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921.
922.
Balse-Srinivasan P Grieco P Cai M Trivedi D Hruby VJ 《Journal of medicinal chemistry》2003,46(17):3728-3733
It has been shown by extensive studies that alpha-MSH bioactivity is critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, however with poor selectivity for the human MC3R-MC5R. The structure-activity relationships study here is aimed at identifying lead structures or templates of this core sequence by the use of different conformational constraints that might impart changes in its topography and thus promote differences in potency and selectivity at these receptors. Our peptide library consists of a novel series of cyclic alpha-MSH analogues that have disulfide bridges between Cys or Cys-like residues at positions 4 and 10, giving rise to 23-membered rings fused at the C-terminal end with the C-terminal fragment of beta-MSH (Pro-Pro-Lys-Asp). While such constraints of the peptide backbone with disulfide bridges of different chirality affect potency and selectivity at these receptors, further changes in the hydrophobicity at position 7 with either a D-Phe or D-Nal(2') and replacement of a His with a Pro in position 6 cause additional effects. Thus, the most interesting lead compounds that emerged from this study are (1) compound 5, Ac-c[Cys-Glu-His-D-Phe-Arg-Trp-D-Cys]-Pro-Pro-Lys-Asp-NH(2) (IC(50) = 10 nM), which is the first potent and highly selective antagonist ligand for the hMC5R (560-fold vs the MC3R and 1000-fold vs the MC4R); (2) compound 7, Ac-c[Cys-Glu-Pro-D-Nal(2')-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH(2) (IC(50) = 31 nM), which is a highly selective antagonist analogue for the MC3R (560-fold vs the hMC4R and about 3000-fold vs the hMC5R; and (3) compound 9, Ac-c[Pen-Glu-His-D-Nal(2')-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH(2) (IC(50) = 3 nM), which is more potent than 7 at the MC3R but not as selective. 相似文献
923.
Ying J Gu X Cai M Dedek M Vagner J Trivedi DB Hruby VJ 《Journal of medicinal chemistry》2006,49(23):6888-6896
Intensive efforts have been made to develop potent and selective ligands for certain human melanocortin receptors as possible treatments for obesity and sexual dysfunction due to the role of these receptors in feeding behavior, energy homeostasis, sexual function, etc. A number of novel alpha-MSH analogues were designed and synthesized primarily on the basis of our previous MTII NMR structure. In these peptide analogues, a disulfide or lactam bridge between residues at positions 5 and 8 was used as a conformational constraint to enhance the beta-turn spanning His6 and D-Phe7, while the pharmacophore group in Arg8 was mimicked via Nalpha-alkylation of residues 8 or 9 with the guanidinylbutyl group. Biological assays for binding affinities and adenylate cyclase activities for the hMC1R, hMC3R, hMC4R, and hMC5R showed that three analogues have good binding affinity for the hMC4R (0.7-4.1 nM), but have no binding affinity up to 10 microM at the other three melanocortin receptors. Interestingly, the three hMC4R selective analogues display only 50% binding efficiency, suggesting there is allosteric modulation of the melanocortin-4 receptor. These analogues were found to act as antagonists of the hMC4R. This result represents a discovery of very selective peptide-based antagonists for the hMC4R. The high selectivity may be due to the strong conformational constraint via ring contraction as compared to MTII, and the rigid conformation preferred by these new ligands allows them to recognize only the hMC4R, but not to activate the second messenger. The MTII NMR structure-based design thus not only examined the structural model of melanocortin ligands, but also yielded new biologically unique alpha-MSH analogues. 相似文献
924.
Lee NY de Arruda FF Puri DR Wolden SL Narayana A Mechalakos J Venkatraman ES Kraus D Shaha A Shah JP Pfister DG Zelefsky MJ 《International journal of radiation oncology, biology, physics》2006,66(4):966-974
PURPOSE: The aim of this study was to compare toxicity/efficacy of conventional radiotherapy using delayed accelerated concomitant boost radiotherapy (CBRT) vs. intensity-modulated radiotherapy (IMRT) in the setting of concurrent chemotherapy (CT) for locally advanced oropharyngeal carcinoma. METHODS AND MATERIALS: Between September 1998 and June 2004, a total of 293 consecutive patients were treated at our institution for cancer of the oropharynx. Of these, 112 had Stage III/IV disease and squamous cell histology. In all, 41 were treated with IMRT/CT and 71 were treated with CBRT/CT, both to a median dose of 70 Gy. Most common CT was a planned two cycles given every 3 to 4 weeks of cisplatin, 100 mg/m2 i.v., but an additional cycle was given to IMRT patients when possible. Both groups were well-matched for all prognostic factors. RESULTS: Median follow-up was 46 months (range, 3-93 months) for the CBRT patients and 31 months (range, 20-64 months) for the IMRT group. Three-year actuarial local-progression-free, regional-progression-free, locoregional progression-free, distant-metastases-free, disease-free, and overall survival rates were 85% vs. 95% (p = 0.17), 95% vs. 94% (p = 0.90), 82% vs. 92% (p = 0.18), 85% vs. 86% (p = 0.78), 76% vs. 82% (p = 0.57), and 81% vs. 91% (p = 0.10) for CBRT and IMRT patients, respectively. Three patients died of treatment-related toxicity in the CBRT group vs. none undergoing IMRT. At 2 years, 4% IMRT patients vs. 21% CBRT patients were dependent on percutaneous endoscopic gastrostomy (p = 0.02). Among those who had > or =20 months follow-up, there was a significant difference in Grade > or =2 xerostomia as defined by the criteria of the Radiation Therapy and Oncology Group, 67% vs. 12% (p = 0.02), in the CBRT vs. IMRT arm. CONCLUSION: In the setting of CT for locally advanced oropharyngeal carcinoma, IMRT results in lower toxicity and similar treatment outcomes when compared with CBRT. 相似文献
925.
Pandey U Sarma HD Ingle AD Kulloli BS Samuel G Venkatesh M 《Cancer biotherapy & radiopharmaceuticals》2006,21(3):257-262
Radioactive bandages incorporating 32P, a high-energy beta- emitter, were prepared with an aim to have a radiation source that can be used for the treatment of superficial tumors. 32P-Chromic phosphate particles were prepared and filtered through Millipore filters. Filter incorporating 32P activity was immobilized between nitrocellulose membranes and placed on an adhesive bandage. There was no leakage of radioactivity from the bandage when tested in saline. Efficacy of the radioactive bandage for treatment of superficial tumors was tested in melanoma-bearing C57BL/6 mice. A single dose of treatment with 74 MBq 32P bandage resulted in tumor growth delay, whereas multiple dose treatment with 74 MBq 32P bandage at twice-weekly intervals resulted in complete tumor regression when treatment was started, when the tumor was merely palpable. Histology sections from the treated animals showed absence of tumor. 相似文献
926.
Mruthyunjaya P Wirostko WJ Chandrashekhar R Stinnett S Lai JC Deramo V Tang J Dev S Postel EA Connor TB Fekrat S 《Retina (Philadelphia, Pa.)》2006,26(3):285-291
PURPOSE: To describe the clinical features of persons who developed central retinal vein occlusion (CVO) while being treated with Coumadin for chronic anticoagulation. METHODS: In a retrospective, comparative, noninterventional case series of patients diagnosed with CVO while being treated with Coumadin as a systemic anticoagulant, visual and anatomical outcomes were compared with those for a cohort of patients diagnosed with CVO who were not treated with any systemic anticoagulation. RESULTS: Fourteen eyes of 14 patients treated with Coumadin were identified. At presentation, the median international normalization ratio (INR) was 2.20 (range, 1.3-5.0). Eight patients (57%) had a therapeutic INR at the time of CVO. Their visual acuity and perfusion status were similar to those of patients with subtherapeutic INR. At the last follow-up (median, 16 months), visual acuity and perfusion status of the group of 14 eyes were similar to baseline findings (P = 0.62). Clinical features and outcomes were similar to those for a cohort of patients with CVO who were not being treated with systemic anticoagulation. CONCLUSION: CVO can occur in patients being treated with Coumadin for systemic anticoagulation. Final visual acuity and perfusion status were similar to those in a cohort of patients with CVO who were not treated with Coumadin. Although visual acuity is unaffected, ensuring that the INR for these patients remains in the therapeutic range may be important to help prevent secondary systemic thrombotic and embolic disease. 相似文献
927.
Dev KK 《IDrugs : the investigational drugs journal》2006,9(4):279-282
RNA interference (RNAi) is a biological process that controls gene silencing in all living cells. Targeting the RNAi system represents a novel therapeutic strategy that has the ability to intercede with multiple disease-related genes and so target many human diseases. Recently, the design of small interfering RNA (siRNA)-selective compounds has become more straightforward because of the significant progress made in predictive modeling. Exciting new data show that siRNA blocks gene function in vivo, suggesting that it has potential as a therapeutic approach for humans. This article highlights recent advances in siRNA research and discusses the aims of the pharmaceutical and biotechnology industries to progress siRNA compounds into the clinical. In the fight against disease, the use of RNAi is a powerful new tactic that adds to the arsenal of small-molecule inhibitors and antibody-blocking approaches. 相似文献
928.
Angiogenesis--a new target for future therapy 总被引:30,自引:0,他引:30
929.
Effect of leaf extract of Seabuckthorn on lipopolysaccharide induced inflammatory response in murine macrophages 总被引:1,自引:0,他引:1
Padwad Y Ganju L Jain M Chanda S Karan D Kumar Banerjee P Chand Sawhney R 《International immunopharmacology》2006,6(1):46-52
Nitric oxide (NO) is synthesized in large quantities by activated inflammatory cells and has been demonstrated to be involved in the pathogenesis of acute and chronic inflammatory conditions. Seabuckthorn (SBT) has been used in traditional medicine systems for the treatment of various diseases like cardiovascular, pain relief, oral inflammation and promotion of tissue regeneration. The present study focuses on the effects of SBT leaf extract on NO production induced by lipopolysaccharide (LPS) in the murine macrophage cell line RAW 264.7. In addition, cell viability, free radical-scavenging activity and inducible nitric oxide synthase (iNOS) expression were also evaluated. Seabuckthorn leaf extract significantly inhibited the enhanced production of NO induced by LPS in a dose dependent manner. Treatment with SBT did not reduce cell viability at any dose used. The extract showed significant scavenging of NO radicals released by the NO donor. Treatment of macrophages with SBT leaf extract also caused a significant inhibition of iNOS activation. These observations suggest that the inhibition of net NO production by SBT leaf extract may be due to its scavenging activity and/or its inhibitory effects on iNOS activation. The study suggests that SBT leaf extract has significant anti-inflammatory activity and has potential for the treatment of inflammatory diseases. 相似文献
930.