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31.
IM Bell JM Erb RM Freidinger SN Gallicchio JP Guare MT Guidotti RA Halpin DW Hobbs CF Homnick MS Kuo EV Lis DJ Mathre SR Michelson JM Pawluczyk DJ Pettibone DR Reiss S Vickers PD Williams CJ Woyden 《Canadian Metallurgical Quarterly》1998,41(12):2146-2163
The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases. 相似文献
32.
EA Koller L Green JM Gertner M Bost SN Malozowski 《Canadian Metallurgical Quarterly》1998,83(7):2380-2383
A role for GH in the pathogenesis of diabetic retinopathy has long been postulated. Previous clinical studies, however, have been confounded by hyperglycemia. We have identified 2 cases of retinopathy associated with exogenous GH therapy in nondiabetic patients. Cases were identified through the MedWatch drug surveillance system of the U.S. Food and Drug Administration. Causality by concomitant medications was excluded by a search of the literature and the FDA data base. The first patient, an obese, 31-yr-old male with traumatic hypothalamic injury, presented with nonproliferative retinopathy and macular edema, resulting in decreased visual acuity (OD 20/40-1; OS count fingers), which required laser surgery. Human GH had been initiated at 0.009 mg/ kg.day, 14 months earlier, and titrated to 0.017 mg/kg.day. The second patient, a nonobese, 11-yr-old girl receiving GH for the management of short stature in Turner's Syndrome, presented with neovascularization. GH doses were 0.033 mg/kg.day for the first 17 months and 0.043 mg/ kg.day for the following 5 months. Cumulative laboratory and clinical observations suggest that GH and related peptides have a role in retinal pathology independent of the degree of glucose tolerance. 相似文献
33.
PURPOSE: To analyze the likelihood of perioperative transfusion using the data of the abstracted patient discharge records. MATERIAL AND METHODS: It was studied the data of the records of the pediatric patients in whom were done surgical procedures for 1996. The abstracted patient discharge records are codified according the ICD-9-CM codes. RESULTS: 1,166 pediatric patients were operated, of whom were transfused 25 (2.1%). The transfusion rate was higher in patients less than 3 years old, who were operated with three o more surgical procedures simultaneously, who were admitted newly after the admittance here studied, and patients operated of spine, dorsolumbar spine, pharynx, thorax and mediastinum, central nervous system, colon, vessels and hip. CONCLUSIONS: Given the variability of the transfusion rate, to know it will allow a better planning of the surgical transfusions, the policy of the hospital blood bank and to increase the information to patient about the risk of the elective surgery. 相似文献
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35.
Manual differentiation of electroencephalography (EEG) paper recordings in cases of depression is not very helpful. So, a Multilayer Perceptron (MLP) has been used to differentiate the EEG power density spectra (qEEG) in the wakeful state from animals (control, exercised and depressed). The qEEG ranging from 1 to 30 Hz, at 1 Hz increments (30 input features) and also a slow, medium and fast activity (represented by three ranges of frequencies at the input) were used. After training with depressed and control qEEG only, the MLP has been found to distinguish successfully between the normal and the depressed rats in more than 80% of the cases, identifying, in the process, most of the exercised groups' EEG as normal. The reduction in the dimension of input features from 30 individual frequencies to 3 frequency bands has produced similar results. The rules generated for making such distinctions have been found to be similar to the clinical views. 相似文献
36.
A new sequential image processing method for motion compensation of a moving object with stringy shape has been developed for estimating the pharyngeal pulsation of the nematode Caenorhabditis elegans under several environmental conditions. The method is based on the pixel data transfer on a new image frame while changing the boundary shape and the position but preserving the conformation of the inner structure of an object. All digitized image frames of C. elegans were first converted to motion-compensated images to arrange the pulsation site in the same region of the every transformed frame. The pulsation site was then automatically detected by determining the pixels where the temporal brightness variation was much larger than that of the other pixels. Finally, the pulsation frequency was determined by the Fourier analysis. The validity of our method has been confirmed by analyzing various test data, and the method has been applied for detecting the pharyngeal pulsation frequencies of C. elegans on some environmental conditions, i.e. feed bacteria-free/rich, doping of nerve inactivating ethyl-alcohol and nerve stimulant neurochemical substance of serotonin. The motion compensation method automatically provided reasonable pulsation frequencies which were found to be comparable to those obtained by manual counting. Thus the method is useful for systematic investigations on the variation of pharyngeal pulsation associated with the activity change of the nervous system in environments. 相似文献
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39.
SN Kulikov 《Canadian Metallurgical Quarterly》1994,37(1):18-23
Glycogen synthesis and degradation were studied in cultured rat hepatocytes prelabeled by incubation with [14C]glucose or [14C]galactose. During prelabeling about 75% of the accumulated glycogen was synthesized from glucose and about 25% from gluconeogenic precursors. Following the labeling period, glycogen synthesis and degradation were estimated at 5 and 12.5 mM glucose and varying concentrations of insulin and glucagon. At 12.5 mM glucose and 10 nM insulin the accumulation of glycogen was comparable to in vivo values, whereas the level of radioactivity in prelabeled glycogen remained constant. Further addition of 0.1 nM glucagon resulted in constant values of both content and radioactivity of glycogen. Increasing the concentration of glucagon to 10 nM resulted in a parallel decrease of content and radioactivity in glycogen. At 5 mM glucose, 10 nM insulin, and 0.1 nM glucagon both the content and the radioactivity of glycogen were constant, whereas addition of 10 nM glucagon resulted in a parallel decrease of content and radioactivity of glycogen, which was 64% higher than that observed with 12.5 mM glucose. In the absence of insulin, prostaglandin D2 had effects similar to those of 10 nM glucagon, whereas no effects was observed in the presence of insulin. From these results and from calculated rates of glucose 6-phosphate formation, it is concluded that the rate of glycogen degradation is less than 10% of the rate of synthesis under conditions favoring glycogen accumulation. At conditions favoring glycogen degradation (10 nM insulin plus 10 nM glucagon or prostaglandin in the absence of insulin) no synthesis could be detected. Results from cells prelabeled with [14C]galactose suggested that glycogen degradation is not an absolutely ordered process, but that some random degradation takes place. 相似文献
40.
Eight dopamine receptor-like cDNA clones were isolated from the carp (Cyprinus carpio) retina and four dopamine receptor-like cDNA clones were isolated from the European eel (Anguilla anguilla) retina. These cDNA clones show high sequence and structural homology to the known dopamine receptor subtypes. The sequence similarity and phylogenetic analysis revealed that five subtypes (D1A3, D1A4, D1B, D1C and D1X) in the carp retina and four subtypes (D1A1, D1A2, D1B and D1C) in the eel retina are D1-like receptor subtypes, and three (D2, D4A and D4B) in the carp retina are D2-like receptor subtypes; no D2-like receptor was found in the eel. Carp D1A3 and D1A4, carp D4A and D4B, and eel D1A1 and D1A2 are highly homologous pairs of receptors which show significant, domain-specific differences to each other and to their species homologues. The structure of the third cytoplasmic loop in the carp D1X receptor was particularly different from the other D1-like receptors. The implications of these structural differences in terms of dopamine receptor activation and signalling are discussed. It is suggested that the known diverse physiological and pharmacological effects of dopamine on the retinal neurones are likely to be mediated through these multiple receptor subtypes which may be coupled to different signal transduction pathways. 相似文献