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1.
Gary D. Pipes Phillip Campbell Pavel V. Bondarenko Bruce A. Kerwin Michael J. Treuheit Himanshu S. Gadgil 《Journal of pharmaceutical sciences》2010,99(11):4469-4476
A middle-down LC/MS approach, for the rapid quantitation and characterization of site-specific methionine oxidation in a recombinant monoclonal IgG1 molecule, is described. An IgG1 antibody was digested with endoprotease LysC under limited proteolytic conditions to produce two major components; an antigen binding fragment (Fab) and a crystallizable fraction (Fc). These fractions were then reduced to produce three major species; light chain (LC), Fc/2 which is the C terminal region of the heavy chain (HC) and the N-terminal heavy chain region (Fd). These three fragments were separated by reversed-phase HPLC using a diphenyl column. The diphenyl column resolved site-specific methionine oxidation in all three subunits. Middle- down N-terminal sequencing with a LCT premier mass spectrometer was used to identify the sites of oxidation in the LC. Sites of oxidation in the Fc/2 were identified using middle-down collision-induced dissociation (CID) on a Qtof premier. This method allowed for the rapid quantitation and identification of oxidation on each methionine residue in an IgG1 molecule. 相似文献
2.
David G Witte Michael E Brune Sweta P Katwala Ivan Milicic Deanne Stolarik Yu-Hua Hui Kennan C Marsh James F Kerwin Michael D Meyer Arthur A Hancock 《The Journal of pharmacology and experimental therapeutics》2002,300(2):495-504
Fiduxosin is a new alpha(1)-adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the alpha(1)-adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC(50) values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC(50) values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC(50)/IUP IC(50), were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of alpha(1)-adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an alpha(1a)-/alpha(1d)-subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular alpha(1)-adrenoceptors in human and should be a novel, long-acting, uroselective alpha(1)-adrenoceptor antagonist. 相似文献
3.
S. Shaikh D. A. Collier P. Sham L. Pilowsky T. Sharma L. K. Lin M. A. Crocq M. Gill R. Kerwin 《American journal of medical genetics. Part A》1995,60(6):541-545
We have examined the hypothesis that a variable number of tandem repeats in the third cytoplasmic loop of the dopamine D4 receptor influences clinical response to clozapine using a sample of 189 schizophrenic patients. Alleles of the 48-bp repeat, which range from two to ten copies in the normal human population, were analysed by the polymerase chain reaction using genomic DNA as template. Association between these alleles and response to clozapine was tested using the difference in pre-and post-treatment GAS scores as a measure of response. We found no statistically significant variation between genotypic groups and response by analysis of variance. We conclude that the variation of the number of 48-bp repeats alone does not determine response to clozapine. Larger studies are underway to determine if there is a more subtle relationship with sequence variation within the repeats or at other polymorphic sites within the gene that may provide evidence for a component of clozapine's action being at D4 receptors. © 1995 Wiley-Liss, Inc. 相似文献
4.
Memory following cholinergic (NBM) and noradrenergic (DNAB) lesions made singly or in combination: potentiation of disruption by scopolamine 总被引:1,自引:0,他引:1
A Sahgal A B Keith S Lloyd J M Kerwin E K Perry J A Edwardson 《Pharmacology, biochemistry, and behavior》1990,37(4):597-605
Groups of rats were trained on either delayed matching or nonmatching to position tasks, then divided into four subgroups and given the following bilateral lesions: (a) SHAM [vehicle injection into the nucleus basalis magnocellularis (NBM) and dorsal noradrenergic bundle (DNAB)], (b) DNAB (6-hydroxydopamine lesion of the DNAB, vehicle into the NBM), (c) NBM (quisqualic acid lesion of the NBM, vehicle into the DNAB) and (d) DUAL (neurotoxin lesions of both DNAB and NBM). Following postoperative recovery, the DUAL lesion subjects were slightly impaired, but by the seventh day of testing all groups were performing at similar levels. This strongly suggests that quisqualate lesions of the NBM are not sufficient to produce severe and lasting mnemonic disorders resembling those seen in Alzheimer's disease (AD). These data also indicate that the noradrenergic system may not be of critical importance with respect to cognition. It was reasoned that an additional anticholinergic treatment might exacerbate an underlying deficiency. All groups were injected, peripherally, with the cholinergic antagonist scopolamine (0-0.5 mg/kg). This drug dose-dependently disrupted performance in all groups. Moreover, the highest dose had a marked effect in the DUAL group, impairing performance even when no mnemonic burden was present (at zero delay). The results suggest that cholinergic NBM and noradrenergic DNAB lesions produce only transient mnemonic deficiencies. A combination of the two can be disruptive, but longer term task (or reference) memory is the primary process affected, and only under certain conditions. The implication of these findings to research concerning animal models relating to Alzheimer's disease is discussed. 相似文献
5.
Geraldo F. Busatto Lyn S. Pilowsky Durval C. Costa John Mertehs Dirk Terriere Peter J. Ell Rachel Mulligan Michael J. Travis Josée E. Leysen Dominic Lui Sveto Gacinovic Wendy Waddington Anne Lingford-Hughes Robert W. Kerwin 《European journal of nuclear medicine and molecular imaging》1997,24(2):119-124
The mapping of 5-HT2 receptors in the brain using functional imaging techniques has been limited by a relative lack of selective radioligands.
Iodine-123 labelled 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150 or123I-R93274) is a new ligand for single-photon emission tomography (SPET), with high affinity and selectivity for 5-HT2A receptors. This study reports on preliminary123I-5-I-R91150 SPET, wholebody and blood distribution findings in five healthy human volunteers. Maximal brain uptake was approximately
2% of total body counts at 180 min post injection (p.i.). Dynamic SPET sequences were acquired with the brain-dedicated, single-slice
multi-detector system SEM-810 over 200 min p.i. Early peak uptake (at 5 min p.i.) was seen in the cerebellum, a region free
from 5HT2A receptors. In contrast, radioligand binding in the frontal cortex increased steadily over time, up to a peak at approximately
100–120 min p.i. Frontal cortex-cerebellum activity ratios reached values of 1.4, and remained stable from approximately 100
min p.i. onwards. Multi-slice SPET sequences showed a pattern of regional variation of binding compatible with the autoradiographic
data on the distribution of 5-HT2A receptors in (cerebral cortex>striatum>cerebellum). These findings suggest that123I-5-I-R91150 may be used for the imaging of 5-HT2A receptors in the living human brain with SPET. 相似文献
6.
Brandon JC; Teplick SK; Haskin PH; Sammon JK; Muhr WF; Hofmann AF; Gambescia RA; Zitomer N 《Radiology》1988,166(3):665-667
The authors describe their experience with methyl tertiary butyl ether (MTBE) in a larger series of patients than previously reported in order to acquaint physicians with both its effectiveness for dissolution of common bile duct calculi and the limitations of its use. Ten patients with 13 biliary calculi underwent percutaneous stone dissolution treatment with the experimental cholesterol solvent, MTBE. Three stones completely dissolved within 30 minutes, seven were reduced in size, and three were visibly unaffected. All stones not completely dissolved were easily extracted by means of a stone basket except for one in a patient taken to surgery. Although MTBE perfusion is an effective technique for management of biliary calculi, practitioners should be aware that its use is quite time consuming and its odor difficult to control. 相似文献
7.
R. Parker Ward MD Mouaz H. Al-Mallah MD Gabriel B. Grossman MD PhD Christopher L. Hansen MD Robert C. Hendel MD Todd C. Kerwin MD Benjamin D. McCallister Jr MD Rupa Mehta MD Donna M. Polk MD MPH Peter L. Tilkemeier MD Aseem Vashist MD Kim Allan Williams MD David G. Wolinsky MD Edward P. Ficaro PhD 《Journal of nuclear cardiology》2007,14(6):911-e38
8.
R. Parker Ward Mouaz H. Al-Mallah Gabriel B. Grossman Christopher L. Hansen Robert C. Hendel Todd C. Kerwin Benjamin D. McCallister Rupa Mehta Donna M. Polk Peter L. Tilkemeier Aseem Vashist Kim Allan Williams David G. Wolinsky Edward P. Ficaro 《Journal of nuclear cardiology》2007,14(6):e26-e38
Conclusion The ACCF/ASNC AC for SPECT MPI provides recommendations for the appropriate use of SPECT MPI. After the publication of the
AC document in 2005, the AC has been used by nuclear cardiology practices with many clinical studies evaluating the list of
indications in routine clinical practice. From these data. ASNC recommends minor but important changes to the indication list,
suggesting the addition of 6 new indications and the modification of the definitions for “chest pain syndrome” and “CHD high
risk.”. An objective review of existing indications focused on only those indications that had significant variability among
the reviewers (n=20). These indications were reviewed in the presence of existing and new evidence-based data, and ASNC recommends
that the grades for 6 indications be re-evaluated.
The AC for SPECT MPI will require periodic review as new evidence becomes available or as clinical practice evolves. ASNC
recognizes the importance of these criteria to improve the quality of patient care, and it will continue to play a key role
in assembling the information for this ongoing review. From the current summary of evidence, ASNC consensus opinions, and
ASNC recommendations in this document, ASNC strongly recommends that the AC guidelines be reviewed
Prepared by the American Society of Nuclear Cardiology Quality Assurance Subcommittee for Quality in Imaging Standards.
Reviewed by members of the American Society of Nuclear Cardiology Quality Assurance Committee.
Approved by the American Society of Nuclear Cardiology Board of Directors, September 6, 20. 相似文献
9.
Intestinal obstruction proximal to a transition zone without an interposed physical barrier usually indicates Hirschsprung disease. The authors report one case of focal small bowel muscular thinning just distal to a transition zone that produced clinical and radiographic findings that simulated long-segment Hirschsprung disease in a 2-day-old infant. 相似文献
10.
Image-directed percutaneous biopsies with a biopsy gun 总被引:3,自引:0,他引:3
Core tissue for histologic study is believed by many pathologists to be more diagnostic than material from needle aspiration. Recently, a biopsy "gun" has been introduced, which simplifies core biopsies. With this device, 182 biopsies of multiple anatomic sites were performed with ultrasonic, computed tomographic, and fluoroscopic guidance and 18-gauge needles. High-quality histopathologic specimens were obtained in 177 of the biopsies, and diagnostic target tissue was obtained in 167. Only three significant complications occurred: one bleeding complication that required transfusion and two cases of pneumothorax that necessitated placement of chest tubes. The biopsy gun eliminated the disjointed movements of conventional "skinny" needle biopsies, and none of the samples demonstrated significant "crush" artifact or obscuring blood, problems that are commonly associated with manual biopsy techniques. Patient discomfort was decreased with this system compared with that of manual biopsies, and the total procedure time was reduced. Because of these distinct advantages, the authors now use the biopsy gun exclusively for all percutaneous biopsies and recommend that other institutions consider the use of this biopsy method. 相似文献