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991.
The pharmacokinetics of tasidotin (ILX651), a depsipeptide currently in phase II for the treatment of advanced solid tumors, and tasidotin-C-carboxylate, the main metabolite, were characterized in male nude mice implanted with LOX tumors, which are sensitive to tasidotin, or H460 tumors, which are resistant to tasidotin. The pharmacokinetics of tasidotin and its metabolites were characterized after single-dose administration of tasidotin (20 and 120 mg/kg), tasidotin-C-carboxylate (150 mg/kg), or tasidotin (53 mg/kg) in the presence and absence of Z-prolyl prolinal (5 mg/kg administered 1 hour prior to tasidotin administration), a competitive antagonist of prolyl oligopeptidase, the enzyme responsible for the metabolism of tasidotin to tasidotin-C-carboxylate. A secondary study was done comparing tumor growth in tasidotin-treated mice with implanted LOX tumors in the presence and absence of Z-prolyl-prolinal. After tasidotin administration, the pharmacokinetics of tasidotin and tasidotin-C-carboxylate were similar in plasma and tumors in LOX- and H460-implanted mice, indicating the resistance was not due to pharmacokinetic factors. Tumor carboxylate concentrations were much higher than in plasma after tasidotin administration. The metabolite appeared to contribute approximately 17% to 33% to the total exposure in LOX tumors and 20% to 49% in H460 tumors but <5% in plasma. Less than 5% of the administered tasidotin dose was converted to tasidotin-C-carboxylate, with no apparent differences between LOX- and H460-treated animals. The presence of Z-prolyl-prolinal decreased the amount of tasidotin converted to tasidotin-C-carboxylate from 5.5% to 0.90%, a reduction of almost 80%. After tasidotin-C-carboxylate administration, the half-life was on the order of minutes compared with hours when observed after tasidotin administration. Tasidotin-C-carboxylate elimination was not dependent on tasidotin pharmacokinetics, suggesting that the rate of efflux from cells into plasma was the rate-limiting step in its elimination. Tasidotin-C-carboxylate was also further metabolized to desprolyl-tasidotin-C-carboxylate, although the metabolite ratios were <10%. Pretreatment with Z-prolyl-prolinal completely abolished the antitumor activity of tasidotin, indicating that the metabolite is the main moiety responsible for activity and that, despite tasidotin itself having activity in vitro, tasidotin is acting mainly as a prodrug. 相似文献
992.
993.
994.
Apathy is a common problem observed in numerous neurologic, psychiatric, and other medical conditions. It is independent from other symptoms and has been associated with a variety of negative outcomes. However, little empirical research has been conducted on potential psychologic or pharmacologic treatments for apathy. The impact of several different medications has been investigated, but very few reports have used well-controlled study designs. At present, agents that potentiate dopamine release and/or delay dopamine reuptake in the central nervous system appear promising for use in apathy. Among these, atypical antipsychotics and methylphenidate have received the greatest attention, and both have been demonstrated to reduce apathy in several patient populations. These findings appear consistent with evidence supporting a role for frontal-subcortical circuitry abnormality in the etiology of apathy. Another class of medication that has been the subject of a larger number of investigations is the acetylcholinesterase inhibitors. These have been reported to reduce apathy in patients with dementia and individuals with traumatic brain injury. Several psychologic interventions have been assessed, largely in geriatric populations, but most have been the subject of only one or a very small number of studies. With this caveat, interventions that have shown promise include participation in discussion groups and cognitive stimulation. Despite some promising findings, further large-scale, well-controlled clinical trials of potentially helpful pharmacologic and psychologic interventions for apathy are essential before any firm recommendations can be made. In the interim, careful evaluation of possible psychosocial and biological contributors to apathy in any given patient is suggested, with treatment planning based accordingly. 相似文献
995.
Schweizer R Martin DD Haase M Roth J Trebar B Binder G Schwarze CP Ranke MB 《BONE》2007,41(5):875-881
BACKGROUND AND AIMS: Treatment with GH in short children has focused on height development. Little is known about the concomitant changes in muscle mass, bone structure and bone strength. METHODS: Muscle area as well as parameters of bone architecture (bone mineral content, BMC; volumetric cortical density, total bone area, TBA; cortical area, cortical thickness, CT; and marrow area) were measured by means of pQCT (Stratec) at 65% of the proximal length of the forearm. The strength-strain index (SSI) was calculated as an indicator of bone strength. RESULTS: Prepubertal children with GHD (mean values: age; 7.2 years; height SDS=-2.9 SDS; GH dose: 30 microg/kg/d) were followed at 0, 6, 12 (n=74) and 24 (n=55) months. Prepubertal children with SGA (mean values: age: 7.1 years; height SDS=-3.4 SDS; GH dose: 55 mug/kg/d) were followed at 0, 6, 12 (n=47) and 24 (n=35) months. Both groups showed a similar increase in height. At GH start, muscle mass and bone characteristics were lower than normal but similar in SGA vs. GHD. Muscle area (mean values, SDS) increased from -3.0 to -1.5 in SGA and from -2.4 to -1.0 in GHD. Bone geometry changed in a biphasic mode, with an increase in total bone area and lowering of bone mineral content (BMC) during the first 12 months, followed by an increase of BMC and CT thereafter. SSI (mean values, mm(3)) improved from 78 to 114 in GHD and from 62 to 101 in SGA after 24 months on GH. The increment in terms of SDS did not reach significance in SGA. SSI correlated positively with muscle area before and during GH treatment. CONCLUSIONS: Bone strength and muscle mass are impaired in prepubertal children with GHD and SGA. Exogenous GH can indirectly improve bone structure and strength by inducing an increase in muscle mass. Our findings support the assumption that, in SGA, there is impaired tissue responsiveness to GH. 相似文献
996.
Kasibhatla S Baichwal V Cai SX Roth B Skvortsova I Skvortsov S Lukas P English NM Sirisoma N Drewe J Pervin A Tseng B Carlson RO Pleiman CM 《Cancer research》2007,67(12):5865-5871
A novel series of 4-arylaminoquinazolines were identified from a cell-based screening assay as potent apoptosis inducers. Through structure-activity relationship studies, MPC-6827 and its close structural analogue, MPI-0441138, were discovered as proapoptotic molecules and mitotic inhibitors with potencies at low nanomolar concentrations in multiple tumor cell lines. Photoaffinity and radiolabeled analogues of MPC-6827 were found to bind a 55-kDa protein, and this binding was competed by MPC-6827, paclitaxel, and colchicine, but not vinblastine. MPC-6827 effectively inhibited the polymerization of tubulin in vitro, competed with colchicine binding, and disrupted the formation of microtubules in a variety of tumor cell lines, which together showed the molecular target as tubulin. Treatment of MCF-7 breast carcinoma or Jurkat leukemia cells with MPC-6827 led to pronounced G2-M cell cycle arrest followed by apoptosis. Apoptosis, as determined by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay, was preceded by loss of mitochondrial membrane potential, cytochrome c translocation from mitochondria to nuclei, activation of caspase-3, and cleavage of poly(ADP-ribose) polymerase. MPC-6827 was equipotent in an in vitro growth inhibition assay in several cancer cell lines regardless of the expression levels of the multidrug resistance ABC transporters MDR-1 (Pgp-1), MRP-1, and BCRP-1. In B16-F1 allografts and in OVCAR-3, MIAPaCa-2, MCF-7, HT-29, MDA-MB-435, and MX-1 xenografts, statistically significant tumor growth inhibition was observed with MPC-6827. These studies show that MPC-6827 is a microtubule-disrupting agent with potent and broad-spectrum in vitro and in vivo cytotoxic activities and, therefore, MPC-6827 is a promising candidate for development as a novel therapeutic for multiple cancer types. 相似文献
997.
Ohtani S Iwamaru A Deng W Ueda K Wu G Jayachandran G Kondo S Atkinson EN Minna JD Roth JA Ji L 《Cancer research》2007,67(13):6293-6303
101F6 is a candidate tumor suppressor gene harbored on chromosome 3p21.3, a region with frequent and early allele loss and genetic alterations in many human cancers. We previously showed that enforced expression of wild-type 101F6 by adenoviral vector-mediated gene transfer significantly inhibited tumor cell growth in 3p21.3-deficient non-small cell lung cancer (NSCLC) cells in vitro and in vivo. The molecular mechanism of 101F6-mediated tumor suppression is largely unknown. A computer-aided structural and functional model predicts the 101F6 protein to be a member of the cytochrome b561 protein family that is involved in the regeneration of the antioxidant ascorbate. 101F6 protein is expressed in normal lung bronchial epithelial cells and fibroblasts but is lost in most lung cancers. Treatment with 101F6 nanoparticle-mediated gene transfer in combination with a subpharmacologic dose (200-500 micromol/L) of ascorbate synergistically and selectively inhibited lung cancer cell growth in vitro. Systemic injection of 101F6 nanoparticles plus the i.p. injection of ascorbate synergistically inhibited both tumor formation and growth in human NSCLC H322 orthotopic lung cancer mouse models (P<0.001). Furthermore, exogenous expression of 101F6 enhanced intracellular uptake of ascorbate, leading to an accumulation of cytotoxic H(2)O(2) and a synergistic killing of tumor cells through caspase-independent apoptotic and autophagic pathways. The antitumor synergism showed by the combination treatment with systemic administration of 101F6 nanoparticles and ascorbate on lung cancer offers an attractive therapeutic strategy for future clinical trials in cancer prevention and treatment. 相似文献
998.
Although seborrheic keratoses of the vulva are described in textbooks, to our knowledge, inverted follicular keratosis has not been reported. A 27-year-old woman underwent an excisional biopsy for a small lesion of the left labium majus. Squamous cell carcinoma was considered in the clinical differential diagnosis. The initial pathologic diagnosis suggested squamous cell carcinoma in situ, and the consultation diagnosis was superficially invasive squamous cell carcinoma. On pathologic examination, a symmetrical, endophytic, epithelial tumor was observed consisting of a proliferation of basaloid cells with many areas of reactive squamous cells showing numerous squamous eddies, focal reactive nuclear atypia, and occasional mitotic figures. After the pathologic diagnosis of inverted follicular keratosis was made, a history of close perineal shaving and total body tanning was obtained. Because inverted follicular keratosis is postulated to be related to follicular injury, it is likely that the trauma of close shaving is a significant etiologic factor. There is less evidence that ultraviolet ray exposure is of etiologic importance. 相似文献
999.
J J Roth J J Sung M S Granick M P Solomon M T Longaker V L Rothman R F Nicosia G P Tuszynski 《Annals of plastic surgery》1999,42(5):553-563
Thrombospondin 1 (TSP-1), an adhesive glycoprotein, plays an important role in platelet adhesion, inflammation, cell-cell interaction, and angiogenesis. TSP-1 is expressed by endothelial cells, fibroblasts, and macrophages. The unique cysteine-serinevaline-threonine-cysteine-glycine (CSVTCG) binding domain of TSP-1 also plays an important role in cell binding and modulation of cellular processes. The purpose of this study was to evaluate histologically and quantitatively TSP-1 and its CSVTCG receptor in fetal skin wounds over time. Pregnant ewes underwent laparotomy and hysterotomy. At 65 days gestation (term, 145 days), incisional and excisional wounds were created on the fetal back in a similar position on each animal. The uterus and laparotomy were closed. The wounds were harvested on days 1, 3, 7, 21, and 28. Expression of TSP-1 and its CSVTCG receptor was evaluated immunohistochemically and quantitated by computer image analysis in units of absorbance. Immunoglobulin G (negative) controls were performed and subtracted from the TSP-1 sample to eliminate background absorbance readings. Serum (negative) control was used for the CSVTCG receptor. Platelet concentrates were used as the positive control: TSP-1, 63.43; CSVTCG, 58.72. Results are expressed as absorbance+/-SEM. Results of TSP-1 are as follows: day 1, 33.02+/-0.26; day 3, 22.21+/-0.14; day 7, 20.56+/-1.07; day 21, 7.76+/-0.40; and day 28, 5.99+/-0.03. TSP-1 displays an early peak during fetal skin repair, followed by a steep decrease over the viewed time period. Results of CSVTCG receptor are as follows: day 1, 26.19+/-2.43; day 3, 30.20+/-0.64; day 7, 24.56+/-0.80; day 21, 24.70+/-0.40; and day 28, 21.65+/-1.39. Thus, CSVTCG receptor displays a slowed decrease in expression over time during fetal repair. No significant differences were noted between incisional and excisional samples. Temporal and histological differences exist in the localization and expression of TSP-1 and its CSVTCG receptor during fetal wound repair. TSP-1 is upregulated in tissues early. This corresponds with the known role of TSP-1 in cell-cell interaction, including potentiation of growth factor activity. TSP-1 also modulates matrix, allowing scar-free provisional matrix in the earlier stages of repair deposited by platelets. The potentiation of cell-associated protease activity by TSP-1 can support tissue and matrix turnover. This activity of TSP-1 may contribute to the formation of a scarless wound. TSP-1 destabilizes extracellular matrix contacts, and facilitates mitosis and migration. The action of TSP-1 as an adhesive protein allows numerous different cells to adhere to the extracellular membrane. CSVTCG receptor expression decreases during fetal repair as the cells migrate to the epithelial surface, suggesting a significant role of the CSVTCG receptor in keratinocytic maturation, differentiation, and epithelization. 相似文献
1000.
F Oeffner T Korn H Roth A Ziegler A Hinney H Goldschmidt W Siegfried J Hebebrand K H Grzeschik 《International journal of obesity (2005)》2001,25(6):767-769
BACKGROUND: NDN, which codes for the human necdin protein, is a candidate gene for Prader-Willi syndrome (PWS). One feature of this neurogenetic disorder is hyperphagia resulting in extreme obesity observed later in development. OBJECTIVE AND DESIGN: In this study we have used single-strand conformation polymorphism (SSCP) analysis to identify sequence variants at the human necdin gene. Furthermore we tested whether these variants were associated with obesity in extremely obese German children and adolescents. RESULTS: Two gene variants could be identified: a g.1352T-->C polymorphism in the putative promotor region and a silent g.2311C-->T polymorphism in the coding region. Genotype and allele frequency distribution of both of the polymorphisms were not significantly different between lower and higher body mass index (BMI) subjects. CONCLUSIONS: Hence, it is unlikely that these polymorphisms play a major role in the emergence of juvenile onset human obesity. 相似文献