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排序方式: 共有10000条查询结果,搜索用时 312 毫秒
31.
Sean Ekins Dayna C Mankowski Dennis J Hoover Michael P Lawton Judith L Treadway H James Harwood 《Drug metabolism and disposition》2007,35(3):493-500
CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. To predict the interaction of inhibitors with the active site of human CYP51, a three-dimensional quantitative structure-activity relationship model was constructed. This pharmacophore model of the common structural features of CYP51 inhibitors was built using the program Catalyst from multiple inhibitors (n = 26) of recombinant human CYP51-mediated lanosterol 14alpha-demethylation. The pharmacophore, which consisted of one hydrophobe, one hydrogen bond acceptor, and two ring aromatic features, demonstrated a high correlation between observed and predicted IC(50) values (r = 0.92). Validation of this pharmacophore was performed by predicting the IC(50) of a test set of commercially available (n = 19) and CP-320626-related (n = 48) CYP51 inhibitors. Using predictions below 10 microM as a cutoff indicative of active inhibitors, 16 of 19 commercially available inhibitors (84%) and 38 of 48 CP-320626-related inhibitors (79.2%) were predicted correctly. To better understand how inhibitors fit into the enzyme, potent CYP51 inhibitors were used to build a Cerius(2) receptor surface model representing the volume of the active site. This study has demonstrated the potential for ligand-based computational pharmacophore modeling of human CYP51 and enables a high-throughput screening system for drug discovery and data base mining. 相似文献
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Keith J Murphy Andrew G Foley Alan W O'connell Ciaran M Regan 《Neuropsychopharmacology》2006,31(1):90-100
Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders. 相似文献
34.
Response rates,duration of response,and dose response effects in phase I studies of antineoplastics 总被引:4,自引:0,他引:4
Summary Over a period of 14 years, 7,960 patients were treated in 228 phase I trials. In these patients, there were 75 complete and 432 partial responses for an overall objective response rate of 6%. Complete responses lasted a median of six months (range 1–18), while partial responses lasted a median of three months (range 1–17). Of note is that no drug has made it to the market which has not had a response in phase I trials. Responses were noted in very diverse histologic types of tumors. Although there were responses at doses which were as low as 3–5% of the recommended dose for phase II trials, the majority of responses did occur at 80–120% of the dose recommended for phase II trials. Although the response rate in phase I trials is indeed low, responses do occur. This response rate information should help the clinician provide facts for the patient considering a phase I trial with new anticancer agents. These findings also emphasize that although phase I trials are characteristically dose-finding studies, if no responses are noted in phase I studies, it is unlikely the drug will be used routinely in the clinic. 相似文献
35.
OBJECTIVES: The objectives of this randomised controlled study were to determine if pre-admission patient education affects post-operative pain levels, domiciliary self-care capacity and patient recall following a laparoscopic cholecystectomy (LC). Participants were randomised to receive the standard preadmission program (SP) or an individualised, education intervention (El). DESIGN: A pre-operative questionnaire was administered in the pre-admission clinic to determine participants' knowledge of LC and post-operative management. Telephone follow-up and post-operative questionnaire were conducted approximately 14 days post discharge. SETTING: Preadmission clinic of a Sydney, Australia, tertiary referral hospital. SAMPLE: Ninety-three elective LC patients. RESULTS: EI participants experienced lower pain levels and had significantly greater recall of provided information. However, no significant differences were found between the control and intervention groups for domiciliary self-care. CONCLUSION: Pre-admission education intervention helps reduce post-operative pain levels following LC and significantly increases patients' knowledge of self-care and complication management. 相似文献
36.
37.
Robert B. Forbes David J. Murray Judith B. Dillman David L. Dull 《Journal canadien d'anesthésie》1989,36(2):160-164
Plasma methohexitone concentrations were determined in 60 children, aged one to six years, following administration of 15 mg.kg-1, 20 mg.kg-1, 25 mg.kg-1 or 30 mg.kg-1 two per cent rectal methohexitone. Time to the onset of sleep was determined by a blinded observer and venous blood samples obtained 15, 30, 45 and 120 minutes following drug administration. Fifty of 60 children were asleep within 15 minutes. Nine of the ten children that did not fall asleep were sedate and could be separated easily from their parents to undergo inhalational induction of anesthesia. Time to the onset of sleep was inversely related to the dose of rectal methohexitone administered. Sleep was achieved more reliably following the use of 25 to 30 mg.kg-1 rectal methohexitone. In addition, plasma methohexitone concentrations following 30 mg.kg-1 rectal methohexitone were significantly higher for up to 120 minutes following drug administration than the plasma concentrations achieved after 15 mg.kg-1 or 20 mg.kg-1 methohexitone. There was no difference in the incidence of complications. The authors recommend that clinical circumstances be carefully considered and the dose of rectal methohexitone administered be individualized to meet the specific anaesthetic requirements of each child. 相似文献
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39.
Judith L. Marks PhD Elizabeth M. Hill PhD Cynthia S. Pomerleau PhD Sharon A. Mudd PhD Frederic C. Blow PhD 《Journal of substance abuse treatment》1997,14(6):337-527
We compared nicotine dependence and withdrawal in male alcoholic and control ever-smokers, controlling for relevant demographic and clinical variables. Alcoholics were more likely to meet criteria for moderate or severe nicotine dependence and endorse more nicotine dependence symptoms. Symptoms reported more frequently by alcoholics included: (a) using nicotine in larger amounts or over a longer time than intended; (b) continued use despite problems caused or exacerbated by nicotine; (c) marked tolerance; and (d) experiencing characteristic nicotine withdrawal symptoms. Alcoholics also smoked more heavily. Other than “headaches,” and “decreased heart rate,” alcoholics consistently endorsed nicotine withdrawal symptoms at a higher rate. After controlling for demographic and clinical variables and level of nicotine dependence, only “feel depressed” differed significantly between groups. Our research supports previous findings suggesting that nicotine dependence is more severe in those with a history of alcohol dependence. As a result, alcoholics may experience greater discomfort from nicotine withdrawal upon smoking cessation. 相似文献
40.
Frances Rudnick Levin Judith M. Hess David A. Gorelick Nancy A. Kreiter Paul J. Fudala 《The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions》1993,2(2):109-115
The authors systematically evaluated the frequency patterns of cocaine use in 85 cocaine-dependent outpatients and found four patterns of use: continuous (27%), intermittent patterned (35%), intermittent nonpatterned (25%), and occasional (13%). Few subjects reported consistent cycling between binges and crashes. There were no significant differences in patterns of use associated with gender, race, educational level, route of administration, or recency of heroin use. Continuous users and occasional users were older than intermittent users. Because different contingencies may control patterned vs. nonpatterned cocaine use, pattern of use may have implications for treatment, even in individuals reporting similar amounts of cocaine use. 相似文献