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21.
McNeill Stephen C. Potts Russell O. Francoeur Michael L. 《Pharmaceutical research》1992,9(11):1422-1427
There is considerable uncertainty over whether and to what extent topically applied drugs can be delivered directly to anatomical sites beneath the skin, without prior entry into the systemic blood circulation. The in vivo studies reported in this work were designed to assess whether local enhanced topical delivery (LETD) can be achieved with piroxicam, a nonsteroidal antiinflammatory drug. Equivalent doses of tritium-labeled drug were administered by the i.v. or topical routes to male rats. The topical plasma profile reveals a maximum concentration (Cpmax) at 12 hr, compared to a typical, multiexponential decline in plasma concentration after i.v. dosing. All four muscles from the topically dosed shoulder exhibit two distinct peaks, the first at 4 hr and a later one at 12 hr (which coincides with the topical Cpmax). The contralateral muscles from the non-dosed shoulder, in contrast, produce only a single peak at 12 hr after topical dosing. After the i.v. administration of piroxicam, the concentration-time profiles for each muscle closely parallel that seen for the i.v. plasma. Tissue-to-plasma ratios (T/P) show that the topical nondosed and the i.v. muscles are nearly constant over the entire time course of this study, indicating a pseudo-equilibrium between the plasma and those muscles. However, the early T/P ratios for the topically dosed muscles are markedly elevated and gradually decline to a constant value only after 12 hr, indicating that a similar pseudo-equilibrium is not established in this case. Thus, these results strongly imply that the topical administration of a drug can lead to LETD for tissues subjacent to the skin. Further, based on the elevated T/P ratios, these local enhanced drug levels cannot be solely attributed to entry from the systemic blood and suggest summarily that the cutaneous microvasculature is simply not an infinite sink for removal of all topically applied drugs. 相似文献
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WF Paterson E McNeill S Reid AS Hollman MD Donaldson 《Archives of disease in childhood》1998,79(4):323-327
OBJECTIVE: To assess the efficacy of a longer acting preparation of the gonadotrophin releasing hormone (GnRH) analogue goserelin (Zoladex LA, 10.8 mg) in 12 girls with central precocious or early puberty. METHODS: Two girls started treatment de novo; the remainder had been on suppressive treatment for a median duration of 1.5 (range, 0.2-5.6) years. Assessment comprising auxology, pubertal staging, and pelvic ultrasound examination was carried out at weeks 0, 4, 8, 10, and 12 (first cycle) and weeks 8, 10, and 12 (second cycle) to evaluate the required injection frequency. Thereafter, assessment was performed on the day of injection. Zoladex LA was given every 12 weeks unless pubertal progression occurred. RESULTS: Satisfactory control was achieved in eight patients using this regimen, and three patients required more frequent injections. One girl was removed from the study because of clinical progression and extreme mood swings. No serious adverse effects occurred. Mean height velocity during the study period was 4.5 cm/year (range, 3.1-6.6) compared with 6.5 cm/year (range, 3.8-9.6) before treatment in nine patients for whom data were available. CONCLUSIONS: Zoladex LA was effective in controlling precocious puberty in girls when given at intervals of 9-12 weeks and it is recommended that an initial assessment is made eight weeks after beginning treatment. 相似文献
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Ruth A Pyle-Chenault John A Stolk David A Molesh Dianne Boyle-Harlan Patricia D McNeill Elizabeth A Repasky Zhong Jiang Gary R Fanger Jiangchun Xu 《Tumour biology》2005,26(5):245-257
The discovery of genes that are overexpressed in ovarian cancers provides valuable insight into ovarian cancer biology and will lead to the development of more effective treatment strategies for combating this disease. To identify genes exhibiting ovarian- and ovarian cancer-specific expression, we generated four subtracted cDNA libraries from primary and metastatic ovarian adenocarcinoma tissues. 3,400 cDNA clones from these libraries were analyzed by microarray for tissue distribution and tumor specificity using 32 pairs of fluorophore-labeled cDNA samples from a variety of normal tissues and ovarian tumor tissues. cDNA clones showing elevated expression in ovarian tumors were identified by DNA sequencing with comparison to public databases, and the most promising candidates were further analyzed by quantitative real-time polymerase chain reaction and Northern blot. This systematic approach led to the identification of a number of genes including vascular smooth muscle growth-promoting factor (VSGP/F-spondin), a secreted protein previously identified and cloned from bovine and human ovary. VSGP/F-spondin protein was observed in ovarian carcinomas but not in normal ovarian epithelium by immunohistochemistry with a VSGP/F-spondin antibody. The expression profile of VSGP/F-spondin identifies this molecule as a potential diagnostic marker or target for developing therapeutic strategies to treat ovarian carcinoma. 相似文献
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Background: The Modification of Diet in Renal Disease‐derived estimation of glomerular filtration rate (eGFR) is used widely. Although validated in stable chronic kidney disease (CKD) outpatients, it is not known how it performs in those presenting with acute medical illness. Aim: We aimed to compare eGFR with Cockroft Gault (CG) – the renal function assessment tool available prior to eGFR – to assess the difference in clinical outcome that would occur when one over another estimation is used in practice. In particular, we wished to assess whether use of eGFR would have resulted in a change of dose of commonly used acutely administered medications. Methods: Acute medical admissions presenting to a tertiary hospital between August and December 2008 were included. Serum creatinine concentration, age, sex, height and weight were collected. Renal function was estimated by both estimates. Movement from CKD class 3 to 4 or 5 was measured – a clinically used cut‐off point for changes in management. Results: A total of 54 patients was included. eGFR values were higher than those estimated by CG. Almost half of patients categorized as CKD stage 4–5 using CG were only categorized as CKD stage 3 using eGFR. Conclusion: Although we did not use a gold standard estimation of GFR, this study shows that estimates of renal function vary in a clinically significant manner. As estimates of GFR are used to adjust drug dosages and to stratify for many other treatments, it is imperative that we find a method of estimating kidney function that is readily available, consistent and accurate. 相似文献
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Despite 6 decades of research, only 3 drugs have been approved for astrocytomas, the most common malignant primary brain tumors. However, clinical drug development is accelerating with the transition from empirical, cytotoxic therapy to precision, targeted medicine. Preclinical animal model studies are critical for prioritizing drug candidates for clinical development and, ultimately, for their regulatory approval. For decades, only murine models with established tumor cell lines were available for such studies. However, these poorly represent the genomic and biological properties of human astrocytomas, and their preclinical use fails to accurately predict efficacy in clinical trials. Newer models developed over the last 2 decades, including patient-derived xenografts, genetically engineered mice, and genetically engineered cells purified from human brains, more faithfully phenocopy the genomics and biology of human astrocytomas. Harnessing the unique benefits of these models will be required to identify drug targets, define combination therapies that circumvent inherent and acquired resistance mechanisms, and develop molecular biomarkers predictive of drug response and resistance. With increasing recognition of the molecular heterogeneity of astrocytomas, employing multiple, contemporary models in preclinical drug studies promises to increase the efficiency of drug development for specific, molecularly defined subsets of tumors. 相似文献