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41.
Bialer Meir Hadad Salim Kadry Bashier Abdul-Hai Ali Haj-Yehia Abdulla Sterling Jeff Herzig Yaacov Yagen Boris 《Pharmaceutical research》1996,13(2):284-289
Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics.
Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD).
Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life.
Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the position to the carbonyl, such as in the case of TMCD, or a substitution in the and in the positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic. 相似文献
42.
Primo N Lara Paul Frankel Philip C Mack Paul H Gumerlock Irina Galvin Cynthia L Martel Jeff Longmate James H Doroshow Heinz Josef Lenz Derick H M Lau David R Gandara 《Clinical cancer research》2003,9(12):4356-4362
PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. EXPERIMENTAL DESIGN: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. RESULTS: Three of four chemotherapy-na?ve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. CONCLUSION: Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003. 相似文献
43.
Marilyn A Roubidoux Judith Salmon Kaur Kent A Griffith Barbara Stillwater Paul Novotny Jeff Sloan 《Cancer epidemiology, biomarkers & prevention》2003,12(10):1081-1086
The purpose is to determine breast cancer risk factors and correlates of mammographic parenchymal patterns among Alaska Native women. A retrospective review was performed of mammograms and mammogram records among 528 sequential screening mammogram examinations performed in Anchorage, Alaska. Mammogram density was classified by American College of Radiology (Breast Imaging Reporting and Data System) density patterns 1-4 (fat-->dense) and by percent density. Clinical data, including risk factors, ethnic group (Indian, Aleut, or Eskimo), and smoking status were obtained. Results were analyzed by univariate and multivariate analyses. Of 528 women, 164 were Indian, 155 were Aleut, and 209 were Eskimo. Mean age at first birth was lower and parity higher compared with published data in white women. Breast cancer risk factors were similar across ethnic groups. In multivariate analysis, patient age, parity, hormone replacement therapy, hysterectomy, and history of biopsy were associated, and smoking was not associated with density scores. Aleut and Indian women were less likely to have high-density mammograms than were Eskimo women (P = 0.0448). No significant differences were found between ethnic group for conventional breast cancer risk factors. Mammogram density was associated with age at screening, parity, hormone replacement therapy, hysterectomy, history of biopsy, and ethnicity but not smoking status. Eskimo women had higher mammogram density than Aleuts or Indians. 相似文献
44.
Ranjan K. Sur Bernard Donde Victor Levin Juan Pacella Jeff Kotzen Kum Cooper Martin Hale 《The Laryngoscope》1997,107(9):1276-1280
A retrospective analysis was performed of 50 patients with adenoid cystic carcinoma who were seen in the Department of Radiation Oncology, University of Witwatersrand, Johannesburg, South Africa, in the past 10 years. There were 25 men and 25 women with a mean age of 52 years (age range, 21 to 88 years). Five patients had metastatic disease, and 17 had neural invasion. Thirty-four patients had surgery (11, complete; 23, microscopic residual). Sixteen patients had radiotherapy as initial management. The disease-free survival was 26%, overall survival was 29%, and local control was 30% at 10 years. Most recurrences occurred in the first 3 years. Nine patients had metastasis following treatment. The mean survival after metastasis was 15 months. Seven prognostic variables were analyzed using the log-rank test. There was no impact of age, site, type of salivary gland (major vs. minor), tumor stage, node positivity, or neural invasion on disease-free survival, overall survival, or local control. Extent of surgical resection (complete vs. microscopic residual) had a significant impact on disease-free survival and local control (P < 0.05) but no impact on overall survival (P > 0.05) because of the slow-growing nature of these tumors. Similarly, patients who had microscopic residual after surgery and were treated with radiotherapy did better than those who had biopsy and radiotherapy, although this was not significant statistically (P > 0.05). Thus, whenever possible, every attempt must be made to remove all microscopic tumor by surgery. Addition of postoperative radiotherapy with high-energy photons did not improve the locoregional control or survival in our series. There is a place for neutrons in the treatment of adenoid cystic carcinomas in advanced cases of inoperable or recurrent tumors, as a review of literature shows. 相似文献
45.
Using Vignettes to Compare the Quality of Clinical Care Variation in Economically Divergent Countries 下载免费PDF全文
John W. Peabody Fimka Tozija Jorge A. Muñoz Robert J. Nordyke Jeff Luck 《Health services research》2004,39(6P2):1951-1970
Objective. To determine whether clinical vignettes can measure variations in the quality of clinical care in two economically divergent countries.
Data Source/Study Setting. Primary data collected between February 1997 and February 1998 at two Veterans Affairs facilities in the United States and four government-run outpatient facilities in Macedonia.
Study Design. Randomly selected, eligible Macedonian and U.S. physicians (>97 percent participation rate) completed vignettes for four common outpatient conditions. Responses were judged against a master list of explicit quality criteria and scored as percent correct.
Data Collection/ Extraction. An ANOVA model and two-tailed t-tests were used to compare overall scores by case, study site, and country.
Principal Findings. The mean score for U.S. physicians was 67 percent (+/−11 percent) compared to 48 percent (+/−11 percent) for Macedonian physicians. The quality of clinical practice, which emphasizes basic skills, varied greatly in both sites, but more so in Macedonia. However, the top Macedonian physicians in all sites approached or—in one case—exceeded the median score in the U.S. sites.
Conclusions. Vignettes are a useful method for making cross-national comparisons of the quality of care provided in very different settings. The vignette measurements revealed that some physicians in Macedonia performed at a standard comparable to that of their counterparts in the United States, despite the disparity of the two health systems. We infer that in poorer countries, policy that promotes improvements in the quality of clinical practice—not just structural inputs—could lead to rapid improvements in health. 相似文献
Data Source/Study Setting. Primary data collected between February 1997 and February 1998 at two Veterans Affairs facilities in the United States and four government-run outpatient facilities in Macedonia.
Study Design. Randomly selected, eligible Macedonian and U.S. physicians (>97 percent participation rate) completed vignettes for four common outpatient conditions. Responses were judged against a master list of explicit quality criteria and scored as percent correct.
Data Collection/ Extraction. An ANOVA model and two-tailed t-tests were used to compare overall scores by case, study site, and country.
Principal Findings. The mean score for U.S. physicians was 67 percent (+/−11 percent) compared to 48 percent (+/−11 percent) for Macedonian physicians. The quality of clinical practice, which emphasizes basic skills, varied greatly in both sites, but more so in Macedonia. However, the top Macedonian physicians in all sites approached or—in one case—exceeded the median score in the U.S. sites.
Conclusions. Vignettes are a useful method for making cross-national comparisons of the quality of care provided in very different settings. The vignette measurements revealed that some physicians in Macedonia performed at a standard comparable to that of their counterparts in the United States, despite the disparity of the two health systems. We infer that in poorer countries, policy that promotes improvements in the quality of clinical practice—not just structural inputs—could lead to rapid improvements in health. 相似文献
46.
Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. 总被引:13,自引:0,他引:13
Matthew P Goetz David Toft Joel Reid Matthew Ames Bridget Stensgard Stephanie Safgren Araba A Adjei Jeff Sloan Pamela Atherton Vlad Vasile Sandra Salazaar Alex Adjei Gary Croghan Charles Erlichman 《Journal of clinical oncology》2005,23(6):1078-1087
PURPOSE: We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. PATIENTS AND METHODS: An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. RESULTS: Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m(2) were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t(1/2)) of 17-AAG were 11.6 L/h/m(2) and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t(1/2) of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. CONCLUSION: The MTD of weekly 17-AAG is 308 mg/m(2). 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy. 相似文献
47.
Primo N Lara Philip C Mack Timothy Synold Paul Frankel Jeff Longmate Paul H Gumerlock James H Doroshow David R Gandara 《Clinical cancer research》2005,11(12):4444-4450
BACKGROUND: UCN-01 (7-hydroxy-staurosporine) is a novel antineoplastic agent targeting cyclin-dependent kinases, which shows potent in vitro and in vivo activity against a broad range of tumor types. Our group has previously shown that UCN-01 potentiates the apoptotic response of agents such as cisplatin in vitro by preventing sequence-specific abrogation of G2 arrest caused by DNA-damaging chemotherapies. PATIENTS AND METHODS: This National Cancer Institute-sponsored phase I trial was designed to determine the safety, maximum tolerated dose, and pharmacokinetics of escalating doses of cisplatin in combination with UCN-01 in patients with advanced malignant solid tumors, as well as to do molecular correlative studies on tumor specimens. Cisplatin was infused over 1 hour before UCN-01 (45 mg/m2/d) given as a 72-hour continuous infusion. Escalation of cisplatin was planned through five dose levels at 20, 30, 45, 60, and 75 mg/m2. RESULTS: Ten patients were accrued. Accrual was halted at dose level 2 (cisplatin, 30 mg/m2) due to dose-limiting toxicities consisting of grade 5 sepsis with respiratory failure associated with grade 3 creatinine (one patient) and grade 3 atrial fibrillation (one patient). Plasma and salivary pharmacokinetics of UCN-01 were unaffected by cisplatin. Pretreatment and posttreatment tumor biopsies showed that UCN-01 was active against a key molecular target, the checkpoint kinase Chk1.CONCLUSIONS: This phase I trial failed to achieve targeted therapeutic dose levels of cisplatin when combined with prolonged infusion UCN-01. However, because preclinical data indicate that UCN-01 potentiates response to platinum, further studies with alternative dose schedules of the combination, or with other platinum analogues, are warranted. 相似文献
48.
Scott H Kaufmann Judith E Karp Louis Letendre Timothy J Kottke Stephanie Safgren Jackie Greer Ivana Gojo Pamela Atherton Phyllis A Svingen David A Loegering Mark R Litzow Jeff A Sloan Joel M Reid Matthew M Ames Alex A Adjei Charles Erlichman 《Clinical cancer research》2005,11(18):6641-6649
PURPOSE: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. EXPERIMENTAL DESIGN: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. RESULTS: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). CONCLUSIONS: The maximum tolerated dose was 1.6 mg/m(2)/d topotecan plus 150 mg/m(2)/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression. 相似文献
49.
Jennifer R. Brown John C. Byrd Paolo Ghia Jeff P. Sharman Peter Hillmen Deborah M. Stephens Clare Sun Wojciech Jurczak John M. Pagel Alessandra Ferrajoli Priti Patel Lin Tao Nataliya Kuptsova-Clarkson Javid Moslehi Richard R. Furman 《Haematologica》2022,107(6):1335
Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: , NCT02029443, NCT02475681 and NCT02970318). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with high-risk CLL (clinicaltrials gov. Identifier: NCT02337829) prospectively assess differences in CV toxicity between the two agents. NCT02477696相似文献
50.
Charles E. Hendrick Jeff R. Jorgensen Charu Chaudhry Iulia I. Strambeanu Jean-Francois Brazeau Jamie Schiffer Zhicai Shi Jennifer D. Venable Scott E. Wolkenberg 《ACS medicinal chemistry letters》2022,13(7):1182
A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach with a focus on linker effects. A large number of linker analogs—with varying length, polarity, and rigidity—were rapidly prepared and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure–activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity. Unexpected aspects of linker SAR was discovered, consistent with literature reports on “linkerology”, and the method dramatically speeds up empirical optimization. Physicochemical property trends emerged, and the platform has the potential to rapidly expand training sets for more complex prediction models. In-depth validation studies were carried out and confirm the D2B platform is a valuable tool to accelerate PROTAC design–make–test cycles. 相似文献