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Screening Trials (screening + trials)

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Medical Sciences	63%

Selected Abstracts

Cocaine Rapid Efficacy Screening Trials (CREST): lessons learned

ADDICTION, Issue 2005
Kyle M. Kampman
ABSTRACT Aims The Cocaine Rapid Efficacy Screening Trials (CREST) were designed by the National Institute on Drug Abuse Division of Treatment Research and Development (NIDA, DT R&D) to rapidly screen a number of medications potentially useful for the treatment of cocaine dependence. Design Each CREST trial was designed to compare several medications in a single trial against an unmatched placebo. The placebo group was included in each trial to avoid the nearly universal positive response to medications seen in open-label trials. In addition, a common set of procedures and outcome measures were employed throughout to increase comparability of results obtained from different trials and from different times. Participants In all, 18 medications were screened in seven different trials, conducted in four different sites throughout the United States involving 398 cocaine-dependent patients. Findings Three medications were found to be promising enough to include in subsequent larger trials. Common statistical procedures for evaluating medications were developed to facilitate comparisons across sites and across time. A portion of the data were pooled and analyzed, which yielded some useful insights into cocaine dependence and its treatment. Finally, a review of individual trials together with the pooled analysis revealed several potential improvements for future screening trials. Conclusions Overall, the CREST trials proved to be useful for rapidly screening medications for treatment of cocaine dependence, but several modifications in design should be made before this framework is applied further. [source]

Bayesian Optimal Design for Phase II Screening Trials

BIOMETRICS, Issue 3 2008
Meichun Ding
Summary Most phase II screening designs available in the literature consider one treatment at a time. Each study is considered in isolation. We propose a more systematic decision-making approach to the phase II screening process. The sequential design allows for more efficiency and greater learning about treatments. The approach incorporates a Bayesian hierarchical model that allows combining information across several related studies in a formal way and improves estimation in small data sets by borrowing strength from other treatments. The design incorporates a utility function that includes sampling costs and possible future payoff. Computer simulations show that this method has high probability of discarding treatments with low success rates and moving treatments with high success rates to phase III trial. [source]

Fast determination of prominent carotenoids in tomato fruits by CEC using methacrylate ester-based monolithic columns

ELECTROPHORESIS, Issue 22 2007
Ana Maria Adalid
Abstract In this study, the major carotenoids (,-carotene and lycopene) present in tomato fruits were analyzed by CEC with a methacrylate ester-based monolithic column. The effects of the porogenic solvent ratio, and the hydrophobicity of bulk monomer employed were examined on carotenoids separations. A fast separation of these analytes was achieved in less than 5.0,min in a mobile phase containing 35% THF, 30% ACN, 30% methanol, and 5% of a 5,mM Tris aqueous buffer, pH,8, with lauryl methacrylate-based monoliths. The CEC method was evaluated in terms of detection limit and reproducibility (retention time, area, and column preparation) with values below 1.6,,g/mL and 7.2%, respectively. The proposed procedure was successfully applied to the determination of both carotenoids in fruits of several tomato-related species and its usefulness to analyze large series of samples for nutritional quality screening trials in tomato breeding programs is demonstrated. To our knowledge, this is the first work that exploits the powerful and user-friendly monolithic technology for quality breeding and germplasm evaluation program purposes. [source]

Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence

ADDICTION, Issue 2005
Domenic A. Ciraulo
ABSTRACT Aims The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence. Design A multi-arm, modified blinded, placebo-controlled design was used. Setting The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU). Participants Participants met criteria for cocaine dependence during a 2-week screening period. Intervention Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study. Measurements Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period. Findings None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated. Conclusions This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups. [source]

Cocaine Rapid Efficacy Screening Trials (CREST): lessons learned

Role of the Clinical Breast Examination in Breast Cancer Screening

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 7 2001
Does This Patient Have Breast Cancer?
QUESTION: The authors, in an article for the JAMA section on the rational clinical examination, consider the evidence on whether and how to use clinical breast examination as a cancer screening technique. BACKGROUND: Breast cancer is a common disease, particularly in older women. The authors note that by age 70 the annual incidence of breast cancer is one in 200 women. Breast cancer survival is strongly influenced by the stage of the disease at the time of diagnosis. As a result, it is important to consider how best to screen for this disease. In recent years there has been considerable attention in the clinical literature and in the popular media paid to the screening strategies of breast self-examination and of screening mammography, but somewhat less to the potential role of the breast examination by the healthcare provider. In actual clinical practice, the same woman may be the recipient of any, none, or all of these screening modalities. The best way to combine these screening strategies, particularly in the case of the older woman, remains a subject of some uncertainty and controversy. DATA SOURCES: Data were obtained from a MEDLINE search of the English-language literature for 1966 through 1997 and additional articles as identified by the authors. STUDY SELECTION CRITERIA: In their evaluation of the effectiveness of clinical breast examination, the authors included both controlled trials and case-controlled studies in which clinical breast examination was used as a component of the screening. Study of breast examination technique considered both clinical studies and studies using silicone breast models. DATA EXTRACTION: The combined data from the trials included information on approximately 200,000 women who received a breast cancer screening intervention (mammography and/or clinical breast examination). However, none of the studies made the direct comparison of a group receiving clinical breast examination as a sole intervention with a control group that did not receive any screening. Data on the utility of clinical breast examination were partially derived from studies where that screening modality was used in combination with mammography. MAIN RESULTS: A number of trials of cancer screening have demonstrated a reduction in mortality from the use of mammography and clinical breast examination as combined screening strategies compared with no screening, with the inference that the reduction in mortality comes from the earlier detection of breast cancer. The percentage of the detected cancers that are detected in the trials by clinical breast examination despite having been missed on mammography varies across the trials from a low of 3% of the detected cancers to a high of 45%. It is speculative whether the marginal contribution of clinical breast examination to the mortality reduction in these screening trials corresponds to the percentage of cancers detected by clinical breast examination alone. In most of the clinical trials, the technique of breast examination reportedly was not well described. It is unclear therefore how much the technique of breast examination used varied within and among the clinical trials. Data from studies using examinations of breast models made of silicone demonstrated that test performance accuracy correlated with a lengthier breast examination, better breast examination technique, and perhaps with examiner experience. The report includes data from six comparator studies and from two demonstration projects. Of the six comparator studies, four compared a screened population with an unscreened population and two compared different intensities of screening strategies. None of the eight clinical trials was directed to a geriatric population and in fact older women were excluded by upper age entry criteria from the six comparator studies. (The upper age limit for study entry in the six comparator studies varied from 49 to 64.) CONCLUSION: The authors drew on the pooled results of these eight studies to conclude that clinical breast examination has a sensitivity of 54% (95% confidence interval, 48.3,59.8) and a specificity of 94% (95% confidence interval, 90.2,96.9). The authors conclude that screening clinical breast examination should be done for women age older than 40. [source]

Effects of impurities on membrane-protein crystallization in different systems

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2009
Christopher A. Kors
When starting a protein-crystallization project, scientists are faced with several unknowns. Amongst them are these questions: (i) is the purity of the starting material sufficient? and (ii) which type of crystallization experiment is the most promising to conduct? The difficulty in purifying active membrane-protein samples for crystallization trials and the high costs associated with producing such samples require an extremely pragmatic approach. Additionally, practical guidelines are needed to increase the efficiency of membrane-protein crystallization. In order to address these conundrums, the effects of commonly encountered impurities on various membrane-protein crystallization regimes have been investigated and it was found that the lipidic cubic phase (LCP) based crystallization methodology is more robust than crystallization in detergent environments using vapor diffusion or microbatch approaches in its ability to tolerate contamination in the forms of protein, lipid or other general membrane components. LCP-based crystallizations produced crystals of the photosynthetic reaction center (RC) of Rhodobacter sphaeroides from samples with substantial levels of residual impurities. Crystals were obtained with protein contamination levels of up to 50% and the addition of lipid material and membrane fragments to pure samples of RC had little effect on the number or on the quality of crystals obtained in LCP-based crystallization screens. If generally applicable, this tolerance for impurities may avoid the need for samples of ultrahigh purity when undertaking initial crystallization screening trials to determine preliminary crystallization conditions that can be optimized for a given target protein. [source]

When less is more: a more efficient vapour-diffusion protocol

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2003
Kirsty V. Dunlop
Reducing protein consumption during crystallization screening is of utmost importance to crystallographers because of the time, effort and money that goes into producing pure protein. One approach is to reduce sample volumes with robotics, but a patent and the high cost of equipment limits access. Here, it is shown that the same result can be obtained by reducing the sample concentration in a modified vapour-diffusion protocol, the dilution method. In this protocol, the protein and mother liquor in the crystallization drop are both diluted, while the mother liquor in the well remains undiluted. Vapour diffusion will shrink the initial volume of the crystallization drop, e.g. 1,µl or more, to a drop size equivalent to one dispensed by a robot. This new crystallization method circumvents some of the current problems associated with robotic crystallization screening trials. Because of the large initial volume of the crystallization drop, the evaporation problem is eliminated and dispensing accuracy is improved. In addition, the likelihood that the crystallization experiment starts in the undersaturated region is increased. [source]

First Exposure in Man: Toxicological Considerations

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2000
Per Spindler
Recommendations on the type and extent of preclinical safety studies that should be conducted prior to first dose in man have been developed by the International Conference on Harmonisation, and the European Committee for Proprietary Medicinal Products. These recommendations include studies designed to characterise local tolerance and general toxicity of the drug candidate as well as its genotoxic potential and ability to interfere with reproduction. For trials which can be categorised as low dose PK screening trials and trials with products where rodent and non-rodent (primarily dog) models do not show any biological response (e.g. some biotechnology-derived hormones and cytokines) other testing paradigms should be used. The present recommendations for preclinical testing have had an important impact on the documented impressive safety record of phase I clinical trials. In this spirit we extend our warmest and sincerest thanks to Professor Jens S. Schou for his long and deep engagement in European and International harmonisation of preclinical test recommendations. His efforts have had a substantial impact on the present testing recommendations, which are of obvious benefit to the safety of the patient. [source]

A novel hypothesis on the sensitivity of the fecal occult blood test,

CANCER, Issue 11 2009
Results of a joint analysis of 3 randomized controlled trials
Abstract BACKGROUND: Estimates of the fecal occult blood test (FOBT) (Hemoccult II) sensitivity differed widely between screening trials and led to divergent conclusions on the effects of FOBT screening. We used microsimulation modeling to estimate a preclinical colorectal cancer (CRC) duration and sensitivity for unrehydrated FOBT from the data of 3 randomized controlled trials of Minnesota, Nottingham, and Funen. In addition to 2 usual hypotheses on the sensitivity of FOBT, we tested a novel hypothesis where sensitivity is linked to the stage of clinical diagnosis in the situation without screening. METHODS: We used the MISCAN-Colon microsimulation model to estimate sensitivity and duration, accounting for differences between the trials in demography, background incidence, and trial design. We tested 3 hypotheses for FOBT sensitivity: sensitivity is the same for all preclinical CRC stages, sensitivity increases with each stage, and sensitivity is higher for the stage in which the cancer would have been diagnosed in the absence of screening than for earlier stages. Goodness-of-fit was evaluated by comparing expected and observed rates of screen-detected and interval CRC. RESULTS: The hypothesis with a higher sensitivity in the stage of clinical diagnosis gave the best fit. Under this hypothesis, sensitivity of FOBT was 51% in the stage of clinical diagnosis and 19% in earlier stages. The average duration of preclinical CRC was estimated at 6.7 years. CONCLUSIONS: Our analysis corroborated a long duration of preclinical CRC, with FOBT most sensitive in the stage of clinical diagnosis. Cancer 2009. © 2009 American Cancer Society. [source]

Ovarian carcinoma screening in women at intermediate risk

CANCER, Issue 2 2005
Impact on quality of life, need for invasive follow-up
Abstract BACKGROUND Women with family histories suggestive of an increased risk of ovarian carcinoma who have not had a deleterious BRCA1 or BRCA2 mutation identified are commonly suggested to consider ovarian carcinoma screening with transvaginal ultrasound and/or assessment of CA 125 levels. Limited information is available regarding the impact of this approach on either quality of life (QOL) or need for invasive follow-up in this group of women. METHODS From November 1999 to October 2002, 184 women at intermediate risk of ovarian carcinoma were enrolled in a prospective study. Participants were screened with twice yearly transvaginal ultrasound and CA 125 assessments. Impact on QOL was measured using the Mental Component Summary (MCS) score of the Medical Outcomes Studies Short Form-36. Need for invasive follow-up was determined by questionnaire and medical record review. RESULTS In the current study, 135 participants underwent , 1 follow-up assessment. During a mean of 19.8 months of follow-up, 12.9% of ultrasounds and 3.8% of CA 125 assessments were abnormal. The authors reported that 38.5% of participants had , 1 abnormal ovarian screen that required a short interval follow-up. Because of either abnormal bleeding or ultrasound abnormalities, 24% of participants underwent , 1 endometrial sampling. Controlling for a history of breast carcinoma and menopausal status, abnormal ovarian screening results were associated with a decrease in MCS score (P = 0.034), whereas the need for endometrial sampling was not (P = 0.87). CONCLUSIONS Ovarian carcinoma screening in women at intermediate risk was associated with a substantial rate of abnormal screen results, endometrial sampling, and in women with abnormal ovarian screening findings, a decrease in MCS scores. These findings may have important implications for women considering ovarian carcinoma screening and for the design of future ovarian carcinoma screening trials. Cancer 2005. © 2005 American Cancer Society. [source]