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981.
A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066 总被引:7,自引:0,他引:7
Snape MF Misra A Murray TK De Souza RJ Williams JL Cross AJ Green AR 《Neuropharmacology》1999,38(1):181-193
The in vitro and in vivo effects of the novel acetylcholinesterase inhibitors donepezil and NXX-066 have been compared to tacrine. Using purified acetylcholinesterase from electric eel both tacrine and donepezil were shown to be reversible mixed type inhibitors, binding to a similar site on the enzyme. In contrast, NXX-066 was an irreversible non-competitive inhibitor. All three compounds were potent inhibitors of rat brain acetylcholinesterase (IC50 [nM]; tacrine: 125 +/- 23; NXX-066: 148 +/- 15; donepezil: 33 +/- 12). Tacrine was also a potent butyrylcholinesterase inhibitor. Donepezil and tacrine displaced [3H]pirenzepine binding in rat brain homogenates (IC50 values [microM]; tacrine: 0.7; donepezil: 0.5) but NXX-066 was around 80 times less potent at this M1-muscarinic site. Studies of carbachol stimulated increases in [Ca2+]i in neuroblastoma cells demonstrated that both donepezil and tacrine were M1 antagonists. Ligand binding suggested little activity of likely pharmacological significance with any of the drugs at other neurotransmitter sites. Intraperitoneal administration of the compounds to rats produced dose dependent increases in salivation and tremor (ED50 [micromol/kg]; tacrine: 15, NXX-066: 35, donepezil: 6) with NXX-066 having the most sustained effect on tremor. Following oral administration, NXX-066 had the slowest onset but the greatest duration of action. The relative potency also changed, tacrine having low potency (ED50 [micromol/kg]; tacrine: 200, NXX-066: 30, donepezil: 50). Salivation was severe only in tacrine treated animals. Using in vivo microdialysis in cerebral cortex, both NXX-066 and tacrine were found to produce a marked (at least 30-fold) increase in extracellular acetylcholine which remained elevated for more than 2 h after tacrine and 4 h after NXX-066. 相似文献
982.
OBJECTIVE: This study examines the factor structure and the predictive power of drinking restraint for men and women as measured by the Temptation and Restraint Inventory (TRI). The TRI assesses two factors: Cognitive-Emotional Preoccupation (CEP) and Cognitive-Behavioral Control (CBC). METHOD: A group of 418 drinkers was drawn from a university sample and divided by gender into two groups. Men (n = 122) were of a mean age (+/-SD) of 23 +/- 7 years; women (n = 296) were of a mean age of 22.5 +/- 8 years. Subjects completed the TRI and the Alcohol Dependence Scale (ADS) and validated quantity and frequency of drinking indices. RESULTS: Drinking restraint for the men was found to better predict alcohol dependence, quantity of drinking and frequency of drinking. Moreover, two factors confirming the TRI's CEP and CBC model were extracted for the men, but only one factor was extracted for the women. CONCLUSIONS: It was proposed that, as men tend to drink greater amounts of alcohol more often, they have learned to distinguish more clearly the conflicts in their personal control over drinking. If the TRI is to be used as a diagnostic and treatment tool, it is recommended that clinicians be cognizant of possible gender differences in restrained drinking behavior. 相似文献
983.
BACKGROUND: The role of immunosuppressive therapy in ulcerative colitis remains controversial. There is little information available on how frequently immunosuppressives are used, the circumstances, dose and duration of use and perceived benefit. METHODS: A postal survey was sent to consultant gastroenterologist members of the British Society of Gastroenterology. RESULTS: Questionnaires were returned by 81% of the 496 UK consultants approached. Azathioprine use was frequent, with 93% reporting previous use and 86% use within the past year. Although 95% usually prescribed a < or =2 mg/kg dose, only 39% were prepared to prescribe higher doses. There was marked variation in duration of use, with 46% using azathioprine for <2 years and 17% continuing it for 4 years or longer. Consultants with more experience of azathioprine in ulcerative colitis used it at higher maintenance doses for longer periods, and in patients with less extensive disease. Cyclosporin use was reported by 47% of those caring for ulcerative colitis patients, with 36% having used it at least once in the past year. However, 65% of users estimated that fewer than 50% of patients subsequently avoided colectomy. On stopping cyclosporin only 21% always introduced an alternative immunosuppressive, while 23% never did so. Potentially serious side-effects attributable to azathioprine and cyclosporin were reported by 36% and 45% of users of each drug, respectively. CONCLUSIONS: This survey reveals considerable variation in the amount and pattern of immunosuppressive use in ulcerative colitis, with serious side-effects commonly seen. There is a pressing need for further randomized controlled trials to provide reliable evidence as to how immunosuppressive therapy should be used in ulcerative colitis. 相似文献
984.
Pappa KA Williams BO Payne JE Buaron KS Mussari KL Ciociola AA 《Alimentary pharmacology & therapeutics》1999,13(4):467-473
BACKGROUND: Ranitidine 75 mg (Zantac 75) has been shown to be effective for the treatment of pre-existing heartburn symptoms. AIM: To compare the efficacy of dosing ranitidine 75 mg or placebo 30 min prior to a proven heartburn-provoking meal in completely preventing or reducing subsequent heartburn symptoms. METHODS: A randomized, double-blind, parallel methodology was used at nine investigative centres. Following a screening visit, patients ate a standard test meal consisting of chili, chips and a soft drink on two occasions. On the first occasion, patients received single-blind placebo 30 min before the meal. This meal was used to qualify patients and to ensure the onset of a minimum level of heartburn. Patients who qualified were randomized (n = 284) to receive double-blind ranitidine 75 mg or placebo 30 min before a second test meal administered 4-14 days later at the treatment visit. Patients recorded whether heartburn was present and rated heartburn severity by completing visual analogue scales at 15-min intervals over the 4. 5 h meal evaluation periods. RESULTS: Statistically significant differences favouring ranitidine 75 mg were determined for complete prevention of heartburn (P < 0.006), heartburn severity area under the curve (P < 0.001), a clinical success end-point (P < 0.001), and all other end-points (P < 0.001). CONCLUSIONS: These data clearly demonstrate that ranitidine 75 mg is effective in completely preventing or decreasing heartburn when administered 30 min prior to a provocative meal. 相似文献
985.
Van Der Hulst Lamouliatte Megraud Pounder Stolte Vaira Williams & Tytgat 《Alimentary pharmacology & therapeutics》1999,13(9):1171-1177
BACKGROUND: Novel technology based on laser optogalvanic spectroscopy called the LARA (Laser Assisted Ratio Analyser) system was developed to measure 12C/13C ratios in breath samples using stable 13C isotopes, to detect Helicobacter pylori infection. AIM: To determine the sensitivity and specificity of the 13C-LARA-urea breath test in the detection of H. pylori infection in a prospective European multicentre trial; FDA-and EMEA-approved. METHODS: Consecutive dyspeptic patients underwent diagnostic gastroscopy with biopsies for culture and histopathology, to detect H. pylori infection (gold standard). Subsequently, the LARA-urea breath test was performed using either a system without a cold trap (part I) or a system with a cold trap (part II). In both instances baseline, 30-min and 60-min breath samples were collected. The optimum cut-off level for 12C/13C ratios was determined by Receiver Operator Characteristics analysis. RESULTS: In part I, 544 out of 604 patients were evaluable (low CO2: 47; withdrawn: 13). 284 out of 544 patients (52%) were H. pylori-positive according to the gold standard. The sensitivity of the LARA-urea breath test was 95% and the specificity 94%. In part II, 257 out of 272 were evaluable (low CO2: 14; withdrawn: 1). Sensitivity and specificity were 93% and 96%, respectively. CONCLUSION: The LARA-technology represents an accurate and non-invasive testing system for the detection of H. pylori infection. Its major advantages are the use of stable 13C isotope, the high throughput of samples and the easy means of collecting, storing and transporting the samples, thus making the system convenient to both patient and clinician. 相似文献
986.
Warren G. Darling A. J. Butler T. E. Williams 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1996,112(1):127-134
The purpose of the present experiment was to determine the preferred visual straight ahead or anterior/posterior (a/p) axis at the perceptual level. The ability of 12 neurologically normal, young adult subjects to position a rod parallel to the head and trunk a/p axes while viewing eccentrically located visual targets were studied under six conditions: 1. fixed — subjects stood erect with the head aligned to the trunk and viewed a central target while visually aligning a hand-held rod to the head and trunk a/p axis. 2. eyes — subjects moved only their eyes to view eccentric targets and aligned the rod to the head and trunk a/p axis. 3. head-trunk — subjects viewed the eccentric targets by rotating the head about a vertical axis and aligned the rod to the trunk a/p axis. 4. head-head — subjects viewed the targets as in 3 and positioned the rod parallel to the head a/p axis. 5. trunk-head — subjects viewed the targets by rotating the trunk and head as a unit about the vertical axis and aligned the rod parallel to the head a/p axis (note that the head and trunk a/p axes were misaligned by the experimenter prior to target viewing). 6. trunk-trunk — subjects viewed targets as in 5 and positioned the rod parallel to the trunk a/p axis. Subjects performed 25–35 consecutive trials within each condition. Perceptual errors were similar for aligning the rod to the trunk and head a/p axes; however, moving the trunk produced much larger constant and variable perceptual errors than moving the head. In a second experiment, four subjects controlled the position of a lighted rod held by a robot arm in complete darkness. They were instructed to align the rod to either the head or trunk a/p axis under conditions similar to the fixed, head-trunk, and head-head tasks described above. Perceptual errors were much larger when aligning the rod to the head a/p axis than to trunk a/p axis when the head was moved. This shows that the trunk a/p axis is clearly preferred at the perceptual level when visual background cues are not present.These data strongly suggest that the visual coordinate system uses a trunk-fixed a/p axis to define the subjective straight-ahead direction and right/left position of a target. Implications of these findings for sensorimotor transformations in control of upper limb movements to visual targets are discussed. 相似文献
987.
Inhibition of dopamine uptake into PC-12 cells by analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 总被引:1,自引:0,他引:1
The inhibition of uptake of radioactive dopamine into PC-12 cells by analogues of MPTP with systematic variations of structure was studied in order to assess the steric constraints of the transmembrane dopamine transporter. Of 15 analogues tested, 11 were found to inhibit dopamine uptake, all being competitive inhibitors. Major changes to the phenyl ring of MPTP, e.g. replacement of the phenyl by a naphthyl group, had a relatively modest effect on the inhibition of uptake of dopamine. Minor modifications to the N-methyl moiety reduced the ability to inhibit uptake, although the unmethylated analogue still had inhibitory properties. Therefore, in considering environmental agents resembling MPTP as potential causes of idiopathic Parkinson's disease, the size of aromatic groups attached to the alicyclic ring appears not to be critical in terms of the dopamine transporter. Uptake of unmethylated secondary amines is also possible, but these are likely to need to be bioactivated by transamination as well as oxidation to generate neurotoxins. 相似文献
988.
In eliciting health state valuations, two widely used methods are the standard gamble (SG) and the time trade off (TTO). Both methods make assumptions about individual preferences that are too restrictive to allow them to act as perfect proxies for utility. Therefore, a choice between them might instead be made on empirical grounds. This paper reports on a study which compared a "props" (using specifically-designed boards) and a "no props" (using self-completion booklets) variant of each method. The results suggested that both non props variants might be susceptable to framing effects and that TTP props outperformed SG props. 相似文献
989.
Lumbers M Driver LT Howland RJ Older MW Williams CM 《Clinical nutrition (Edinburgh, Scotland)》1996,15(3):101-107
The possible relationship between nutritional status and clinical outcome following orthopaedic hip surgery was investigated. The nutritional status of 60 elderly female patients admitted for elective total hip replacement (THR) and emergency fractured neck of femur surgery (FNF) was measured over time. Specific measures of clinical outcome, including well-being and functional status, were monitored during hospital stay and at 4, 8 and 26 weeks following discharge. Patients were allocated to a high nutritional risk group where any three of the following were less than the 5th percentile value: serum albumin, haemoglobin, triceps skinfold thickness, mid-upper arm muscle circumference and body weight. Using this definition, malnutrition was present in 4% of THR patients and 41% of FNF patients. It was found that the high risk patients had significantly longer convalescence periods, (median stay 27.5 days compared with 0 days, P < 0.0009), and a greater proportion were dependent upon walking frames at 6 months (46% compared with 11%, P < 0.01). Fifty percent of the high risk patients had been living independently prior to admission, in contrast only 29% had returned to their homes at 6 months after discharge. The results indicate an apparent link between clinical outcome and nutritional status based upon the allocation procedure employed, which has the potential for ensuring cost-effective nutritional intervention. 相似文献
990.