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排序方式: 共有231条查询结果,搜索用时 15 毫秒
1.
Pharmacological properties of fluphenazine-mustard, an irreversible calmodulin antagonist 总被引:1,自引:0,他引:1
We describe an improved synthesis and properties of fluphenazine-mustard, a potent phenothiazine having an alkylating chlorethylamine chain in its structure. The drug possesses anticalmodulin activity equivalent to the parent compound, but unlike fluphenazine dihydrochloride, the mustard derivative irreversibly antagonizes the ability of calmodulin to activate cyclic nucleotide phosphodiesterase. This property is partially calcium-dependent and can be overcome by coincubation with excess fluphenazine dihydrochloride. The compound irreversibly inactivated calmodulin when incubated with intact cells and caused single-stranded breakage of DNA. Fluphenazine-mustard possesses potent antiproliferative and cytotoxic properties against malignant cell lines that are likely to be mediated through both of these actions. 相似文献
2.
Anti-ischemic effects of atenolol versus nifedipine in patients with coronary artery disease and ambulatory silent ischemia 总被引:1,自引:0,他引:1
P C Deedwania E V Carbajal J R Nelson H Hait 《Journal of the American College of Cardiology》1991,17(4):963-969
The anti-ischemic effects of atenolol and nifedipine were compared in a randomized double-blind crossover manner in 24 patients with stable exertional angina and transient silent ischemia during ambulatory electrocardiographic (ECG) monitoring. Both atenolol and nifedipine were effective (p less than 0.005) in reducing the average number and duration of transient ischemic events, but therapy with atenolol was associated with a significantly greater reduction in the mean number (p less than 0.05) and duration (p less than 0.01) of silent ischemic events. Analyses of the silent ischemic activity during the morning hours revealed that only therapy with atenolol produced a significant reduction in the average duration per patient (139 +/- 54 vs. 1,609 +/- 468 s, p less than 0.01) and in the average duration of silent ischemia per event between 6 AM and 12 noon (62 +/- 21 vs. 208 +/- 24 s, p less than 0.005). There were fewer adverse experiences during therapy with atenolol. These results show that although both atenolol and nifedipine are effective in reducing silent ischemic events, treatment with atenolol is associated with significantly greater efficacy, particularly on the morning surge of silent myocardial ischemia. 相似文献
3.
Tawfiq Froukh Omar Nafie Sana' A. S. Al Hait Lucia Laugwitz Julia Sommerfeld Marc Sturm Aya Baraghiti Tala Issa Anis Al-Nazer Philipp A. Koch Johannes Hanselmann Beate Kootz Peter Bauer Wael Al-Ameri Rami Abou Jamra Ayman J. Alfrook Moath Hamadallah Linda Sofan Angelika Riess Tobias B. Haack Olaf Riess Rebecca Buchert 《Clinical genetics》2020,97(4):621-627
We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability. 相似文献
4.
J. R. Murren Henry J. Durivage Antonio C. Buzaid Michael Reiss Stuart D. Flynn Darryl Carter William N. Hait 《Cancer chemotherapy and pharmacology》1996,38(1):65-70
Overexpression of P-glycoprotein (P-gp) has been implicated as the mechanism of multidrug resistance (MDR) in a number of
human cancers, including carcinoma of the breast. We conducted a clinical trial to determine whether the P-gp inhibitor, trifluoperazine,
could sensitize patients with refractory breast cancer to vinblastine chemotherapy. Adult patients with histologically confirmed,
refractory, advanced breast cancer were treated with vinblastine at a dose of 1.7 mg/m2 per day by continuous infusion for five consecutive days. Patients who did not respond after two cycles were subsequently
treated with vinblastine plus trifluoperazine at a dose of 8 mg twice daily during the five days of chemotherapy. In patients
from whom tumor samples were available, the expression of P-gp was determined by immunocytochemistry. Of 35 patients enrolled,
30 were evaluable, 2 of whom (7%) achieved a partial response to vinblastine alone. Among the 16 patients treated with vinblastine
plus trifluoperazine there was one response (6%) which lasted 16 weeks. Tumor samples were available from 16 patients, and
14 (87%) were immunoreactive for P-gp. P-gp expression was detected both in the patient who responded to vinblastine plus
trifloperazine and in one of the two patients who responded to vinblastine alone. Continuous-infusion vinblastine demonstrated
limited activity in this study. Furthermore, trifluoperazine did not effectively reverse established resistance to vinblastine.
This failure may be related the presence of multiple mechanisms of drug resistance in this heavily pretreated population,
or because ineffective concentrations of the modulator were achieved in vivo. Future studies should evaluate more effective
modulators, and attempt to reverse MDR earlier in the course of treatment, before other forms of resistance can develop.
Received: 12 January 1995/Accepted: 11 August 1995 相似文献
5.
Sullivan GF Garcia-Welch A White E Lutzker S Hait WN 《Journal of experimental therapeutics & oncology》2002,2(1):19-26
A variety of anticalmodulin drugs can increase the cytotoxicity of bleomycin, a DNA damaging cancer chemotherapeutic. The combination has been shown to produce greater than expected DNA damage compared wot what was observed with either drug alone. Promising preclinical results led to Phase I and Phase II trials of trifluoperazine and bleomycin, which revealed activity in non-Hodgkin's lymphoma. Despite the unique activity of the combination, the mechanism underlying the DNA damaging effect remained poorly understood. In several systems, DNA damage leads to the induction of programmed cell death or apoptosis, which is characterized by interoligonucleosomal cleavage of DNA. To determine whether the activity of the combination of bleomycin with trifluoperazine was due to induction of apoptosis, we exposed L1210 leukemic lymphocytes to bleomycin in the presence or absence of trifluoperazine. The combination produced DNA laddering, cellular shrinkage, and chromatin condensation typical of programmed cell death. Cell cycle analyses revealed a blockade of cells in G2/M, suggesting the presence of mutant p53, which was confirmed by immunoanalysis. In addition, L1210 cells were found not to overexpress Bcl-2 in the presence or absence of drugs. These results indicate that the enhancement of bleomycin induced DNA damage by trifluoperazine is mediated, at least in part, through the induction of apoptosis. 相似文献
6.
7.
8.
神经生长因子对小鼠突触体内Ca^2+水平的调节作用 总被引:3,自引:1,他引:3
观察了多次海马内微注射NGF对小鼠突触体内游离钙水平的影响,并在离体情况下观察NGF对EGTA和CaCl2分别造成突触体内低钙和高钙状态的调节作用。结果如下:(1)在体实验表明,一定剂量的NGF可显著降低老年小鼠海马突触体内游离钙水平(P<005);(2)离体实验表明,当突触体游离钙水平降低时,适当剂量的NGF具有升高游离钙水平的作用;而突触体内游离钙水平升高时,则NGF有降低游离钙水平的作用。提示NGF对游离钙水平的双向调节作用可能是NGF改善老年性记忆衰退的作用机制。 相似文献
9.
Daniel TP Fong Mak-Ham Lam Miko LM Lao Chad WN Chan Patrick SH Yung Kwai-Yau Fung Pauline PY Lui Kai-Ming Chan 《Journal of orthopaedic surgery and research》2008,3(1):7
Background
Excessive pronation (or eversion) at ankle joint in heel-toe running correlated with lower extremity overuse injuries. Orthotics and inserts are often prescribed to limit the pronation range to tackle the problem. Previous studies revealed that the effect is product-specific. This study investigated the effect of medial arch-heel support in inserts on reducing ankle eversion in standing, walking and running. 相似文献10.
Calmodulin is a ubiquitous, calcium-binding protein that is responsible for many of the intracellular actions of calcium. Recent evidence suggests that calmodulin may regulate cellular proliferation and that its function may be altered in malignancy. The discovery that drugs such as phenothiazines antagonize the action of calmodulin led to the study of these antagonists against tumor cells. It is now appreciated that calmodulin antagonists are cytotoxic, can restore the sensitivity of resistant cells to drugs such as doxorubicin and vincristine, and can augment the cytotoxicity of bleomycin. This report addresses the possibility of developing new forms of chemotherapeutic agents that work by disrupting the function of this intriguing molecule. 相似文献