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41.
P D Williams M G Bock R D Tung V M Garsky D S Perlow J M Erb G F Lundell N P Gould W L Whitter J B Hoffman 《Journal of medicinal chemistry》1992,35(21):3905-3918
A new structural class of cyclic hexapeptide oxytocin antagonists derived from Streptomyces silvensis and typified by L-365,209 (cyclo-[L-prolyl1-D-phenylalanyl2-L- isoleucyl3-D-dehydropiperazyl4-L-dehydroperazyl5-D-(N- methyl)phenylalanyl6]) was recently reported. In this paper we further delineate the structure-activity profile for this new class by systematic study of L-365,209 analogs obtained by total synthesis. The optimal combination of cyclic amino acid ring sizes at positions 1, 4, and 5 and the role of the N-alkyl substituent at position 6 was elucidated. The lipophilic amino acids at positions 2 and 3 and the unusual amino acid D-dehydropiperazic acid at position 4 were found to be the most critical residues for obtaining good oxytocin receptor affinity. Analogs containing a basic side chain at the less critical 5- and 6-positions maintained good receptor affinity and also had useful levels of water solubility for intravenous formulation. By combining potency- and solubility-enhancing substitutions, several analogs were identified that have the desired combination of properties in vitro (22, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L-pipeco lyl-D- histidyl]; 25, cyclo-[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L -pipecolyl-D- histidyl]; 26, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-dehydropiperazyl-L-++ pipecolyl-D-histidyl]; 33, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L- piperazinylcarboxy-D-(N-methyl)phenylalanyl]; 34, cyclo-[L-prolyl-D-phenylalanyl-L-isoleucyl-D-dehydropiperazyl-L-or nithyl- D-(N-methyl)phenylalanyl]). In general, this class exhibited good selectivity for binding to the oxytocin receptor versus the arginine vasopressin V1a and V2 receptor subtypes, although increased V2 receptor affinity was observed in one case (32, cyclo[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L- lysyl-D-(N- methyl)phenylalanyl]). Unexpectedly, compound 33 was found to stimulate contractions of the isolated rat uterus via activation of the uterine bradykinin receptor. Compounds 22, 25, 26, 33, and 34 were found to be potent antagonists of oxytocin-stimulated contraction of the rat uterus in vitro and in vivo. Compounds 22 and 25 were additionally characterized as potent antagonists of oxytocin-stimulated uterine contractions in the near-term pregnant rhesus monkey. These studies thus demonstrate the selectivity and efficacy of certain members of this novel class of antagonists and suggest their use as pharmacological tools in further defining the role of oxytocin in both term and preterm labor. 相似文献
42.
A recent study by C.F. Burant et al. (13) demonstrates that GLUT5 is a high-affinity fructose transporter with a much lower capacity to transport glucose. To characterize the potential role of GLUT5 in fructose and glucose transport in insulin-sensitive tissues, we investigated the distribution and insulin-stimulated translocation of the GLUT5 protein in human tissues by immunoblotting with an antibody to the COOH-terminus of the human GLUT5 sequence. GLUT5 was detected in postnuclear membranes from the small intestine, kidney, heart, four different skeletal muscle groups, and the brain, and in plasma membranes from adipocytes. Cytochalasin-B photolabeled a 53,000-M(r) protein in small intestine membranes that was immunoprecipitated by the GLUT5 antibody; labeling was inhibited by D- but not L-glucose. N-glycanase treatment resulted in a band of 45,000 M(r) in all tissues. Plasma membranes were prepared from isolated adipocytes from 5 nonobese and 4 obese subjects. Incubation of adipocytes from either group with 7 nM insulin did not recruit GLUT5 to the plasma membrane, in spite of a 54% insulin-stimulated increase in GLUT4 in nonobese subjects. Thus, GLUT5 appears to be a constitutive sugar transporter that is expressed in many tissues. Further studies are needed to define its overall contribution to fructose and glucose transport in insulin-responsive tissues and brain. 相似文献
43.
Kambiz Dowlatshahi M. D. Ming Fan M. D. Mahsa Shekarloo B. A. Kenneth J. Bloom M. D. Victor E. Gould M. D. 《The breast journal》1996,2(5):304-311
Abstract: Coagulation leading to fibrosis of mammo-graphically detected breast cancers by interstitial laser therapy was tested as an alternative to surgical removal. Availability of computerized stereotaxic digital imaging allows the precise placement of laser and thermal needles into the target tumor and its controlled ablation by heat. The methodology of interstitial laser therapy (ILT), evolution of the subsequently removed tumors, and their histologic appearance are outlined.
Eight patients with mammographically well-defined tumors were selected. Definitive diagnosis and receptor evaluation were made on core biopsies. Under local anesthesia, stereotaxically guided diode laser energy at 5–10 w was delivered via a 400 xm fiber in a 19-gauge needle placed into the center of the tumor until the peripheral temperature exceeded 60°C. Patients experienced transient pain and pyrexia. Subsequent to ILT, seven invasive carcinomas were excised while one case of multiple papillomas was kept under surveillance. Histologic study revealed central necrosis but some peripheral residual tumor in the first five cases. In the last two, central necrosis surrounded by concentrically arranged, recognizable but severely injured, focally "windswept" and "ghostlike" tumor and granulation tissue were noted. The multiple papillomas showed radiologic shrinkage at 5 months and extensive fibrosis on needle biopsy.
ILT is an attractive new method of treating small, well-defined breast tumors and offers a potentially significant alternative to surgical removal; further exploration is warranted. 相似文献
Eight patients with mammographically well-defined tumors were selected. Definitive diagnosis and receptor evaluation were made on core biopsies. Under local anesthesia, stereotaxically guided diode laser energy at 5–10 w was delivered via a 400 xm fiber in a 19-gauge needle placed into the center of the tumor until the peripheral temperature exceeded 60°C. Patients experienced transient pain and pyrexia. Subsequent to ILT, seven invasive carcinomas were excised while one case of multiple papillomas was kept under surveillance. Histologic study revealed central necrosis but some peripheral residual tumor in the first five cases. In the last two, central necrosis surrounded by concentrically arranged, recognizable but severely injured, focally "windswept" and "ghostlike" tumor and granulation tissue were noted. The multiple papillomas showed radiologic shrinkage at 5 months and extensive fibrosis on needle biopsy.
ILT is an attractive new method of treating small, well-defined breast tumors and offers a potentially significant alternative to surgical removal; further exploration is warranted. 相似文献
44.
Nasal response of rhinitic and non-rhinitic subjects to histamine and methacholine: a comparative study. 总被引:2,自引:1,他引:1
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The nasal responses to provocation with histamine and methacholine were compared in 20 subjects with and 20 without rhinitis. Two variables were measured: nasal airways resistance and the development of rhinorrhoea. Histamine had a greater effect than methacholine in increasing nasal airways resistance while the converse was true for rhinorrhoea. Rhinitic subjects had a significantly greater response to histamine induced changes in nasal airways resistance (p less than 0.05), rhinorrhoea (p less than 0.05) and methacholine induced rhinorrhoea (p less than 0.01) than those without rhinitis. No significant differences were found between the two groups in methacholine induced changes in nasal airways resistance. The findings show that, like the lower airways of patients with asthma, the nasal mucosa of rhinitic subjects shows a greater responsiveness to non-specific agonists than that of non-rhinitic subjects. 相似文献
45.
F M MacKenzie S V Smith K E Milne K Griffiths J Legge I M Gould 《Journal of cystic fibrosis》2004,3(3):151-157
BACKGROUND: Over a 19-month pilot phase, 93 multiply resistant Gram-negative isolates from Scottish cystic fibrosis patients were sent to a referral laboratory for further investigation. METHODS: In common with the referring diagnostic laboratories, disc diffusion testing was carried out. Antibiotic susceptibility testing was also established by MIC methodology. NCCLS methods were used throughout. Twenty antibiotics were tested. RESULTS: Comparing disc diffusion results against MIC results, there were 167 (14%) major errors. By MIC, Pseudomonas aeruginosa (n = 59), Stenotrophomonas maltophilia (n = 16), Burkholderia cepacia (n = 10) and Alcaligenes xylosoxidans (n = 7) were susceptible to 18%, 11%, 4% and 35% of the antibiotics tested, respectively. Colistin and tobramycin were the most active agents against P. aeruginosa with 60% and 49%, respectively, testing susceptible. Minocycline and gentamicin were most active against S. maltophilia with 58% and 18%, respectively, testing susceptible. B. cepacia were most susceptible to co-trimoxazole (10%) and ciprofloxacin (10%). Five and six of the seven A. xylosoxidans isolates were susceptible to piperacillin and imipenem, respectively. CONCLUSIONS: Improved methods for susceptibility testing of such clinical isolates need to be employed in routine diagnostic laboratories. Levels of resistance in referred isolates were very high and similar to those described in the USA. 相似文献
46.
47.
Bhattacharya B Sariya D Reddy VB Kluskens L Gould VE Gattuso P 《Diagnostic cytopathology》2002,26(6):384-386
A 4(1/2)-yr-old female presented with right-sided pleural effusion and a retroperitoneal mass. Cytologic analysis of the pleural fluid yielded malignant small round blue cells, which were noncohesive, 3-4 times the size of lymphocytes. The malignant cells had hyperchromatic, pleomorphic nuclei with moderate amounts of vacuolated cytoplasm. A few fiber-shaped cells were also seen. Immunostains for desmin, muscle-specific actin were positive; ultrastructural findings of thick and thin actin-myosin filaments confirmed the diagnosis of embryonal rhabdomyosarcoma. This case illustrates the importance of performing appropriate immunohistochemical stains and ultrastructural studies on cytological material to arrive at a definitive diagnosis. 相似文献
48.
Emotional abuse, self-blame, and self-silencing in women with irritable bowel syndrome 总被引:5,自引:0,他引:5
Ali A Toner BB Stuckless N Gallop R Diamant NE Gould MI Vidins EI 《Psychosomatic medicine》2000,62(1):76-82
OBJECTIVE: The purpose of this study was to investigate the presence of emotional abuse and two psychosocial constructs (self-blame and self-silencing) in a sample of women diagnosed with irritable bowel syndrome (IBS) relative to a comparison sample of women diagnosed with inflammatory bowel disease (IBD). METHODS: Women diagnosed with IBS (N = 25) were compared with women diagnosed with IBD (N = 25) on measures of history of abuse, self-blame, and self-silencing. RESULTS: It was found that women in the IBS sample scored significantly higher on emotional abuse, self-blame, and self-silencing than did women in the IBD sample. These three variables were also found to be significantly intercorrelated in both the IBS and IBD samples. Finally, emotional abuse was significantly higher in IBS patients than in IBD patients beyond the differences accounted for by physical and/or sexual abuse history. CONCLUSIONS: These findings empirically demonstrate an association between IBS and emotional abuse, as well as a possible connection with psychosocial variables, that may mediate the connection between emotional abuse and functional bowel symptoms. We suggest that these variables be further evaluated in the context of clinically relevant research on IBS. 相似文献
49.
50.
In order to establish referential hematological parameters, blood samples were taken from 100 healthy specimens of the Argentine
tegu lizard (Tupinambis merianae) by means of venipuncture of ventral coccigeal vein. The determination of red blood cells, leukocyte and thrombocyte count,
hematocrit, hemoglobin concentration, hematometric index and differential leukocyte count were performed, and compared with
other saurian species. No statistically significant changes were observed as function as sex and age (p > 0.01). During winter, high values of red blood cell counts, hematocrit and hemoglobin were observed (p < 0.01), while in summer significantly increased leukocyte and thrombocyte counts were observed (p < 0.01). The differential leukocyte counts were not affected by the studied factors. 相似文献