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81.
82.
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
83.
Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility. 总被引:6,自引:0,他引:6
Sabine Gesierich Claudia Paret Dagmar Hildebrand Jürgen Weitz Kaspar Zgraggen Friedrich H Schmitz-Winnenthal Vaclav Horejsi Osamu Yoshie Dorothee Herlyn Leonie K Ashman Margot Z?ller 《Clinical cancer research》2005,11(8):2840-2852
PURPOSE: Patients with pancreatic adenocarcinoma have a poor prognosis due to the extraordinary high invasive capacity of this tumor. Altered integrin and tetraspanin expression is suggested to be an important factor. We recently reported that after protein kinase C activation, colocalization of alpha6beta4 with the tetraspanin CO-029 strongly supports migration of a rat pancreatic adenocarcinoma. The finding led us to explore whether and which integrin-tetraspanin complexes influence the motility of human pancreatic tumors. EXPERIMENTAL DESIGN: Integrin and tetraspanin expression of pancreatic and colorectal adenocarcinoma was evaluated with emphasis on colocalization and the impact of integrin-tetraspanin associations on tumor cell motility. RESULTS: The majority of pancreatic and colorectal tumors expressed the alpha2, alpha3, alpha6, beta1, and beta4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of alpha6beta4 and CO-029 was restricted to tumor cells, whereas alpha1, alpha2, alpha3, alpha6, beta1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and beta1 expression was observed at comparably high levels in healthy pancreatic tissue. alpha3beta1 frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas alpha6beta4 colocalized and coimmunoprecipitated mostly with CD151 and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151 and CO-029 with beta4 and was accompanied by internalization of the integrin-tetraspanin complex, decreased laminin 5 adhesion, and increased cell migration. CONCLUSION: alpha6beta4 is selectively up-regulated in pancreatic and colorectal cancer. The association of alpha6beta4 with CD151 and CO-029 correlates with increased tumor cell motility. 相似文献
84.
The experience of application of peritoneal dialysis in cardiosurgery of an early age children 总被引:1,自引:0,他引:1
Zhovnir VA Emets IN Mazur AR Rudenko NN Segal EV Boĭchenko EN 《Klinichna khirurhiia / Ministerstvo okhorony zdorov'ia Ukra?ny, Naukove tovarystvo khirurhiv Ukra?ny》2000,(8):31-33
The experience of the peritoneal dialysis (PD) successful application in 16 children of an early age was summarized. In all the patients the terminal state with an acute cardiac and renal insufficiency was noted after cardiosurgical operation conduction using artificial blood circulation. The improvement of hemodynamical indices, renal and pulmonary function as well, were promoted by an early application of PD. 相似文献
85.
Stefan Nierkens Leonie Nieuwenhuijsen Mieke Thomas Raymond Pieters 《Toxicological sciences》2004,79(1):90-97
Immune-mediated idiosyncratic drug reactions are a major problem for susceptible patients, physicians, and the pharmaceutical industry. Validated screening tools to assess the immunosensitizing capacity of orally or intravenously administered pharmaceuticals are currently not available. To date, the popliteal lymph node assay (PLNA) seems the most promising tool for this purpose. The PLNA has recently been extended with the use of reporter antigens (RA) that are coinjected together with the drug of interest. The measurement of isotypes of RA-specific antibody-secreting cells (ASC) enables the distinction of sensitizing chemicals and (nonsensitizing) irritants without radio-isotopic end points. However, the use of footpad injections raises ethical concerns. Therefore, we examined the use of RA after intradermal injection into the ear of BALB/c mice and measured RA-specific ASC in the draining auricular lymph node (ALN). We show that RA-specific IgG isotype ASC numbers are very useful and sensitive parameters to identify drug-induced hypersensitivity in both PLN and ALN. However, the type 1-associated parameters (CD8(+) cells, macrophages, IFN-gamma, TNF-alpha, and IL-1 beta) that are induced in the PLN by streptozotocin were less pronounced in the ALN. Thus, the PLNA may provide more immunologically relevant information on the mechanisms of certain chemical-induced hypersensitivity reactions. The RA-ALN assay may provide an alternative for the RA-PLNA; both assays can be used to distinguish sensitizing compounds from nonsensitizing ones. 相似文献
86.
It has been postulated that urbanisation is an important factor in the genesis of duodenal ulcer. This study of 100 duodenal ulcer patients, and 100 hospital controls, matched according to sex, age, education and occupation, and an additional 50 unmatched endoscopically negative controls, confirmed that duodenal ulcer patients were mainly young men who were more likely to have been born in an urban area than the controls. Furthermore, a significant number of duodenal ulcer patients were born and reared in the smaller towns of South Africa and then moved to Soweto. It is suggested that frustrated aspirations in these towns might even be greater than in Soweto. In the context of the Soweto population where occupational and educational status is generally low, duodenal ulcer patients were of a higher educational and occupational category than Sowetans and unselected controls. Thus factors associated with urbanisation such as education and occupation and the pattern of urbanisation play key roles in duodenal ulcer. Investigation into particular aspects of the work situation such as the degree of autonomy exercised at work, authority over others and attitudes to supervision yielded no significant results. 相似文献
87.
Phthalates rapidly increase production of reactive oxygen species in vivo: role of Kupffer cells 总被引:7,自引:0,他引:7
Rusyn I Kadiiska MB Dikalova A Kono H Yin M Tsuchiya K Mason RP Peters JM Gonzalez FJ Segal BH Holland SM Thurman RG 《Molecular pharmacology》2001,59(4):744-750
The role of oxidants in the mechanism of tumor promotion by peroxisome proliferators remains controversial. The idea that induction of acyl-coenzyme A oxidase leads to increased production of H(2)O(2), which damages DNA, seems unlikely; still, free radicals might be important in signaling in specialized cell types such as Kupffer cells, which produce mitogens. Because hard evidence for increased oxidant production in vivo after treatment with peroxisome proliferators is lacking, the spin-trapping technique and electron spin resonance spectroscopy were used. Rats were given di(2-ethylhexyl) phthalate (DEHP) acutely. The spin trapping agent alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone was also given and bile samples were collected for 4 h. Under these conditions, the intensity of the six-line radical adduct signal increased to a maximum value of 2.5-fold 2 h after administration of DEHP, before peroxisomal oxidases were induced. Furthermore, DEHP given with [(13)C(2)]dimethyl sulfoxide produced a 12-line electron spin resonance spectrum, providing evidence that DEHP stimulates (*)OH radical formation in vivo. Furthermore, when rats were pretreated with dietary glycine, which inactivates Kupffer cells, DEHP did not increase radical signals. Moreover, similar treatments were performed in knockout mice deficient in NADPH oxidase (p47(phox) subunit). Importantly, DEHP increased oxidant production in wild-type but not in NADPH oxidase-deficient mice. These data provide evidence for the hypothesis that the molecular source of free radicals induced by peroxisome proliferators is NADPH oxidase in Kupffer cells. On the contrary, radical adduct formation was not affected in peroxisome proliferator-activated receptor alpha knockout mice. These observations represent the first direct, in vivo evidence that phthalates increase free radicals in liver before peroxisomal oxidases are induced. 相似文献
88.
89.
Zohav E Orvieto R Anteby EY Segal O Meltcer S Tur-Kaspa I 《Journal of assisted reproduction and genetics》2007,24(6):259-261
PURPOSE: To evaluate the role of 3-D US measurement of the endometrium during early IVF-pregnancy and before the appearance of gestational sac in the prediction of pregnancies outcome. METHODS: 60 pregnant women following IVF treatment were included in the study. The women underwent transvaginal 3D US measurements of endometrial volume and thickness on day 15-17 post ET. Patients were followed and classified according to pregnancy outcome into 2 further groups. The group with early pregnancy loss and the group with ongoing pregnancy. RESULTS: While no differences were observed between those who miscarried and those who did not in gestational age, endometrial thickness or volume, spontaneous early pregnancy loss was significantly higher in patients with endometrial volume <2 mL as compared to those with endometrial volume >2 mL. CONCLUSIONS: 3-D US measurement of endometrial volume of less than 2 mL during early IVF pregnancy and prior to the appearance of gestational sac is a powerful predictor of pregnancy loss. 相似文献
90.
Jana Ihlow Sophia Gross Leonie Busack Anne Flrcken Julia Jesse Michaela Schwarz Nina Rosa Neuendorff Ann-Christin von Brünneck Ioannis Anagnostopoulos Seval Türkmen Igor Wolfgang Blau Thomas Burmeister David Horst Lars Bullinger Jrg Westermann 《Haematologica》2022,107(8):1773
In acute myeloid leukemia, there is an ongoing debate on the prognostic value of the early bone marrow assessment in patients receiving intensive therapy. In this retrospective study, we analyzed the prognostic impact of the early response in 1,008 patients with newly diagnosed acute myeloid leukemia, who were treated at our institution with intensive chemotherapy followed by consolidation chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). We found that early blast persistence has an independent negative prognostic impact on overall survival, event-free survival and relapse-free survival. This negative prognostic impact may only be overcome in patients showing at least a partial remission at the early bone marrow assessment and who subsequently achieve blast clearance by additional induction chemotherapy prior to consolidation therapy with allogeneic HSCT. In accordance, we propose that the time slope of remission is an additional leukemia-related dynamic parameter that reflects chemosensitivity and thus may inform post-induction therapy decision-making. In addition to patient-related factors, European LeukemiaNet risk group, measurable residual disease monitoring and donor availability, this may particularly apply to European LeukemiaNet intermediate-risk patients, for whom a decision between consolidation chemotherapy and allogeneic HSCT remains challenging in many cases. 相似文献