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61.
62.
Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive pathogens 总被引:5,自引:0,他引:5
Barbachyn MR Cleek GJ Dolak LA Garmon SA Morris J Seest EP Thomas RC Toops DS Watt W Wishka DG Ford CW Zurenko GE Hamel JC Schaadt RD Stapert D Yagi BH Adams WJ Friis JM Slatter JG Sams JP Oien NL Zaya MJ Wienkers LC Wynalda MA 《Journal of medicinal chemistry》2003,46(2):284-302
A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid. 相似文献
63.
OBJECTIVE: This study examined the relationship between the characteristics of inpatients and staff members' emotional reactions to the patients, particularly the extent to which the reactions were related to patients' aggressive or suicidal behavior. METHODS: The Feeling Word Checklist-58 was used to measure staff members' feelings. Two positive and five negative feeling dimensions were examined: important, confident, rejected, on guard, bored, overwhelmed, and inadequate. A total of 253 staff members from a wide variety of psychiatric wards at a university-affiliated hospital in Oslo, Norway, completed a total of 2473 checklists about their emotional reactions to 207 patients. For each patient, a member of the research team used information from ward staff who knew the patient to complete a Social Dysfunction and Aggression Scale measuring whether the patient had been aggressive (outward aggression) or suicidal (inward aggression). RESULTS: Staff reported positive feelings about patients much more frequently than negative feelings. Multiple regression analysis revealed that patient characteristics explained much more of the variance in negative feelings than in positive feelings. Outward aggression explained an average of 22 percent of the variance in scores on the five negative dimensions. Inward aggression explained an average of 12 percent more of the variance in scores on the five negative dimensions. Gender, age, amount of medication, and diagnosis (psychotic or not psychotic) explained only a small proportion of the variance in feeling scores. CONCLUSIONS: Even though the level of negative feelings toward patients was low, patients' aggressive and suicidal behavior explained a large proportion of the variance in negative feelings. 相似文献
64.
In recent years there has been an increased focus on cancer patients' information needs. The majority of the studies have led to the conclusion that most patients want as much information as possible about their disease and treatment. These studies have been large survey studies, and most of the patients enrolled in them have been out-patients. Very little is known about the information needs of severely ill cancer patients being treated as in-patients-such as those with acute myeloid leukaemia (AML). As part of a larger study dealing with AML patients' illness narratives, this work describes the information needs from the patients' perspective and their information-seeking behaviour. In-depth ethnographic interviews were conducted with each of 21 patients on two occasions: at the time of diagnosis and again 2-5 months later. Most patients did not recall much information from the time of diagnosis, except the diagnosis itself and the feelings it had aroused in them. All patients had basic medical knowledge about their disease. However, many patients-especially the elderly-expressed no need to receive further medical details about their disease. Avoiding information, in particular about the prognosis, was explained as a strategy to maintain hope. Most patients attached more importance to information about problems affecting their everyday life and how other persons had coped with their illness. They did not seek medical information on their own, although especially younger patients expressed the feeling that they "ought" to do this. There was a discrepancy between their expressed attitudes regarding the need for medical information in general and their actual information-seeking behaviour. Being informed and seeking information are discussed as society's expectations of today's cancer patient. 相似文献
65.
The rate of renin secretion from renal juxtaglomerular (JG) cells is the major determinant of the activity of the renin-angiotensin system. However, the mechanisms involved in the excretion and turnover of secretory granules in the JG cells remain obscure. Therefore, in the present study, the whole-cell patch-clamp technique was applied to single JG cells from the mouse kidney to measure changes in cell membrane capacitance (Cm) as an index of secretory activity. Resting JG cell Cm was stable, on average 3. 13+/-0.13 pF (SEM, n=106). In isotonic solutions, Cm was unaffected by [Cl-]i. Cm was consistently increased (7.0+/-1.3% and 7.2+/-3.1%) by intracellular cAMP (1 to 10 micromol/L). This effect was mimicked by extracellular application of the beta-agonist isoproterenol to the JG cells (9.4+/-3.1%). At 100 micromol/L, cAMP induced a paradoxical decrease in Cm of =20%, which was mimicked by forskolin. Cell swelling induced by a 7% reduction in osmolality increased Cm with no significant additional effects to [Cl-]i and cAMP. cAMP increased whole-cell outward current 2- to 4-fold in all groups, but no correlation between changes in whole-cell currents and Cm existed. We conclude that the whole-cell patch-clamp method allows the study of exocytosis and endocytosis in JG cells. Renin release induced by the cAMP pathway and by cell swelling is exocytotic, and high-intracellular cAMP levels activate membrane retrieval mechanisms. 相似文献
66.
67.
Fredholt K Ostergaard J Savolainen J Friis GJ 《International journal of pharmaceutics》1999,178(2):223-229
Desmopressin [1-(mercaptopropanoic acid)-8-D-arginine vasopressin; dDAVP] is a vasopressin analogue with a selective antidiuretic effect. The oral bioavailability of desmopressin is limited due both to its high hydrophilicity leading to a low intestinal permeability and to low enzymatic stability. The degradation of desmopressin was investigated in aqueous buffer solutions (pH 6.00-9.00) containing the enzyme alpha-chymotrypsin at a concentration of 0.50 mg/ml at 37 degrees C. The degradation of desmopressin was also studied in solutions containing alpha-chymotrypsin in the concentration range 0.10-1.00 mg/ml (pH 7.40 and 37 degrees C). The rate of degradation was shown to be highly dependent on both enzyme concentration and pH. Maximal alpha-chymotrypsin activity was observed in the pH range 7.40-8.00. It was observed that phenylalanine was formed during the degradation of desmopressin. Phenylalanine was formed in the amount of 20% in 120 min. In the same time period 95% of desmopressin was degraded. The formation of phenylalanine can be explained from the substrate specificity of alpha-chymotrypsin. Cyclodextrins are known to stabilize drugs including peptides against both chemical and enzymatic degradation. In this study it was shown that hydroxypropyl cyclodextrins (alpha, beta and gamma) stabilized desmopressin against alpha-chymotrypsin-catalyzed degradation. The stabilization was by a factor of 3, 9 and 8 at the concentration 12.5% (w/v) for hydroxypropyl-alpha-cyclodextrin, hydroxylpropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin. 相似文献
68.
The bacteriological effect of chemotherapy against mucoid strains of Pseudominas aeruginosa in the lower respiratory tract of patients with cystic fibrosis is reported. A comparison of the effect of high doses of tobramycin (10 mg/kg/24 h) given alone or in combination with carbenicillin showed a significant difference in favour of the combination therapy. In 74.5% of the initially successful courses the patients were recolonized within one month. Fifty-three patients were examined by audiometric and vestibular tests. Only in one patient was it possible to register a transient, high tone hearing impairment at 8000 Hz bilaterally, that might be attributed to the tobramycin treatment. It is concluded that high dose tobramycin treatment in children and adolescents with normal kidney function implies only a minimal clinical risk of adverse ototoxic effects, even after repeated courses of treatment. No nephrotoxic side-effects were found in this material. 相似文献
69.
Cancer occurrence after cosmetic breast implantation in Denmark 总被引:2,自引:0,他引:2
Mellemkjaer L Kjøller K Friis S McLaughlin JK Høgsted C Winther JF Breiting V Krag C Krüger Kjaer S Blot WJ Olsen JH 《International journal of cancer. Journal international du cancer》2000,88(2):301-306
Most studies on cancer incidence after breast implantation have focused on breast cancer, while the risk of cancers at other sites has been less well investigated. We examined cancer incidence among 1,653 women who underwent cosmetic breast implant surgery at private clinics of plastic surgery in Denmark and 1,736 women attending the same clinics for other reasons during the period 1973-1995. Furthermore, we updated previously reported results among 1,114 women who received implants for cosmetic indications at public hospitals. All women were followed for cancer through the Danish Cancer Registry. In comparison with the general female population, the overall standardized incidence ratio (SIR) for cancer among women who received implants in private clinics was 1.65 [95% confidence interval (CI) = 1.17-2.27]. This elevated SIR reflected increased incidence ratios for almost all major cancer sites; however, only for non-melanoma skin cancer was there an excess of more than 2 cases. No significant excess of cancer was observed among women who received implants in public hospitals (SIR = 1.10, 95% CI = 0.76-1.52) or among women attending the private clinics for other problems (SIR = 1.10, 95% CI = 0.78-1.52). The SIRs for breast cancer after breast implantation were 1.1 (95% CI = 0.5-2.2) among private clinic patients and 0.9 (95% CI = 0.4-1.7) among public hospital patients. The overall findings of these 2 implant cohorts and results from other investigations suggest that cancer risk is probably not increased among women receiving cosmetic breast implants. The inconsistent results for private clinics and public hospitals are likely related to selection bias and confounding among the private clinic patients, but our data did not permit exploration of these possibilities. Further research into the determinants of these inconsistencies is warranted. 相似文献
70.
Panic disorder in chest pain patients referred for cardiological outpatient investigation 总被引:3,自引:0,他引:3
T. Dammen H. Arnesen Ø. Ekeberg T. Husebye S. Friis 《Journal of internal medicine》1999,245(5):497-507
OBJECTIVES: The aims of the study were to: (i) determine the prevalence of panic disorder (PD) in patients referred to cardiological outpatient clinics for evaluation of chest pain; (ii) compare psychiatric comorbidity, psychological distress, pain characteristics and suicidal ideation in PD and non-PD patients: (iii) compare the prevalence of coronary risk factors and medical comorbidity in PD and non-PD patients; and (iv) describe current PD treatment and need for PD treatment as expressed by PD patients. DESIGN: A cross-sectional study based on psychiatric and cardiological investigation. SETTING: Four cardiological outpatient clinics in Oslo, Norway. SUBJECTS: One-hundred and ninety-nine consecutive patients without known heart disease referred to out-patient clinics for investigation of chest pain. MAIN OUTCOME MEASURES: Psychiatric state diagnosis (axis I); scores on self-assessment rating scales of psychological factors and pain modalities; cardiological diagnosis. RESULTS: Thirty-eight per cent of the patients met criteria for current panic disorder (PD). Panic disorder was associated with psychological distress, comorbid psychiatric disorders, medical disorders and significantly higher prevalence of coronary risk factors (P<0.05). Furthermore. the results suggest that these patients were not identified and appropriately treated for panic disorder prior to cardiological investigation. The results indicate that the patients are positive to screening for psychiatric disorder and communicate a need for treatment early in the investigation process. CONCLUSION: PD commonly occurs in this chest pain population. Thus, there is a need to educate physicians caring for these patients about PD identification and treatment. 相似文献