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991.
Palmer BD Thompson AM Booth RJ Dobrusin EM Kraker AJ Lee HH Lunney EA Mitchell LH Ortwine DF Smaill JB Swan LM Denny WA 《Journal of medicinal chemistry》2006,49(16):4896-4911
High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties. 相似文献
992.
Grunewald GL Seim MR Regier RC Martin JL Gee CL Drinkwater N Criscione KR 《Journal of medicinal chemistry》2006,49(18):5424-5433
3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH- could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH- with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the alpha2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT Ki = 1.3 microM) is the most potent compound in this series and is quite selective for PNMT versus the alpha2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT Ki = 0.13 microM). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones. 相似文献
993.
Population pharmacokinetics of tacrolimus in whole blood and plasma in asian liver transplant patients 总被引:2,自引:0,他引:2
Sam WJ Tham LS Holmes MJ Aw M Quak SH Lee KH Lim SG Prabhakaran K Chan SY Ho PC 《Clinical pharmacokinetics》2006,45(1):59-75
OBJECTIVES: The objectives of this study were to develop population pharmacokinetic models of tacrolimus in an Asian population with whole blood and plasma drug concentration data, to compare the variability of the pharmacokinetic parameters in these two matrices and to search for the main patient characteristics that explain the variability in pharmacokinetic parameters. STUDY DESIGN: Prospective pharmacokinetic assessment followed by model fitting. PATIENTS: Whole blood samples from 31 liver transplant patients in a local hospital receiving oral tacrolimus as part of their immunosuppressive therapy were assessed. Plasma samples from 29 of the 31 patients were also evaluated. Concentrations of tacrolimus in whole blood and plasma were determined by an electrospray high-performance liquid chromatography with tandem mass spectrometry. Two hundred and thirteen whole blood and 157 plasma tacrolimus concentrations were used for building two nonlinear mixed-effects population models to describe the disposition of tacrolimus in whole blood and plasma, respectively. Covariates that were investigated included demographic characteristics, biological markers of liver and renal functions, corticosteroid dose and haematological parameter. RESULTS: A one-compartment model was used to describe the whole blood and plasma concentration-time data of tacrolimus after oral administration. For the whole blood population model, the population estimates of the first-order absorption rate constant (k(a)), apparent clearance based on whole blood concentration after oral administration (CL(B)/F) and apparent volume of distribution based on whole blood concentrations after oral administration (V(d,B)/F) were 2.08h(-1), 14.1 L/h and 217L, respectively. The coefficient of variations (CVs) of interpatient variabilities in CL(B)/F and V(d,B)/F were 65.7% and 63.8%, respectively. Bodyweight, liver and renal function influenced CL(B)/F, while height and haematocrit influenced V(d,B)/F. The residual (unexplained) variability was 34.8%. For the plasma population model, the population estimates of the k(a), apparent clearance based on plasma concentrations after oral administration (CL(P)/F) and apparent volume of distribution based on plasma concentrations after oral administration (V(d,P)/F) were 5.21h(-1), 537 L/h and 563L, respectively. The CVs of interpatient variabilities in CL(P)/F and V(d,P)/F were 96.0% and 105.4%, respectively. Bodyweight was found to influence CL(P)/F, while the erythrocyte-to-plasma concentration ratio influenced V(d,P)/F. The residual (unexplained) variability was 49.8% at the mean plasma concentration of 1.1 ng/mL. CONCLUSIONS: Whole blood and plasma population pharmacokinetic models of tacrolimus in Asian adult and paediatric liver transplant patients were developed using prospective data in a clinical setting. This has identified and quantified sources of interindividual variability in CL(B)/F, V(d,B)/F, CL(P)/F and V(d,P)/F of tacrolimus in Asian liver transplant patients. Information derived from the whole blood population model may subsequently be used by clinicians for dosage individualisation through Bayesian forecasting. 相似文献
994.
Senti G Martínez Gómez JM Rettig L Wüthrich B Kündig TM Johansen P 《Inflammation & allergy drug targets》2006,5(4):243-252
The last decades have shown an increasing incidence of allergic illnesses such as rhinoconjunctivitis, with a prevalence of 20-30% in some industrialised parts of the world. The only treatment that may change the natural course of allergic disease is allergen-specific immunotherapy (SIT), which has been shown to prevent the development of asthma in rhinitic patients and anaphylaxis in insect venom allergic patients. However, the risk-benefit ratio for subcutaneous immunotherapy has changed little from when it was first developed in 1911. Novel developments of adjuvants, and allergens as well as methods of administration, now offer improvements in both the efficacy and safety of SIT. This review describes and discusses these new developments in the context of the many recent advances in our understanding of the mechanisms by which immunotherapy appears to act. 相似文献
995.
Kerker BD Bainbridge J Kennedy J Bennani Y Agerton T Marder D Forgione L Faciano A Thorpe LE 《American journal of public health》2011,101(3):546-553
Objectives. We compared estimated population-based health outcomes for New York City (NYC) homeless families with NYC residents overall and in low-income neighborhoods.Methods. We matched a NYC family shelter user registry to mortality, tuberculosis, HIV/AIDS, and blood lead test registries maintained by the NYC Department of Health and Mental Hygiene (2001–2003).Results. Overall adult age-adjusted death rates were similar among the 3 populations. HIV/AIDS and substance-use deaths were 3 and 5 times higher for homeless adults than for the general population; only substance-use deaths were higher than for low-income adults. Children who experienced homelessness appeared to be at an elevated risk of mortality (41.3 vs 22.5 per 100 000; P < .05). Seven in 10 adult and child deaths occurred outside shelter. Adult HIV/AIDS diagnosis rates were more than twice citywide rates but comparable with low-income rates, whereas tuberculosis rates were 3 times higher than in both populations. Homeless children had lower blood lead testing rates and a higher proportion of lead levels over 10 micrograms per deciliter than did both comparison populations.Conclusions. Morbidity and mortality levels were comparable between homeless and low-income adults; homeless children''s slightly higher risk on some measures possibly reflects the impact of poverty and poor-quality, unstable housing.Most studies examining the health of homeless populations have involved single adults and have identified higher rates of death, tuberculosis (TB), HIV/AIDS, mental health disorders, substance use, poor birth outcomes, and cardiovascular disease than in the general population.1–7 Whether these findings can be generalized to homeless families is not known, as the 2 populations differ greatly. Nationally, homeless families overwhelmingly consist of a young female head of household with children, whereas single homeless adults are mostly men aged 31 to 50 years.8 Homeless families are also distinct in their reasons for becoming homeless, citing poverty more often and substance use and mental illness less often than is the case for their single adult counterparts.9 Based on their demographic and socioeconomic profiles, the health of homeless families may be more like that of other low-income families than that of homeless single adults.Recent economic conditions have led to a rise in the number of homeless families nationwide. Although overall US homelessness held fairly constant from 2007 to 2008, the number of homeless families increased by 9%. According to the latest available national data, an estimated 516 700 adults and children were sheltered as families over a 1-year period in 2008, constituting roughly a third of the overall sheltered homeless population during that time.8 More recent data from a sampling of localities found that, as of September 2009, the count of sheltered families had increased 10% from the previous quarter, as foreclosure and unemployment rates continued to rise.10In New York City (NYC), the Department of Homeless Services (DHS) supplies apartment-style shelters and support services such as childcare, housing assistance, and health care referral to homeless families. Because the city provides emergency shelter to eligible families, virtually all homeless families use shelter facilities. In 7 years of an annual count of street homeless, a family has never been found on the street.11 A small share of homeless families is sheltered by city agencies other than DHS. However, analyses based on DHS shelter registry likely include the vast majority of the NYC homeless family population.Our objective was to systematically characterize the health of adults and children who used the NYC family shelter system. We matched the DHS family shelter registry with 4 health registries managed by the NYC Department of Health and Mental Hygiene, and we compared estimates of morbidity and mortality in the homeless family population with those of the NYC general and lowest-income neighborhood populations. 相似文献
996.
R. Charon Gwynn Magdalena Berger Elizabeth Needham Waddell Lorna E. Thorpe Renu K. Garg Robyn Philburn 《Preventing chronic disease》2011,8(3)
Introduction
Body mass index (BMI) and indicators of central adiposity have been associated with cardiovascular disease (CVD) risk factors, but ambiguity remains about which measure optimally predicts CVD risk and is best suited for different racial/ethnic groups. We sought to characterize excess adiposity among New York City adults and assess the potential associations between multiple adiposity indicators and CVD risk factors, by race/ethnicity.Methods
The New York City Health and Nutrition Examination Survey (NYC HANES) is a population-based survey of noninstitutionalized New York City adult residents aged 20 years or older. We compared the prevalence of obesity (BMI ≥30 kg/m2), elevated waist circumference (>102 cm for men, >88 cm for women), and elevated waist-to-height ratio (≥0.5) for participants in the 2004 NYC HANES (n = 1,912) and the 2003-2004 National Health and Nutrition Examination Survey (n = 4,075). Logistic regression was used to assess potential associations between each of these indicators of excess adiposity and CVD risk factors (diabetes, impaired fasting glucose, hypertension, and hypercholesterolemia), overall and by race/ethnicity.Results
The prevalence of obesity among NYC HANES participants was 26% and of elevated waist circumference was 46%, both significantly lower than national estimates (31% and 52%, respectively), whereas the prevalence of elevated waist-to-height ratio was higher (82% vs 79%). Most measures of excess adiposity were significantly associated with all CVD risk factors. No single measure of excess adiposity emerged as most consistently predictive of CVD risk in the general population or by race/ethnicity.Conclusion
New York City has a lower prevalence of obesity and elevated waist circumference but a higher prevalence of elevated waist-to-height ratio than found nationally. Further investigation into the optimal adiposity measure to predict CVD risk across racial/ethnic populations may be warranted. 相似文献997.
Tony Walter PhD Allison Ford PhD Lorna Templeton MSc Christine Valentine PhD Richard Velleman PhD 《Health & social care in the community》2017,25(6):1714-1721
How to promote compassionate care within public services is a concern in several countries; specifically, some British healthcare scandals highlight poor care for service users who may readily be stigmatised as ‘other’. The article therefore aims to understand better the relationship between stigma and compassion. As people bereaved by a drug‐ or alcohol‐related death often experience stigma, the article draws on findings from a major British study, conducted during 2012–2015 by the authors, of people bereaved in this way, in order to see how service provision can be improved. One hundred and six bereaved family members were interviewed in depth about their experiences of loss and support. Thematic analysis developed theoretical understandings of participants’ lived experiences. This article analyses our data on how bereaved people experienced stigma and kindness from practitioners of all kinds. We found that stigma can be mitigated by small acts of kindness from those encountered after the death. Stigma entails stereotyping, othering and disgust, each of which has emotional and cognitive aspects; kindness entails identification and fellow feeling; professionalism has classically entailed emotional detachment, but interviewees found cold professionalism as disturbing as explicit disgust. Drawing on theories concerning the end of life, bereavement and emotional labour, the article analyses the relationship between stigma, kindness and professionalism, and identifies some strategies to counter stigmatisation and foster compassion. 相似文献
998.
E Berman Z A Arlin J Gaynor W Miller T Gee S J Kempin R Mertelsmann M Andreeff L Reich N Nahmias 《Leukemia》1989,3(2):115-121
Ninety-six patients with de novo acute nonlymphocytic leukemia (ANLL) were randomized to receive either daunorubicin (50 mg/m2, IV) on days 1-3; cytarabine (Ara-C) (25 mg/m2, IV) bolus, followed by 160 mg/m2 as a continuous IV infusion daily for 5 days and 6-thioguanine (6-TG) (100 mg/m2 po) every 12 hr daily for 5 days (DAT); or amsacrine (190 mg/m2, IV) on days 1-3 with Ara-C and 6-TG at the above doses (AAT). Patients achieving complete remission (CR) then received two courses of consolidation therapy with the same combination that had induced remission but at slightly reduced total doses. Patients less than or equal to age 40 with an HLA-identical sibling donor underwent allogeneic transplantation, usually after consolidation therapy. The remaining patients were then randomized to receive either maintenance therapy (alternating cycles of vincristine/methotrexate, cyclophosphamide/6-TG, daunorubicin/hydroxyurea and Ara-C/6-TG) or no further treatment. Ninety-two patients were evaluable for response. Twenty-five of the 46 patients (54%) who received DAT and 32 of the 46 patients (70%) who received AAT achieved CR (p = 0.13). When patients were stratified by age, however, remission induction advantage with AAT became statistically significant (p = 0.03). Additionally, more patients achieved CR following one course of AAT than following one course of DAT (48% vs 28%, p = 0.03). Overall survival in the AAT group was improved as well (p = 0.01). Too few patients were randomized on the maintenance arm of the protocol to make interpretation meaningful. Non-hematologic toxicity was generally comparable in both arms. In conclusion, patients with de novo ANLL who received AAT had a higher remission incidence and slightly longer survival compared to patients who received DAT. Further investigation of this drug combination in untreated patients with ANLL is warranted. 相似文献
999.
David A Reardon Gamal Akabani R Edward Coleman Allan H Friedman Henry S Friedman James E Herndon Ilkcan Cokgor Roger E McLendon Charles N Pegram James M Provenzale Jennifer A Quinn Jeremy N Rich Lorna V Regalado John H Sampson Timothy D Shafman Carol J Wikstrand Terence Z Wong Xiao-Guang Zhao Michael R Zalutsky Darell D Bigner 《Journal of clinical oncology》2002,20(5):1389-1397
PURPOSE: To assess the efficacy and toxicity of intraresection cavity (131)I-labeled murine antitenascin monoclonal antibody 81C6 and determine its true response rate among patients with newly diagnosed malignant glioma. PATIENTS AND METHODS: In this phase II trial, 120 mCi of (131)I-labeled murine 81C6 was injected directly into the surgically created resection cavity of 33 patients with previously untreated malignant glioma (glioblastoma multiforme [GBM], n = 27; anaplastic astrocytoma, n = 4; anaplastic oligodendroglioma, n = 2). Patients then received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy. RESULTS: Median survival for all patients and those with GBM was 86.7 and 79.4 weeks, respectively. Eleven patients remain alive at a median follow-up of 93 weeks (range, 49 to 220 weeks). Nine patients (27%) developed reversible hematologic toxicity, and histologically confirmed, treatment-related neurologic toxicity occurred in five patients (15%). One patient (3%) required reoperation for radionecrosis. CONCLUSION: Median survival achieved with (131)I-labeled 81C6 exceeds that of historical controls treated with conventional radiotherapy and chemotherapy, even after accounting for established prognostic factors including age and Karnofsky performance status. The median survival achieved with (131)I-labeled 81C6 compares favorably with either (125)I interstitial brachy-therapy or stereotactic radiosurgery and is associated with a significantly lower rate of reoperation for radionecrosis. Our results confirm the efficacy of (131)I-labeled 81C6 for patients with newly diagnosed malignant glioma and suggest that a randomized phase III study is indicated. 相似文献
1000.
Personnel time and costs associated with computer-assisted instruction (CAI) and traditional "one-on-one" instruction in basic computer drug-order entry procedures were compared. Both programs consisted of an introduction to the training session, familiarization of users with the computer hardware and keyboard, and step-by-step instructions in unit dose and intravenous admixture order-entry procedures. The CAI module was developed by a pharmacist with no prior programming experience. It was designed to be used side-by-side with the actual inpatient pharmacy computer system. Fifth-year pharmacy students in their clinical clerkship rotation served as the study population. The personnel (both subject and pharmacy supervisor) time and costs associated with each method were evaluated for significant differences by a two-tailed Student's t test. Of 21 subjects who participated in this study, 11 received CAI and 10 received traditional instruction. CAI was associated with significantly less mean total personnel time (99.64 +/- 18.78 minutes) than one-on-one instruction (133.60 +/- 22.89 minutes). Mean total salary expense was significantly lower for CAI ($13.03 +/- 2.15) than for one-on-one instruction ($28.79 +/- 4.91). Program development time for the CAI module was 18.5 hours longer than that for the one-on-one program. The CAI module cost $1577.77 more to develop than the one-on-one program; however, 24 new employees would be required to offset development costs if the hardware were already available and 100 new employees if hardware had to be purchased. Computer-assisted instruction of new employees in computer order-entry procedures can be a cost-effective alternative to traditional training methods.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献