Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.

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.     

海风藤的原植物——腺鳞蒟与山药的比较研究

本文对模式产地的山药Piper haneei Maxim, var, hancei Maxim,和腺鳞蒟P. kancei Maxim var. squamiglanduferum Fan var. nov.进行了原植物形态特征和花序轴、花序梗、茎、叶的显微特征以及化学成分的TLC及UV比较。挥发油的GC—MS研究共鉴定出38个成分,其中28个是胡椒属植物中首次报道的成分。结果证明了在福建长期以来被认为是山药的腺鳞蒟与模式产地的山药有较大差别,尤其是腺鳞蒟叶上表面有腺鳞,是迄今为止第1个发现具有腺鳞的胡椒属植物。据此把腺鳞蒟作为新变种从山药中分出。腺鳞药是福建南部海风藤主要来源之一。     

Quantitative T2 evaluation at 3.0T compared to morphological grading of the lumbar intervertebral disc: a standardized evaluation approach in patients with low back pain

Background

The purpose of our investigation was to compare quantitative T2 relaxation time measurement evaluation of lumbar intervertebral discs with morphological grading in young to middle-aged patients with low back pain, using a standardized region-of-interest evaluation approach.

Patients and methods

Three hundred thirty lumbar discs from 66 patients (mean age, 39 years) with low back pain were examined on a 3.0 T MR unit. Sagittal T1-FSE, sagittal, coronal, and axial T2-weighted FSE for morphological MRI, as well as a multi-echo spin-echo sequence for T2 mapping, were performed. Morphologically, all discs were classified according to Pfirrmann et al. Equally sized rectangular regions of interest (ROIs) for the annulus fibrosus were selected anteriorly and posteriorly in the outermost 20% of the disc. The space between was defined as the nucleus pulposus. To assess the reproducibility of this evaluation, inter- and intraobserver statistics were performed.

Results

The Pfirrmann scoring of 330 discs showed the following results: grade I: six discs (1.8%); grade II: 189 (57.3%); grade III: 96 (29.1%); grade IV: 38 (11.5%); and grade V: one (0.3%). The mean T2 values (in milliseconds) for the anterior and the posterior annulus, and the nucleus pulposus for the respective Pfirrmann groups were: I: 57/30/239; II: 44/67/129; III: 42/51/82; and IV: 42/44/56. The nucleus pulposus T2 values showed a stepwise decrease from Pfirrmann grade I to IV. The posterior annulus showed the highest T2 values in Pfirrmann group II, while the anterior annulus showed relatively constant T2 values in all Pfirrmann groups. The inter- and intraobserver analysis yielded intraclass correlation coefficients (ICC) for average measures in a range from 0.82 (anterior annulus) to 0.99 (nucleus).

Conclusions

Our standardized method of region-specific quantitative T2 relaxation time evaluation seems to be able to characterize different degrees of disc degeneration quantitatively. The reproducibility of our ROI measurements is sufficient to encourage the use of this method in future investigations, particularly for longitudinal studies.     

Image-guided ablation of painful metastatic bone tumors: a new and effective approach to a difficult problem

Painful skeletal metastases are a common problem in cancer patients. Although external beam radiation therapy is the current standard of care for cancer patients who present with localized bone pain, 20–30% of patients treated with this modality do not experience pain relief, and few further options exist for these patients. For many patients with painful metastatic skeletal disease, analgesics remain the only alternative treatment option. Recently, image-guided percutaneous methods of tumor destruction have proven effective for treatment of this difficult problem. This review describes the application, limitations, and effectiveness of percutaneous ablative methods including ethanol, methyl methacrylate, laser-induced interstitial thermotherapy (LITT), cryoablation, and percutaneous radiofrequency ablation (RFA) for palliation of painful skeletal metastases.     

A systematic narrative review of consumer‐directed care for older people: implications for model development

Consumer‐directed care is increasingly becoming a mainstream option in community‐based aged care. However, a systematic review describing how the current evaluation research translates into practise has not been published to date. This review aimed to systematically establish an evidence base of user preferences for and satisfaction with services associated with consumer‐directed care programmes for older people. Twelve databases were searched, including MedLine, BioMed Central, Cinahl, Expanded Academic ASAP, PsychInfo, ProQuest, Age Line, Science Direct, Social Citation Index, Sociological Abstracts, Web of Science and the Cochrane Library. Google Scholar and Google were also searched. Eligible studies were those reporting on choice, user preferences and service satisfaction outcomes regarding a programme or model of home‐based care in the United States or United Kingdom. This systematic narrative review retrieved literature published from January 1992 to August 2011. A total of 277 references were identified. Of these 17 met the selection criteria and were reviewed. Findings indicate that older people report varying preferences for consumer‐directed care with some demonstrating limited interest. Clients and carers reported good service satisfaction. However, research comparing user preferences across countries or investigating how ecological factors shape user preferences has received limited attention. Policy‐makers and practitioners need to carefully consider the diverse contexts, needs and preferences of older adults in adopting consumer‐directed care approaches in community aged care. The review calls for the development of consumer‐directed care programmes offering a broad range of options that allow for personalisation and greater control over services without necessarily transferring the responsibility for administrative responsibilities to service users. Review findings suggest that consumer‐directed care approaches have the potential to empower older people.     

Actualités en phytothérapie

This editorial review of medicinal plant publications, focusing on pharmacological and clinical research, was written for its pharmaceutical and medical value. It is hoped that it will help advance additional studies that could lead to therapeutic applications. Readers must, however, be aware that a pharmacological breakthrough or the demonstration of pharmacological activity does not immediately justify medical use.