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21.
Risk management strategies in the postmarketing period : safety experience with the US and European bosentan surveillance programmes. 总被引:1,自引:0,他引:1
Eleanor S Segal Cecile Valette Laurence Oster Luc Bouley Catarina Edfjall Peter Herrmann Massimo Raineri Mary Kempff Saundra Beacham Cinda van Lierop 《Drug safety》2005,28(11):971-980
In view of the shortcomings of the current system for postmarketing drug surveillance that is based on voluntary spontaneous adverse drug reaction (ADR) reporting, new approaches are needed.We describe an approach involving a combination of limited distribution, patient and physician education, as well as a novel pharmaco-vigilance system that is capable of promoting the safe and adequate use of a new drug. Importantly, it provides the possibility of calculating true ADR occurrence rates, as the exposed population (denominator) and the number of patients with events (numerator) are known. These measures were taken for the oral dual endothelin ET(A)/ET(B) antagonist bosentan (Tracleer). In recent guidelines issued by the European Society of Cardiology, American College of Chest Physicians and the WHO, this drug is considered as first-line oral treatment for the treatment of pulmonary arterial hypertension, a devastating orphan disease associated with a poor prognosis. Bosentan was approved in 2001/2 on the basis of two pivotal studies that showed improved exercise capacity and haemodynamic parameters while delaying time to clinical worsening. Elevations in serum liver aminotransferase levels of >3 times the upper limit of normal were noted in 10.2% of patients (placebo-subtracted incidence). Therefore, liver function tests have to be performed on a regular basis. In addition, bosentan has potential as a teratogen.In the US, a controlled distribution network for bosentan (Tracleer) Access Program [T.A.P.]) and the development of a patient database to follow patients was set up. Accompanied by comprehensive physician and patient education programmes, T.A.P. was developed to provide a mechanism to assist with the primary risk management goals for bosentan therapy, namely pregnancy prevention and liver enzyme monitoring and prevention of hepatic injury.In Europe, the Tracleer) Excellence (TRAX PMS) database is a novel European non-interventional, prospective, internet-based surveillance system initiated by the manufacturer in cooperation with the European Medicines Agency. It collected potential safety signals associated with bosentan use including adverse events, elevations of liver aminotransferase levels, other abnormal laboratory values, death and hospitalisation. TRAX PMS has accrued 79% of all known patients in the EU and the data provide supportive 'real-life' evidence on the long-term safety of bosentan.The two different systems had similar goals and outcomes. The data received concerning thousands of patient-years of use have confirmed the clinical trial results regarding product safety and the favourable benefit/risk ratio of bosentan, especially with regard to known type A adverse events. The clinical monitoring algorithm has also been confirmed. In addition, no rare type B events were uncovered despite the increased reporting rate. These systems might serve as templates for future pharmaco-vigilance efforts regarding drugs that require particular safety attention. 相似文献
22.
Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. 总被引:11,自引:0,他引:11
Ilse Van der Auwera Gert G Van den Eynden Cecile G Colpaert Steven J Van Laere Peter van Dam Eric A Van Marck Luc Y Dirix Peter B Vermeulen 《Clinical cancer research》2005,11(21):7637-7642
PURPOSE: At the time of diagnosis, metastatic dissemination of tumor cells via the lymphatic system has occurred in nearly all patients with inflammatory breast cancer (IBC). The objective of this study was twofold: (a) to determine which is the most suitable marker of lymph vessels in primary breast tumors and (b) to compare histomorphometric lymph vessel variables in IBC and non-IBC. EXPERIMENTAL DESIGN: Serial sections of 10 IBCs and 10 non-IBCs were immunostained for D2-40, LYVE-1, podoplanin, and PROX-1. Relative lymph vessel area, lymph vessel perimeters, and counts and lymphatic endothelial cell proliferation (LECP) were then measured in D2-40/Ki-67 double-immunostained sections of 10 normal breast tissues, 29 IBCs, and 56 non-IBCs. RESULTS: D2-40 was the most suitable antibody for staining peritumoral and intratumoral lymph vessels. D2-40-stained intratumoral lymph vessels were present in 80% of non-IBCs and 82.8% of IBCs (P = 0.76). In non-IBC, lymph vessels located in the tumor parenchyma were smaller and less numerous than those at the tumor periphery (P < 0.0001) whereas in IBC, intratumoral and peritumoral variables were not significantly different. The mean relative tumor area occupied by lymph vessels was larger in IBC than in non-IBC (P = 0.01). LECP at the tumor periphery was higher in IBC than in non-IBC: median LECP was 5.74% in IBC versus 1.83% in non-IBC (P = 0.005). CONCLUSIONS: The high LECP in IBC suggests that lymphangiogenesis contributes to the extensive lymphatic spread of IBC. 相似文献
23.
Hany Goubran Botros Pierre Legrand Cecile Pagan Vincent Bondet Patrick Weber Mariem Ben‐Abdallah Nathalie Lemière Guillaume Huguet Jacques Bellalou Erik Maronde Pierre Beguin Ahmed Haouz William Shepard Thomas Bourgeron 《Journal of pineal research》2013,54(1):46-57
Abstract: Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X‐ray crystal structure of human N‐acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C‐terminal domain, which is typical of other SAM‐dependent O‐methyltransferases, and an N‐terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3‐dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans. 相似文献
24.
Lengacher CA Reich RR Post-White J Moscoso M Shelton MM Barta M Le N Budhrani P 《Journal of behavioral medicine》2012,35(1):86-94
To investigate prevalence and severity of symptoms and symptom clustering in breast cancer survivors who attended MBSR(BC).
Women were randomly assigned into MBSR(BC) or Usual Care (UC). Eligible women were ≥ 21 years, had been diagnosed with breast
cancer and completed treatment within 18 months of enrollment. Symptoms and interference with daily living were measured pre-
and post-MBSR(BC) using the M.D. Anderson Symptom Inventory. Symptoms were reported as highly prevalent but severity was low.
Fatigue was the most frequently reported and severe symptom among groups. Symptoms clustered into 3 groups and improved in
both groups. At baseline, both MBSR(BC) and the control groups showed similar mean symptom severity and interference; however,
after the 6-week post-intervention, the MBSR(BC) group showed statistically-significant reduction for fatigue and disturbed
sleep (P < 0.01) and improved symptom interference items, compared to the control group. For the between-group comparisons, 11 of
13 symptoms and 5 of 6 interference items had lower means in the MBSR(BC) condition than the control condition. These results
suggest that MBSR(BC) modestly decreases fatigue and sleep disturbances, but has a greater effect on the degree to which symptoms
interfere with many facets of life. Although these results are preliminary, MBSR intervention post-treatment may effectively
reduce fatigue and related interference in QOL of breast cancer survivors. 相似文献
25.
Leyla Y. Bustamante S. Josefin Bartholdson Cecile Crosnier Marta G. Campos Madushi Wanaguru Chea Nguon Dominic P. Kwiatkowski Gavin J. Wright Julian C. Rayner 《Vaccine》2013
The lack of an effective licensed vaccine remains one of the most significant gaps in the portfolio of tools being developed to eliminate Plasmodium falciparum malaria. Vaccines targeting erythrocyte invasion – an essential step for both parasite development and malaria pathogenesis – have faced the particular challenge of genetic diversity. Immunity-driven balancing selection pressure on parasite invasion proteins often results in the presence of multiple, antigenically distinct, variants within a population, leading to variant-specific immune responses. Such variation makes it difficult to design a vaccine that covers the full range of diversity, and could potentially facilitate the evolution of vaccine-resistant parasite strains. In this study, we investigate the effect of genetic diversity on invasion inhibition by antibodies to a high priority P. falciparum invasion candidate antigen, P. falciparum Reticulocyte Binding Protein Homologue 5 (PfRH5). Previous work has shown that virally delivered PfRH5 can induce antibodies that protect against a wide range of genetic variants. Here, we show that a full-length recombinant PfRH5 protein expressed in mammalian cells is biochemically active, as judged by saturable binding to its receptor, basigin, and is able to induce antibodies that strongly inhibit P. falciparum growth and invasion. Whole genome sequencing of 290 clinical P. falciparum isolates from across the world identifies only five non-synonymous PfRH5 SNPs that are present at frequencies of 10% or more in at least one geographical region. Antibodies raised against the 3D7 variant of PfRH5 were able to inhibit nine different P. falciparum strains, which between them included all of the five most common PfRH5 SNPs in this dataset, with no evidence for strain-specific immunity. We conclude that protein-based PfRH5 vaccines are an urgent priority for human efficacy trials. 相似文献
26.
Cecile A Marczinski 《Advances in nutrition (Bethesda, Md.)》2015,6(1):96-101
Energy drinks, the fastest growing segment in the beverage market, have become popular mixers with alcohol. The emerging research examining the use of alcohol mixed with energy drinks (AmEDs) indicates that the combination of caffeine-containing energy drinks with alcohol may be riskier than the use of alcohol alone. The public health concerns arising from AmED use are documented in different research domains. Epidemiologic studies reveal that the consumption of AmEDs is frequent among young and underage drinkers, demographic groups that are more likely to experience the harms and hazards associated with alcohol use. In addition, for all consumers, elevated rates of binge drinking and risk of alcohol dependence have been associated with AmED use when compared to alcohol alone. Results from laboratory studies help explain why AmED use is associated with excessive intake of alcohol. When an energy drink (or caffeine) is combined with alcohol, the desire (or urge) to drink more alcohol is more pronounced in both humans and animals than with the same dose of alcohol alone. The experience of drinking alcohol appears to be more rewarding when combined with energy drinks. Given that caffeine in other foods and beverages increases preference for those products, further research on AmEDs may elucidate the underlying mechanisms that contribute to alcohol dependence. 相似文献
27.
Cecile Rousseau Françoise Armand Audrey Laurin‐Lamothe Marie‐France Gauthier Rita Saboundjian 《Child and Adolescent Mental Health》2012,17(3):187-190
Background: To help immigrant and refugee adolescents experiencing a severe academic delay cope with adversity, a school‐based intervention combining drama workshops and language awareness activities was piloted in two classrooms. Method: A qualitative analysis of participant observations was performed and the Strength and Difficulty Questionnaire and its Impairment Supplement was administered before and after the intervention. The observations were carried out in two Montreal high schools serving an underprivileged neighbourhood of immigrants, involving two classrooms of underschooled adolescents (n = 27) and two classes of similarly underschooled adolescents chosen among other teachers interested in the intervention, who accepted to participate as a comparison group (n = 28). Results: The adolescents shared their experiences of adversity and felt empowered by the workshops. Self‐reported impairment decreased in the intervention groups. Conclusion: The protective effect of creative language activities for immigrant and refugee youth should be further investigated. 相似文献
28.
Suman Kundu Lennart C Karssen A Cecile JW Janssens 《European journal of human genetics : EJHG》2012,20(12):1270-1274
Various modeling methods have been proposed to estimate the potential predictive ability of polygenic risk variants that predispose to various common diseases. However, it is unknown whether differences between them affect their conclusions on predictive ability. We reviewed input parameters, assumptions and output of the five most common methods and compared their estimates of the area under the receiver operating characteristic (ROC) curve (AUC) using hypothetical data representing effect sizes and frequencies of genetic variants, population disease risk and number of variants. To assess the accuracy of the estimated AUCs, we aimed to reproduce the AUCs of published empirical studies. All methods assumed that the combined effect of genetic variants on disease risk followed a multiplicative risk model of independent genetic effects, but they either assumed per allele, per genotype or dominant/recessive effects for the genetic variants. Modeling strategy and input parameters differed. Methods used simulation analysis or analytical formulas with effect sizes quantified by odds ratios (ORs) or relative risks. Estimated AUC values were similar for lower ORs (<1.2). When AUCs were larger (>0.7) due to variants with strong effects, differences in estimated AUCs between methods increased. The simulation methods accurately reproduced the AUC values of empirical studies, but the analytical methods did not. We conclude that despite differences in input parameters, the modeling methods estimate similar AUC for realistic values of the ORs. When one or more variants have stronger effects and AUC values are higher, the simulation methods tend to be more accurate. 相似文献
29.
Levy Y Durier C Krzysiek R Rabian C Capitant C Lascaux AS Michon C Oksenhendler E Weiss L Gastaut JA Goujard C Rouzioux C Maral J Delfraissy JF Emilie D Aboulker JP;ANRS Study Group 《AIDS (London, England)》2003,17(3):343-351
BACKGROUND: Intermittent interleukin-2 (IL-2) therapy leads to a sustained increase of CD4 T cells in HIV-1-infected patients. METHODS: Symptom-free HIV-1-infected patients who were naive to all antiretroviral drugs (n = 68) and/or to protease inhibitors (n = 50) and had a CD4 cell count of 200-550 x 10(6) cells/l were randomly assigned to start lamivudine/stavudine/indinavir alone (controls) or combined from week 4 with subcutaneous IL-2 (5 x 10(6) IU twice daily for 5 days: every 4 weeks for three cycles, then every 8 weeks for seven cycles). Immunological and virological results were monitored until week 74. RESULTS: CD4 T cell counts increased more in the IL-2 group than in the controls (median increases 865 and 262 x 10(6) cells/l, respectively; P < 0.0001); an 80% increase in CD4 T cells was achieving by 89% of the IL-2 group and by 47% of the controls (P < 0.0001). Decrease of plasma viral loads was similar in both groups. Compared with controls, IL-2 induced a greater increase of naive and memory CD4 T cells, lymphocyte expression of CD28 and CD25 (P < 0.0001) and natural killer cells (P < 0.001). In a logistic regression analysis, odds of being responders to recall antigens was 8.5-fold higher in IL-2 recipients (P = 0.002) than in controls. The former experienced a higher level of antibody response to tetanus vaccination at week 64 than controls (32 and 8 haemagglutinating units/ml, respectively; P = 0.01). CONCLUSIONS: The combination of antiviral drugs and IL-2 induced a greater expansion and function of CD4 T cells than antiretroviral drugs alone. 相似文献
30.
J. Delforge S. Sovaila L. Alix A. Didon O. Steichen B. Ranque A. Froissart K. Amadou T. Hanslik B. Cador J.F. Bergmann A. Mekininan C. Goujard S. Gayet P. Cathebras B. Fantin D. Raigniac J.C. Weber A. Bourgarit 《La Revue de médecine interne / fondée ... par la Société nationale francaise de médecine interne》2021,42(2):79-85
IntroductionPatients admitted from emergency units represent a large portion of the population in internal medicine departments. The aim of this study is to identify characteristics of patients and organization of these departments.MethodsBetween June 29th and July 26th 2015, voluntary internal medicine departments from the SiFMI group prospectively filled anonymized internet forms to collect data of each patients admitted in their ward from emergency units, during seven consecutive days.ResultsThree hundred and sixty-five patients from emergency departments were admitted in 18 internal medicine inpatients departments, totalling 1100 beds and 33,530 annual stays, 56% of them for emergency units inpatients. Mean age was 68 years, 54% were women, mean Charlson score was 2.6 and 44% of the patients took at least three drugs. Main causes of hospitalization were infectious (29%) and neurological (17%) diseases. Mean length of stay was 9.2 days. The medical team was composed by a median value of 4,5 [2,75–6,25] senior full-time equivalents, 86% were internists. Each department except one received residents, two third of them were from general medicine.ConclusionThis study highlights a high organizational variability among internal medicine departments and patients, and sets internal medicine as a specialty with a great capacity to achieve an integrative/comprehensive management of patients and to offer a comprehensive basis for physicians in training. 相似文献