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Cotreau MM Stonis L Dykstra KH Gandhi T Gutierrez M Xu J Park Y Burghart PH Schwertschlag US 《Journal of clinical pharmacology》2002,42(2):157-165
ERA-923 is a new selective estrogen receptor modulator under clinical investigation for use in tamoxifen refractory metastatic breast cancer. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of once-daily oral ERA-923 (10-200 mg) for 28 days in healthy postmenopausal females. ERA-923 was well tolerated, and adverse events were mild and reversible. No clinically significant changes in laboratory values were found with ERA-923 versus placebo. ERA-923 appeared to undergo extensive metabolism and enterohepatic recirculation. In addition, pharmacokinetic analysis showed that a high-fat breakfast increased the extent of absorption. ERA-923-dosed subjects had no uterine or ovarian changes when evaluated with transvaginal ultrasound and compared to placebo subjects. Overall, ERA-923 was safe and well tolerated in postmenopausal women dosed for 28 days. 相似文献
23.
Byers HR Maheshwary S Amodeo DM Dykstra SG 《The Journal of investigative dermatology》2003,121(4):813-820
Cytoplasmic dynein is a microtubule-associated motor molecule involved in the retrograde transport of membrane-bound organelles. To determine whether the supranuclear melanin cap of transferred, phagocytosed melanosomes in keratinocytes is associated with cytoplasmic dynein, we performed immunofluorescent confocal microscopy on human keratinocytes in situ. We identified the intermediate chain of cytoplasmic dynein by immunoblotting and examined its distribution by confocal microscopy in relation to microtubules and melano-phagolysosomes in vitro. We also used antisense and sense oligonucleotides of the cytoplasmic dynein heavy chain 1 (Dyh1) and time-lapse and microscopy. The intermediate chain of cytoplasmic dynein was identified in extracts of human foreskin epidermis and in isolated human keratinocytes. The intermediate chain localized with the perinuclear melano-phagolysosomal aggregates in vitro and the supranuclear melanin cap in situ. Antisense oligonucleotides directed towards Dyh1 resulted in dispersal of the keratinocyte perinuclear melano-phagolysosomal aggregates after 24 to 48 h, whereas cells treated with diluent or sense oligonucleotides maintained tight perinuclear aggregates. Taken together, these findings indicate that in human keratinocytes, the retrograde microtubule motor cytoplasmic dynein mediates the perinuclear aggregation of phagocytosed melanosomes, participates in the formation of the supranuclear melanin cap or "microparasol" and serves as a mechanism to help protect the nucleus from ultraviolet-induced DNA damage. 相似文献
24.
BACKGROUND: Synthetic grafts have generally been found to exhibit lower survival rates and higher complication rates than native arteriovenous fistulae. We investigated whether survival of grafts relative to fistulae was better in facilities with a preference for grafts, hypothesizing that such facilities may place more grafts because grafts produced superior outcomes. METHODS: The study was based on a national U.S. sample of 133 hemodialysis facilities participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, observational study of dialysis treatment practices and outcomes. Vascular access preferences were ascertained from medical directors, nurse managers, and actual practice within each facility (% graft use among prevalent patients). Logistic regression was used to model the odds ratio (OR) of graft placement (vs. fistula) and Cox regression was used to model time from access creation to initial failure. RESULTS: Grafts were preferred by 21% of medical directors and 40% of nurse managers. Patients in facilities in which the medical director or nurse manager expressed a preference for grafts were more than twice as likely to have a graft than a fistula (AOR = 2.3, P < 0.01; reference group = facilities that did not prefer grafts), suggesting that facility preferences influence the type of access created. Overall, grafts were more prevalent than fistulae in dialysis facilities, but displayed a higher relative risk of failure (RR 1.33, P < 0.0001). However, the risk of graft versus fistula failure did not vary by expressed preference of the medical director: the relative risk of graft versus fistula failure was 1.39 in facilities in which the medical director preferred grafts and 1.39 in facilities in which the medical director preferred fistulae. Moreover, the relative risk of graft versus fistula failure was 1.57 in facilities that used more than the median percentage of grafts and 1.19 in facilities that used less than the median percentage of grafts. CONCLUSIONS: No evidence was found that graft outcomes are superior in facilities that prefer grafts to fistulae. The observed variation in vascular access practice patterns suggests opportunities for quality improvement if optimal practices can be defined. 相似文献
25.
A model system is described for the induction of renal calcium oxalate crystals with intraperitineal injections of sodium oxalate in rats. Early crystals are formed predominantly in cortical areas. Massive amounts of calcium are associated with this process, as demonstrated by potassium pyroantimonate staining. Actual crystal formation appears to be an involved process associated with calcium, oxalate, and cellular membranes. Although overt stone formation was not observed, we feel that the intimate involvement of membranes during crystal formation may be similar to that found in renal stones. 相似文献
26.
Carroll I Thomas JB Dykstra LA Granger AL Allen RM Howard JL Pollard GT Aceto MD Harris LS 《European journal of pharmacology》2004,501(1-3):111-119
Biological studies were conducted on (3R)-7-Hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), the first potent kappa-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (kappa)-opioid receptor agonist, enadoline, AD(50s) of 4.1 and 27.3, respectively, were obtained. A time-course study of JDTic versus enadoline indicated significant antagonist p.o. activity up to 28 days. In contrast, JDTic, s.c., failed to antagonize the analgesic effects of the selective MOP mu-opioid receptor agonist, sufentanil. In the squirrel monkey shock titration antinociception test, JDTic given intramuscularly (i.m.) shifted the trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide (U50,488) dose-effect curve to the right. In the U50,488-induced diuresis rat test, JDTic, s.c., suppressed diuretic activity with a greater potency than that of nor-binaltorphimine (nor-BNI). Thus, JDTic is a potent long- and orally acting selective kappa-opioid antagonist. 相似文献
27.
OBJECTIVE: The Hoechst 33342-effluxing side population (SP) of adult mouse bone marrow (BM) contains most of the hematopoietic stem cells (HSCs). Here we measured the HSC content of specific subsets of SP cells and then used a highly HSC-enriched fraction to investigate the effect of different growth factors on the initial rate of HSC proliferation in vitro and the accompanying maintenance (or loss) of HSCs in the first-division progeny. MATERIALS AND METHODS: Staining with Rhodamine-123 (Rho) was used to subfractionate lineage marker-negative (lin-) SP cells. Cells were assayed for HSCs by examining their ability to generate sustained (>4 months) multi-lineage lympho-myeloid clones in irradiated hosts. Cultures of single lin- Rho- SP cells were used to monitor growth factor effects on HSC proliferation and function. RESULTS: More than 40% of mice injected with single lin- Rho- SP cells showed long-term lympho-myeloid reconstitution. Some clones peaked within 8 weeks but others developed more slowly apparently unrelated to the pattern of lineage representation. 3/3 clones tested repopulated secondary mice. Either Steel factor+interleukin-11 (+/- flt3-ligand) or Steel factor+thrombopoietin stimulated at least 75% of single lin- Rho- SP cells to divide in vitro with the same synchronous kinetics. However, in the first cocktail, the frequency of HSCs among the first-division doublets was preserved but in the latter it was greatly diminished. CONCLUSION: Exogenous growth factors can differentially affect the ability of HSCs to execute a self-renewal division within a single cell cycle even when the kinetics of proliferation are the same. 相似文献
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29.
There is a growing need for novel treatments of refractory arthritis joint pain as the aging population is expanding with many patients who are unable to undergo joint replacement surgery. We are studying the efficacy and safety of intra-articular injection of Botulinum Toxin Type A (IA-BoNT/A) into joints with arthritis pain. In several small open label studies, initial effects for IA-BoNT/A were encouraging because two thirds of the patients had more than 50% reduction in joint pain severity that was associated with a significant improvement in function. Importantly no serious adverse effects of IA-BoN/A were noted. Based on these initial results, we have completed two pilot randomized controlled trials in painful shoulder joints and painful knee joints. In the shoulder study, IA-BoNT/A produced a significant decrease in shoulder pain severity at one month (6.8-4.4 on VAS, p = .002) that was also significantly better than the non-significant change after IA-Saline placebo (1.6 unit difference favoring IA-BoNT/A, p = .014). In the knee study IA-BoNT/A produced a significant 48% decrease in McGill Total Pain Score at one month (p = .01 1) that was still significant at 3 mo after injection (p = .002). There was a strong placebo response in one third of those but the decrease in pain severity was not significant. We are currently conducting a RCT of IA-BoNT/A for painful prosthetic knee joints. Based on these initial studies of IA-BoNT/A we have gone ‘back to the bench’ to standardize a menu of pain behaviors for mice with acute inflammatory arthritis pain and chronic inflammatory arthritis pain. IA-BoNT/A significantly reduced arthritis joint tenderness (evoked pain score) in acute and chronic inflammatory arthritis and normalized impaired spontaneous wheel running in mice with chronic inflammatory arthritis but not in those with acute inflammatory arthritis. With these models of arthritis and pain behavior methods we will be able to screen potential intra-articular analgesics, define dose response curves and injection schedule, and study the relationships of articular pain and loss of function. 相似文献
30.
The multichain immune recognition receptors (MIRRs), including the T cell and B cell antigen receptors and the high affinity receptor for IgE, play an important role in immune cell signaling. The MIRRs have no inherent kinase activity, but rather associate with members of the Src-family kinases to initiate signaling. Although a great deal is understood about the biochemical cascades triggered by MIRRs, the mechanism by which signaling is initiated was not known. The evidence now indicates that the Src-family kinases are concentrated in cholesterol- and sphingolipid-rich membrane microdomains, termed lipid rafts, that exclude the MIRRs. Upon ligand-induced crosslinking the MIRRs translocate into rafts where they are phosphorylated. The MIRRs subsequently form highly ordered, polarized structures termed immunological synapses that provide for prolonged signaling. An understanding of the biochemical composition of rafts and synapses and the mechanisms by which these form should lend insight into the regulation of immune cell activation. 相似文献