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51.
G Bradley T J Ward J C White J Coleman A Taylor K F Rhodes 《Journal of medicinal chemistry》1992,35(9):1515-1520
A series of benzoylureas derived from bicycle amines were prepared and evaluated for 5-HT3 antagonist activity on the rat isolated vagus nerve. From among these compounds, those analogues which were ortho substituted by an alkoxy group on the benzoyl function were shown to be potent 5-HT3 antagonists with similar or greater potency than the standard agent ondansetron. NMR and X-ray crystallography studies showed these o-alkoxy compounds to exist as a planar, hydrogen-bonded, tricyclic ring system. In molecular modeling studies on endo-N-[[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl-amino] carbonyl]-2-(cyclopropylmethoxy)benzamide (30) the central hydrogen-bonded ring was able to mimic an aromatic ring present in previously reported 5-HT3 antagonists. 相似文献
52.
53.
Hein David W.; Flammang Thomas J.; Kirlin Ward G.; Trinidad Alma; Ogolla Fredrick 《Carcinogenesis》1987,8(12):1767-1774
A genetic polymorphism in S-acetyl coenzyme A (AcCoA)-dependentN-acetyltransferase has been associated with a differentialrisk for certain cancers in humans. In this study, several tissuesfrom the inbred Syrian hamster with a genetically defined AcCoA-dependentN-acetyltransferase polymorphism (homozygous rapid acetylator,Bio. 87.20; homozygous slow acetylator, Bio. 82.73/H; and heterozygousacetylator, Bio. 87.20 x Bio. 82.73/H F1), were investigatedfor the relationship of arylamine N-acetyltransferase to theAcCoA-dependent metabolic activation of carcinogenic N-hydroxy(N-OH)-arylamines to bind to DNA (O-acetyltransferase). Thelevels of both 2-aminofluorene (AF) N-acetyltransferase andN-OH-AF O-acetyltransferase activity reflected the N-acetylatorgenotype in liver, intestine, kidney and lung cytosols. A significantacetylator genedose response for AF N-acetyltransferaseand N-OH-AF O-acetyltransferase activities was observed in liverand lung cytosols. In contrast, acetylator genotype was notconsistently expressed for the AcCoA-dependent N-acetylationof 4-aminobiphenyl (ABP), nor for the AcCoA-dependent metabolicactivation of N-OH ABP and N-OH-3,2'-dimethyl-4-aminobiphenylin these me tissue cytosols. Two peaks of acetyltransferaseactivity were partially purified by ion exchange FPLC chromatographyfrom the hepatic cytosol of both the homozygous rapid and homozygousslow acetylator hamster. In contrast to unfractionated cytosol,the isozyme(s) eluting first clearly demonstrated levels ofAcCoA-dependent arylamine N-acetyltransferase and N-OH-arylamineO-acetyltransferase activities that were consistent with N-acetylatorgenotype (polymorphic) for all substrates tested. In contrast,the slower eluting isozyme(s) in each acetylator cytosol showedlevels of AcCoA-dependent N-and O-acetyltransferase activitiesthat did not vary with N-acetylator genotype (monomorphic).The AcCoA-dependent O-acetyltransferase activity of both themonomorphic and polymorphic peaks was paraoxon resistant. Thesestudies demonstrate acetylator genotype-dependent control ofAcCoA-dependent metabolic activation of N-OH-arylamines(O-acetylation)by polymorphic isozyme(s) similar to that for AcCoA-dependentN-acetylation of arylamines in the hamster. The polymorphicgenetic control of N-OH arylamine O-acetyltransferase may bean important risk factor for arylamine-induced cancer, in thosespecies and tissues expressing appreciable levels of O-acetyltransferaseactivity. 相似文献
54.
Cardia: study design, recruitment, and some characteristics of the examined subjects 总被引:28,自引:0,他引:28
Gary D. Friedman Gary R. Cutter Richard P. Donahue Glenn H. Hughes Stephen B. Hulley David R. Jacobs Jr. Kiang Liu Peter J. Savage 《Journal of clinical epidemiology》1988,41(11):1105-1116
In 1984, a prospective cohort study, Coronary Artery Risk Development in Young Adults (CARDIA) was initiated to investigate life-style and other factors that influence, favorably and unfavorably, the evolution of coronary heart disease risk factors during young adulthood. After a year of planning and protocol development, 5,116 black and white women and men, age 18-30 years, were recruited and examined in four urban areas: Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota, and Oakland, California. The initial examination included carefully standardized measurements of major risk factors as well as assessments of psychosocial, dietary, and exercise-related characteristics that might influence them, or that might be independent risk factors. This report presents the recruitment and examination methods as well as the mean levels of blood pressure, total plasma cholesterol, height, weight and body mass index, and the prevalence of cigarette smoking by age, sex, race and educational level. Compared to recent national samples, smoking is less prevalent in CARDIA participants, and weight tends to be greater. Cholesterol levels are representative and somewhat lower blood pressures in CARDIA are probably, at least in part, due to differences in measurement methods. Especially noteworthy among several differences in risk factor levels by demographic subgroup, were a higher body mass index among black than white women and much higher prevalence of cigarette smoking among persons with no more than a high school education than among those with more education. 相似文献
55.
56.
Howard A Israel John Desmond Ward Brenda Horrell Steven J Scrivani 《Journal of oral and maxillofacial surgery》2003,61(6):662-667
PURPOSE: In this investigation, we evaluated a population of patients with chronic orofacial pain who sought treatment at a pain center in an academic institution. These patients were evaluated with respect to 1) the frequency and types of previous oral and maxillofacial surgery procedures, 2) the frequency of previous significant misdiagnoses, and 3) the number of patients who subsequently required surgical treatment as recommended by an interdisciplinary orofacial pain team. The major goal of this investigation was to determine the role of oral and maxillofacial surgery in patients with chronic orofacial pain. Patients and Methods: The study population included patients seen at the Center for Oral, Facial and Head Pain at New York Presbyterian Hospital from January 1999 through April 2001. (120 patients; female-to-male ratio, 3:1; mean age, 49 years; average pain duration, 81 months; average number of previous specialists, 6). The patient population was evaluated by an interdisciplinary orofacial pain team and the following characteristics of this population were profiled: 1) the frequency and types of previous surgical procedures, 2) diagnoses, 3) the frequency of previous misdiagnoses, and 4) treatment recommendations made by the center team. RESULTS: There was a history of previous oral and maxillofacial surgical procedures in 38 of 120 patients (32%). Procedures performed before our evaluation included endodontics (30%), extractions (27%), apicoectomies (12%), temporomandibular joint (TMJ) surgery (6%), neurolysis (5%), orthognathic surgery (3%), and debridement of bone cavities (2%). Surgical intervention clearly exacerbated pain in 21 of 38 patients (55%) who had undergone surgery. Diagnoses included myofascial pain (50%), atypical facial neuralgia (40%), depression (30%), TMJ synovitis (14%), TMJ osteoarthritis (12%), trigeminal neuralgia (10%), and TMJ fibrosis (2%). Treatment recommendations included medications (91%), physical therapy (36%), psychiatric management (30%), trigger injections (15%), oral appliances (13%), biofeedback (13%), acupuncture (8%), surgery (4%), and Botox injections (1%) (Allergan Inc, Irvine, CA). Gross misdiagnosis leading to serious sequelae, with delay of necessary treatment, occurred in 6 of 120 patients (5%). CONCLUSIONS: Misdiagnosis and multiple failed treatments were common in these patients with chronic orofacial pain. These patients often have multiple diagnoses, requiring management by multiple disciplines. Surgery, when indicated, must be based on a specific diagnosis that is amenable to surgical therapy. However, surgical treatment was rarely indicated as a treatment for pain relief in these patients with chronic orofacial pain, and it exacerbated and perpetuated pain symptoms in some of them. 相似文献
57.
The thymidylate synthase (TS) inhibitor ICI D1694 (N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N -methylamino]-2 - thenoyl)-S-glutamic acid) is a structural analogue of the substrate N5,N10-methylenetetrahydrofolate (5,10-CH2FH4) and is currently under clinical evaluation as a treatment for cancer. The compound is shown here to be a mixed non-competitive inhibitor of TS from murine leukemia (L1210) cells when 5,10-CH2FH4 is varied. This result suggests formation of an inactive complex between TS, 5,10-CH2FH4 and the inhibitor. Thus, binding to only one of the two active sites on the TS homodimer may be sufficient to prevent catalysis fully. Treatment of L1210 cells with ICI D1694 is known to cause intracellular accumulation of the tetraglutamate derivative which is shown here to have a 60-fold higher affinity for TS. The IC50 for inhibition of L1210 cell growth is below the Ki value of ICI D1694 for L1210 TS but above that of the tetraglutamate. The formation of polyglutamates and concentration of drug inside cells, therefore, seem to be responsible for biological activity. 相似文献
58.
Compression plating for child and adolescent femur fractures. 总被引:3,自引:0,他引:3
Twenty-five children ranging in age from 6-16 years underwent AO compression plate fixation for treatment of a femur fracture. Generally, the most common reason for plate fixation was to simplify nursing care and rehabilitation of children with an associated severe head injury or polytrauma. Twenty-three fractures healed in 11 weeks on the average, most by periosteal bone formation. Leg length discrepancy was not a clinical problem. Nursing care and polytrauma rehabilitation were simplified in all children. We believe that plate fixation is a reasonable treatment option for femoral fracture care in children aged less than 11 years with severe head injury or associated polytrauma. 相似文献
59.
60.
Fumiharu Kimura R. Glenn Smith Osvaldo Delbono Okot Nyormoi Toni Schneider Wolfgang Nastainczyk Franz Hofmann Enrico Stefani Stanley H. Appel 《Annals of neurology》1994,35(2):164-171
Sporadic amyotrophic lateral sclerosis is an idiopathic human degenerative disease of spinal cord and brain motor neurons. Prior studies demonstrated that most patients with amyotrophic lateral sclerosis posses immunoglobulins that bind to purified L-type voltage-gated calcium channels, that titers of anti–voltage-gated calcium channel antibodies correlate with disease progression rates, and that amyotrophic lateral sclerosis patient-derived antibodies (ALS IgG) produce electrophysiological changes in the function of voltage-gated calcium channels. Using Western transfer immunoblots and enzyme-linked immunosorbent assays, the calcium ionophore–forming α1 subunig of the voltage-gated calcium channel is now identified as the major voltage-gated calcium channel antigen to which ALS IgG binds. Additionally, the binding of an L-type voltage-gated calcium channel α1 subunit–directed monoclonal antibody, which itself mimics the effects of ALS IgG on skeletal muscle voltage-gated calcium channel currents, is selectively prevented by preaddition of ALS IgG. Voltage-gated calcium channel–binding IgG from patients with Lambert-Eaton myasthenic syndrome appears to be differentiated from ALS IgG by the reactivity of the former to both α1 and β subunits of the calcium channel. These assays provide further evidence linking amyotrophic lateral sclerosis to an autoimmune process, and suggest one means to differentiate immunoglobulins from patients with amyotrophic lateral sclerosis from those of patients with another autoimmune disease expressing calcium channel antibodies. 相似文献