study suggests that metformin may improve the outcome in diabetic patients with pancreatic cancer independently of other known prognostic factors. Pancreatic cancer carries extremely poor prognosis; metformin may provide a suitable adjunct therapeutic option for pancreatic cancer in patients with and without diabetes mellitus.^

An evaluation of sleep hypnotic and stimulant effect on human performance using a computerized psychological test battery

This study evaluated the administration-time-dependent effects of a stimulant (Dexedrine 5-mg), a sleep-inducer (Halcion 0.25-mg) and placebo (control) on human performance. The investigation was conducted on 12 diurnally active (0700-2300) male adults (23-38 yrs) using a double-blind, randomized sixway-crossover three-treatment, two-timepoint (0830 vs 2030) design. Performance tests were conducted hourly during sleepless 13-hour studies using a computer generated, controlled and scored multi-task cognitive performance assessment battery (PAB) developed at the Walter Reed Army Institute of Research. Specific tests were Simple and Choice Reaction Time, Serial Addition/Subtraction, Spatial Orientation, Logical Reasoning, Time Estimation, Response Timing and the Stanford Sleepiness Scale. The major index of performance was "Throughput", a combined measure of speed and accuracy.^ For the Placebo condition, Single and Group Cosinor Analysis documented circadian rhythms in cognitive performance for the majority of tests, both for individuals and for the group. Performance was best around 1830-2030 and most variable around 0530-0700 when sleepiness was greatest (0300).^ Morning Dexedrine dosing marginally enhanced performance an average of 3% with reference to the corresponding in time control level. Dexedrine AM also increased alertness by 10% over the AM control. Dexedrine PM failed to improve performance with reference to the corresponding PM control baseline. With regard to AM and PM Dexedrine administrations, AM performance was 6% better with subjects 25% more alert.^ Morning Halcion administration caused a 7% performance decrement and 16% increase in sleepiness and a 13% decrement and 10% increase in sleepiness when administered in the evening compared to corresponding in time control data. Performance was 9% worse and sleepiness 24% greater after evening versus morning Halcion administration.^ These results suggest that for evening Halcion dosing, the overnight sleep deprivation occurring in coincidence with the nadir in performance due to circadian rhythmicity together with the CNS depressant effects combine to produce performance degradation. For Dexedrine, morning administration resulted in only marginal performance enhancement; Dexedrine in the evening was less effective, suggesting the 5-mg dose level may be too low to counteract the partial sleep deprivation and nocturnal nadir in performance. ^

Upregulation of VEGF through p70S6K in ErbB2 -mediated angiogenesis and inhibition by combined herceptin plus taxol therapy

ErbB2 overexpression in breast tumors increases metastasis, angiogenesis, and reduces survival. To study ErbB2 signaling mechanisms in metastasis and angiogenesis, a spontaneous metastasis assay was performed using human breast cancer cells transfected with constitutively active ErbB2 kinase (V659E), an ErbB2 kinase-dead mutant (K753M), or vector control. Mice injected with V659E had increased metastasis and tumor microvessel density; and the increased angiogenesis in vivo from the V659E transfectants paralleled increased angiogenic potential in vitro, which resulted from increased VEGF by increased protein synthesis. This appeared to be mediated through a PI3K, Akt, mTOR, p70S6K-signaling pathway. Furthermore, V659E xenografts had significantly increased phosphorylated Akt, phosphorylated p70S6K, and VEGF compared with control. To validate the clinical relevance of these findings, human breast tumor samples were examined. Tumors overexpressing ErbB2 correlated with p70S6K phosphorylation and VEGF expression, which significantly correlated with higher levels of Akt and mTOR phosphorylation. Additionally, patients with tumors having increased p70S6K phosphorylation showed a trend for worse disease-free survival and increased metastasis. Together, ErbB2 increases VEGF expression by activating the p70S6K signaling pathway, which may serve as targets for antiangiogenic and antimetastatic therapies. ^ Herceptin is an anti-ErbB2 antibody that demonstrated anti-tumor function, especially in combination with other chemotherapies such as Taxol, in patients with ErbB2-overexpressing tumors. Since the repeated administration of low-dose chemotherapy endorsed an antiangiogenic effect in vitro, and Herceptin was shown to inhibit angiogenesis in tumor xenografts, I investigated whether combined Taxol plus Herceptin treatment inhibits ErbB2-mediated angiogenic responses more effectively. Mice with ErbB2-overexpressing xenografts were treated with control, Herceptin, Taxol, or combination Herceptin plus Taxol. Mice treated with the combination exhibited reduced tumor volumes, tumor microvessel densities, and lung metastasis; and ErbB2-overexpressing cells treated with the combination secreted less VEGF, and stimulated less endothelial cell migration. Furthermore, Akt phosphorylation contributed to VEGF upregulation and was most effectively reduced by combination treatment. ^ In summary, ErbB2 activates signaling to Akt and p70S6K leading to increased VEGF and angiogenesis. Combination Herceptin plus Taxol treatment most effectively inhibited ErbB2-mediated angiogenesis, resulting in pronounced tumoricidal effects, and may be mediated through reduction of phosphorylated Akt, a positive regulator in the p70S6K pathway. ^