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排序方式: 共有516条查询结果,搜索用时 15 毫秒
1.
Bromocriptine in Parkinson disease: further studies 总被引:2,自引:0,他引:2
A N Lieberman M Kupersmith G Gopinathan E Estey A Goodgold M Goldstein 《Neurology》1979,29(3):363-369
Bromocriptine was administered to 66 patients with advanced Parkinson disease (PD) and increasing disability despite optimal treatment with levodopa/carbidopa (Sinemet). Forty-five patients tolerated at least 25 mg per day of bromocriptine (the "adequately treated" group) in addition to Sinemet and had significantly decreased rigidity, tremor, bradykinesia, gait disturbance, and total score, but increased involuntary movements. Twenty-five of these 45 patients improved by at least one stage. Among the 45 patients, 27 had "on-off" effects, and in 19 the "on-off" effects decreased on bromocriptine. The mean dose of bromocriptine in adequately treated patients las 47 mg, permitting a 10 percent reduction in the dose of levodopa. Twelve adequately treated patients received bromocriptine for at least 1 year, and 8 continued for longer than this. Bromocriptine was discontinued in 29 of 66 patients because of adverse effects, including mental changes (14 patients) and involuntary movements (9 patients). All adverse effects were reversible. Despite adverse effects, expense, and scarcity, bromocriptine, when added to levodopa, is useful in patients with advanced disease who no longer respond satisfactorily to levodopa, and for whom no other treatment is available. 相似文献
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Most statistical methods for dose-finding in phase I clinical trials determine a maximum tolerable dose based on toxicity while ignoring efficacy. Most phase II designs assume that an acceptable dose has been determined and aim to estimate treatment efficacy, possibly with early stopping rules for safety monitoring. The purpose of this paper is to describe a new statistical strategy for dose-finding in single-arm clinical trials where patient outcome is characterized in terms of both response and toxicity. The strategy, which may be considered a phase I/II hybrid, was first proposed by Thall and Russell [1] and subsequently modified by Thall [2]. The underlying mathematical model expresses the probabilities of response and toxicity as interdependent functions of dose. The method is based on fixed standards for the minimum probability of response and the maximum probability of toxicity appropriate for the particular trial. The best acceptable dose is chosen for each successive patient cohort adaptively, based on the fixed standards and the dose-outcome data from patients treated previously in the trial. The scientific goals are to select one best acceptable dose for future patients and to estimate the response and toxicity probabilities at that dose, or to stop the trial early if it becomes sufficiently unlikely that any dose is both safe and efficacious. An application of the method to a trial of donor lymphocyte infusion as salvage therapy for chemo-refractory AML/MDS patients is described. To illustrate the method's flexibility and potential breadth of application, two additional examples are provided, including a hypothetical trial in which a 5% response rate is of interest. 相似文献
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The anti-apoptotic genes Bcl-X(L) and Bcl-2 are over-expressed and contribute to chemoresistance of non-proliferating leukaemic CD34+ cells 总被引:7,自引:0,他引:7
6.
Estey EH 《American journal of hematology》2012,87(1):89-99
DISEASE OVERVIEW: Acute myeloid leukemia (AML) results from accumulation of abnormal immature cells in the marrow. These cells interfere with normal hematopoiesis can escape into the blood and infiltrate lung and CNS. The most common cause of death is bone marrow failure. It is likely that many different mutations and/or epigenetic aberrations can produce the same disease, with these differences responsible for the very variable response to therapy, which is AML's principal clinical feature. DIAGNOSIS: This rests on demonstration that the marrow or blood has >20% blasts of myeloid lineage. Blast lineage is assessed by multiparameter flow cytometry with CD33 and CD13 being surface markers typically expressed by myeloid blasts. It should be realized that clinical/prognostic considerations, not the blast % per se, should be the main factor determining how a patient is treated. RISK STRATIFICATION: Two features determine risk: the probability of treatment-related mortality (TRM) and, more important, even in patients aged >75 with Zubrod performance status 1, the probability of resistance to standard therapy despite not incurring TRM. The chief predictor of resistance is cytogenetics with a monosomal karyotype (MK) denoting the disease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant (HCT). The most common cytogenetic finding is a normal karyotype (NK) and those of such patients with an NPM1 mutation but no FLT3 internal tandem duplication (ITD), or with a CEBPA mutation, have a prognosis similar to that of patients with the most favorable cytogenetics [inv(16) or t(8;21)] (60-70% cure rate). In contrast, NK patients with a FLT3 ITD have only a 30-40% chance of cure even after HCT. Accordingly analyses of NPM1, FLT3, and CEBPA should be part of routine evaluation, much as is cytogenetics. Risk is best assessed considering several variables simultaneously rather than, for example, only age. RISK-ADAPTED THERAPY: Patients with inv(16) or t(8;21) or who are NPM1+/FLT3ITD- can receive standard therapy (daunorubicin + cytarabine) and should not receive HCT in first CR. It seems likely that use of a daily daunorubicin dose of 90 mg/m(2) will further improve outcome in these patients. There appears no reason to use doses of cytarabine > 1 g/m(2) (for example, bid × 6 days), as opposed to the more commonly used 3 g/m(2) . Patients with an unfavorable karyotype (particularly MK) are unlikely to benefit from standard therapy (even with dose escalation) and are thus prime candidates for clinical trials of new drugs or new approaches to HCT; the latter should be done in first CR. Patients with intermediate prognoses (for example, NK and NPM and FLT3ITD negative) should also receive HCT in first CR and can plausibly receive either investigational or standard induction therapy, with the same prognostic information about standard therapy leading one patient to choose the standard and another an investigational option. 相似文献
7.
Calorie restriction (CR) without malnutrition is the only intervention to consistently increase lifespan in all species tested, and lower age-related pathologies in mammals including humans. It has been suggested that uncoupling of mitochondrial oxidative phosphorylation, using chemical uncouplers, mimics CR, and that overlapping mechanisms underlie the phenotypic changes induced by uncoupling and CR. We aimed to critically assess this using a unique mouse model of skeletal muscle-targeted UCP3-induced uncoupling (UCP3Tg), and focused our studies mainly on skeletal muscle mitochondria. Compared to ad libitum fed Wt mice, skeletal muscle mitochondria from ad libitum fed UCP3Tg mice showed higher basal uncoupling and lower H(2)O(2) emission, with unchanged maximal oxidative phosphorylation, and mitochondrial content. UCP3Tg CR mice showed some tendency for differential adaptation to CR, with lowered H(+) leak conductance and evidence for higher H(2)O(2) emission from skeletal muscle mitochondria following 2 weeks CR, and failure to lower H(2)O(2) emission after 1 month CR. Differential adaptation was also apparent at the whole body level: while UCP3Tg CR mice lost as much weight as Wt CR mice, the proportion of muscle lost was higher in UCP3Tg mice. However, a striking outcome of our studies was the absence of change with CR in many of the parameters of mitochondrial function and content that we measured in mice of either genotype. Overall, our study raises the question of whether CR can consistently modify skeletal muscle mitochondria; alterations with CR may only be apparent under certain conditions such as during the 2 wk CR intervention in the UCP3Tg mice. 相似文献
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9.
Adrian S. Fairey Wassim Kassouf Eric Estey Simon Tanguay Ricardo Rendon David Bell Jonathan Izawa Joseph Chin Anil Kapoor Edward Matsumoto Peter Black Alan So Jean‐Baptiste Lattouf Fred Saad Darrel Drachenberg Ilias Cagiannos Louis Lacombe Yves Fradet Niels‐Erik B. Jacobsen 《BJU international》2013,112(6):791-797
10.
Bassel G. Bachir Armen G. Aprikian Jonathan I. Izawa Joseph L. Chin Yves Fradet Adrian Fairey Eric Estey Niels Jacobsen Ricardo Rendon Ilias Cagiannos Louis Lacombe Jean-Baptiste Lattouf Anil Kapoor Edward Matsumoto Fred Saad David Bell Peter C. Black Alan I. So Wassim Kassouf 《Urologic oncology》2014,32(4):441-448
ObjectiveTo evaluate the effect of body mass index (BMI) on the outcomes of patients with urinary tract carcinoma treated with radical surgery.Materials and methodsData were collected from 10 Canadian centers on patients who underwent radical cystectomy (RC) (1998–2008) or radical nephroureterectomy (RNU) (1990–2010). Various parameters among subsets of patients (BMI<25, 25≤BMI<30, and BMI≥30 kg/m2) were analyzed. Kaplan-Meier and multivariate analyses were performed to assess the effect of BMI on overall survival, disease-specific survival, and recurrence-free survival (RFS).ResultsAmong the 847 RC and 664 RNU patients, there was no difference in histology, stage, grade, and margin status among the 3 patient subsets undergoing either surgery. However, RC patients with lower BMIs (<25 kg/m2) were significantly older (P = 0.004), had more nodal metastasis (P = 0.03), and trended toward higher stage (P = 0.052). RNU patients with lower BMIs (<25 kg/m2) were significantly older (P = 0.0004) and fewer received adjuvant chemotherapy (P = 0.04) compared with those with BMI≥30 kg/m2; however, there was no difference in tumor location (P = 0.20), stage (P = 0.48), and management of distal ureter among the groups (P = 0.30). On multivariate analysis, BMI was not prognostic for overall survival, disease-specific survival, and RFS in the RC group. However, BMI≥30 kg/m2 was associated with more bladder cancer recurrences and worse RFS in the RNU group (HR = 1.588; 95% CI: 1.148–2.196; P = 0.0052).ConclusionsIncreased BMI did not influence survival among RC patients. BMI≥30 kg/m2 is associated with worse bladder cancer recurrences among RNU patients; whether this is related to difficulty in obtaining adequate bladder cuff in patients with obesity requires further evaluation. 相似文献