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101.
Gomtsyan A Bayburt EK Schmidt RG Zheng GZ Perner RJ Didomenico S Koenig JR Turner S Jinkerson T Drizin I Hannick SM Macri BS McDonald HA Honore P Wismer CT Marsh KC Wetter J Stewart KD Oie T Jarvis MF Surowy CS Faltynek CR Lee CH 《Journal of medicinal chemistry》2005,48(3):744-752
Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable. 相似文献
102.
Souers AJ Gao J Brune M Bush E Wodka D Vasudevan A Judd AS Mulhern M Brodjian S Dayton B Shapiro R Hernandez LE Marsh KC Sham HL Collins CA Kym PR 《Journal of medicinal chemistry》2005,48(5):1318-1321
Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHr1) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHr1 and a potent inhibitor of MCH-mediated Ca(2+) release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHr1 antagonist that is efficacious upon oral dosing in a chronic model of weight loss. 相似文献
103.
Introduction: A heavier weight in adults is becoming the norm rather than an abnormal weight. Whether the same trend is happening in children is unknown. Objective: To assess the perception of the weight of 4‐ to 5‐year‐old children and the recognition of overweight by both parents. Design: Population‐based survey. Participants: A questionnaire was sent to parents of 1155 4‐ to 5‐year‐old children. Results: In total, 439 questionnaires (35%) were returned. Of all, 90% of the children had a normal weight, 9.3% were overweight and 4.1% were obese. For all weight classes, the parents depicted the child as lighter on both the verbal and visual scale. Of all, 75% of mothers of overweight children stated that the child had a normal weight. In obese children, 50% of the mothers believed that the child had a normal weight. Conclusion: Children with a weight in the normal range were considered by their parents as a little too light or too light. Overweight was considered as normal weight, and obesity as normal or a little too heavy. The perception of a normal weight in children at 4–5 years is distorted. 相似文献
104.
Practical preclinical model for assessing the potential for unconjugated hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors
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Kempf DJ Waring JF Morfitt DC Werner P Ebert B Mitten M Nguyen B Randolph JT DeGoey DA Klein LL Marsh K 《Antimicrobial agents and chemotherapy》2006,50(2):762-764
A practical preclinical model for the hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors has been developed. Indinavir and atazanavir produced significant hyperbilirubinemia, whereas amprenavir, the negative control, was indistinguishable from the ritonavir booster dose. This model was used to disqualify an exploratory protease inhibitor from development. 相似文献
105.
AJ Wearden L Riste C Dowrick C Chew-Graham RP Bentall RK Morriss S Peters G Dunn G Richardson K Lovell P Powell 《BMC medicine》2006,4(1):1-12
Background
A major change has occurred in the last few years in the therapeutic approach to patients presenting with all forms of acute coronary syndromes. Whether or not these patients present initially to tertiary cardiac care centers, they are now routinely referred for early coronary angiography and increasingly undergo percutaneous revascularization. This practice is driven primarily by the angiographic image and technical feasibility. Concomitantly, there has been a decline in expectant or ischemia-guided medical management based on specific clinical presentation, response to initial treatment, and results of noninvasive stratification. This 'tertiarization' of acute coronary care has been fuelled by the increasing sophistication of the cardiac armamentarium, the peer-reviewed publication of clinical studies purporting to show the superiority of invasive cardiac interventions, and predominantly supporting (non-peer-reviewed) editorials, newsletters, and opinion pieces.Discussion
This review presents another perspective, based on a critical reexamination of the evidence. The topics addressed are: reperfusion treatment of ST-elevation myocardial infarction; the indications for invasive intervention following thrombolysis; the role of invasive management in non-ST-elevation myocardial infarction and unstable angina; and cost-effectiveness and real world considerations. A few cases encountered in recent practice in community and tertiary hospitals are presented for illustrative purposes The numerous and far-reaching scientific, economic, and philosophical implications that are a consequence of this marked change in clinical practice as well as healthcare, decisional and conflict of interest issues are explored.Summary
The weight of evidence does not support the contemporary unfocused broad use of invasive interventional procedures across the spectrum of acute coronary clinical presentations. Excessive and unselective recourse to these procedures has deleterious implications for the organization of cardiac health care and undesirable economic, scientific and intellectual consequences. It is suggested that there is need for a new equilibrium based on more refined clinical risk stratification in the treatment of patients who present with acute coronary syndromes. 相似文献106.
RP Dayasena MBKC Dayasiri C Jayasuriya DSC Perera 《The Australasian medical journal》2011,4(2):101-104
Background
Chronic suppurative otitis media (CSOM) is assumed to be a complication of acute otitis media (AOM), but the risk factors for CSOM are not clear. Objectives: 1. To study the aetiological organisms for CSOM. 2. To identify the effect of demographic factors on disease manifestation.Method
This retrospective study included a case series of 234 patients who had been admitted to National Hospital of Sri Lanka (NHSL), with the complaint of ear discharge and from whom the specimens were sent for microscopy and culture at Department Of Microbiology, NHSL. The period of analysis was 1 year extending from 1 January 2009 to 31 December 2009.Consecutive patients who fulfilled the inclusion criteria were recruited to the retrospective analysis.Results
Among 234 patients studied, 129 (55.1%) were male and 150 (64.1%) were under 40 yrs old. The mean age was 39.5 yrs (range 12 to 60 yrs, SD = 22.6). The mean duration of ear discharge was 1.2 yrs. (range 6 weeks to 20 yrs.) Pseudomonas species (29.5%) was the commonest microbial organism to cause ear discharge, followed by staphylococcus (20.5%) and coliform (16.7%) species. Among the fungal agents identified, candida was the most common. 23.1% of the cultures did not reveal any microbiological agent. Eighteen patients (8%) had a prior history of trauma to the affected ear and 51 patients (21.8%) were diagnosed with diabetes mellitus.Conclusion
The commonest microbial agents implicated in CSOM was pseudomonas species followed by staphylococci and coliforms. Demographic variables such as gender or age did not seem to affect the disease manifestation significantly, though CSOM was less common among elderly and women. 相似文献107.
Ian RP Sunderland Glenn Edwards James Mainprize Oleh Antonyshyn 《CANADIAN JOURNAL OF PLASTIC SURGERY》2015,23(2):95-99
Prefabricated, patient-specific alloplastic implants for cranioplasty reduce surgical complexity, decrease operative times, minimize exposure and risk of contamination, and have resulted in improved aesthetic results. However, in creating a prefabricated custom implant using a patient’s computed tomography data, a stable, unalterable defect must be clearly defined before surgery. In the event that an intraoperative modification of an exiting skull defect is required, or in cases of tumour resection in which the size of the skull defect is unknown preoperatively, these prefabricated implants cannot be used. The ideal method for alloplastic cranioplasty would enable cost-effective creation of a patient-specific implant with the capacity for intraoperative modification.The present article describes a novel technique of cranioplasty that uses a patient’s computed tomography data to create a custom forming tool (ie, mold), enabling intraoperative creation of a patient-specific titanium mesh implant. The utility of these implants in creating a custom reconstructive solution in cases in which the size of the skull defect is unknown preoperatively will be demonstrated using two case presentations. 相似文献
108.
Zhao G Souers AJ Voorbach M Falls HD Droz B Brodjian S Lau YY Iyengar RR Gao J Judd AS Wagaw SH Ravn MM Engstrom KM Lynch JK Mulhern MM Freeman J Dayton BD Wang X Grihalde N Fry D Beno DW Marsh KC Su Z Diaz GJ Collins CA Sham H Reilly RM Brune ME Kym PR 《Journal of medicinal chemistry》2008,51(3):380-383
A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice. 相似文献
109.
110.