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51.
William C Stanley Bin Li Douglas W Bonhaus Lowell G Johnson Keiho Lee Seth Porter Keith Walker Greg Martinez Richard M Eglen Roger L Whiting Sharath S Hegde 《British journal of pharmacology》1997,121(8):1803-1809
- Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine-β-hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study.
- Nepicastat produced concentration-dependent inhibition of bovine (IC50=8.5±0.8 nM) and human (IC50=9.0±0.8 nM)dopamine-β-hydroxylase. The corresponding R-enantiomer (RS-25560-198) was approximately 2–3 fold less potent than nepicastat. Nepicastat had negligible affinity (>10 μM) for twelve other enzymes and thirteen neurotransmitter receptors.
- Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg−1, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg−1, p.o.; b.i.d., for 5 days) produced dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noradrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg−1, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R-enantiomer (RS-25560-198), in the mesenteric artery and left ventricle.
- Administration of nepicastat (2 mg kg−1, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day-6 and day-7 of dosing, respectively.
- The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine-β-hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over-activation of the sympathetic nervous system, such as congestive heart failure.
52.
Seth T. Dahlberg MD Madeleine P. Gilmore Jeffrey A. Leppo MD 《Journal of nuclear cardiology》1994,1(3):270-279
Background
99mTc-labeled teboroxime shows high myocardial extraction in both in vivo animal and in vitro cell culture and isolated heart studies. Whereas in vivo studies show rapid myocardial clearance of teboroxime, in vitro cell culture and isolated heart studies show slower washout comparable to that of201Tl. Binding of teboroxime to blood components may contribute to these conflicting results.Methods and Results
We measured teboroxime extraction in the isolated blood-perfused rabbit heart after injection in saline solution, brief incubation in red blood cell perfusate, or 4-hour incubation with human red blood cells. Teboroxime in saline solution showed high extraction (Emax=0.89±0.02; Enet=0.69±0.02), whereas brief incubation in perfusate (Emax=0.60±0.06; Enet=0.48±0.05) or prolonged incubation with human red blood cells (Emax=0.43±0.09; Ene=0.38±0.07) resulted in reduced extraction. Teboroxime clearance was similar for all groups and was slower than201Tl clearance. Analysis of total residual cardiac teboroxime (comparable to external imaging) showed that teboroxime clearance was biexponential. Reduced extraction of teboroxime in red blood cells resulted in an increased size of the rapidly clearing (unextracted) fraction, giving the appearance of rapid myocardial washout.Conclusions
Teboroxime has a high myocardial extraction. Binding to blood components reduces teboroxime extraction and increases the rate of cardiac teboroxime clearance. 相似文献53.
The myocardial deposition of radiolabeled perfusion agents permits the noninvasive assessment of regional coronary blood flow. The design of imaging protocols and the optimal interpretation of clinical perfusion studies are based on an understanding of the kinetics of blood-tissue exchange for these compounds. Thallium 201 and the technetium 99m-labeled compounds sestamibi, teboroxime, and tetrofosmin show differing myocardial extraction and retention. This review focuses on studies that used cell culture, isolated heart, and intact animal models that form the basis of our current understanding of the myocardial kinetics of these imaging agents. 相似文献
54.
Neurofibrillary tangles are described in Guamanian and post-encephalitic forms of motor neuron discase (MND) but not in sporadic MND. We report the neuropathological findings in a 79-year-old man who died after a 1-year history of MND without extrapyramidal features or dementia. There was no family history of neurological disease and he had not visited Guam. The spinal cord showed loss of anterior horn cells, and skeletal muscle typical changes of denervation. The brain appeared macroscopically normal but histology revealed many neurofibrillary tangles, particularly in medial temporal lobe structures, insula, nucleus basalis, hippocampus, oculomotor nucleus, raphe nuclei and locus ceruleus. Neurofibrillary tangles were not seen in the primary motor cortex, which appeared histologically unremarkable. Occasional tangles were present in the substantia nigra and pontine nuclei. None were seen in the cerebellum, medulla or spinal cord. The tangles were argyrophilic, and, in sections stained with thioflavin-S, both the intracellular and the extracellular tangles fluoresced strongly under ultraviolet light. The intracellular neurofibrillary tangles reacted strongly with an antibody to tau protein, and only occasional tangles showed weak ubiquitin immunoreactivity. Scattered neuropil threads were present in the cortex in the areas of neurofibrillary tangle formation. No plaques were present in any part of the brain and no A4/ protein immunoreactivity was detected. Ultrastructural examination revealed Alzheimer-type neurofibrillary tangles composed of paired helical filaments. The present findings further extend the spectrum of diverse neurological disorders associated with neurofibrillary tangles. 相似文献
55.
S K Kabra Y Jain R M Pandey T MadhulikaSinghal P Tripathi S Broor P Seth V Seth 《Transactions of the Royal Society of Tropical Medicine and Hygiene》1999,93(3):294-298
An epidemic of dengue haemorrhagic fever (DHF) occurred in Delhi in 1996. A total of 240 children between the age of 4 months to 13 years of either sex, admitted in one hospital, were evaluated. Two hundred and sixteen (90%) children were from Delhi. A clinical diagnosis of dengue fever (DF) was made in 25 (10%), dengue fever with unusual bleeding (DFB) in 22 (9%), DHF in 80 (33%) and dengue shock syndrome (DSS) in 113 (47%) of the children strictly according to the WHO classification. The age peaked at 8 years. There was no association between various grades of severity of illness and age-groups though girls suffered from more severe illness. No association between severity of malnutrition and severity of illness was observed. Tourniquet test was positive in 40% with DF, 18% with DFB, 62% with DHF and 64% with DSS. In DSS haematemesis was present in 55 (49%), epistaxis in 39 (35%), melaena in 27 (24%) and ecchymosis in 34 (30%) patients. Children diagnosed as DFB had haematemesis and epistaxis in 12 (55%) and 10 (45%) respectively. Intravenous fluid requirement was clearly less in DFB patients than in DHF/DSS patients. Unusual clinical features in the form of jaundice were present in 7 (6%), hepatic encephalopathy in 6 (5%) and dengue encephalopathy in 6 (5%) patients. Dengue 2 virus was isolated from 10 of the 50 patients for whom viral culture was done on C6/36 clone of Aedes albopictus cell line. Eighteen patients suffering from DSS died giving an overall case fatality of 7.5%. The mortality rate in DHF/DSS was 9.3%. It is further suggested that DFB is a distinct entity. Most patients could be classified by the WHO classification if a retrospective packed cell volume was used to assess haemoconcentration. We suggest that development of area-specific criteria for diagnosis and management is desirable. 相似文献
56.
From a Pediatric Rheumatology Clinic 361 children diagnosed as juvenile rheumatoid arthritis (JRA) according to American Rheumatism
Association-JRA criteria were studied retrospectively for their clinico-immunological profile. The mean age of onset in systemic,
pauciarticular and polyarticular onset, JRA subtypes were 5.2, 6.8 and 7.2 years respectively. There was male preponderance
in systemic and pauciarticular JRA. In seropositive polyarticular JRA, girls outnumbered boys. The frequency of occurence
of systemic, pauciarticular and polyarticular disease was 87 (24%), 108 (30%) and 166 (46%) respectively. The systemic onset
disease was dominated by extra-articular manifestations in terms of fever (100%), rash (57%), hepatomegaly (51%) and lymphadenopathy
(25%). The pauci- and polyarticular illnesses were commonly dominated by joint involvement, morning stiffness, and in few
patients, by extra-articular manifestations also. The joints were involved symmetrically. Most commonly involved joints in
order of decreasing frequency were knee, ankle, wrist and elbow in all the subtypes. Anemia and leucocytosis were observed
in majority with higher frequency in systemic onset JRA. The rheumatoid factor (RF) was present in 15% of polyarticular JRA.
RF was also present in 7 and 9% of patients with pauciarticular and systemic subtypes respectively. The antinuclear antibody
was positive in only 3 out of 66 patients in whom the test was carried out.
The demographic profile and trends in clinical features were similar to the studies reported on caucasian population with
difference in the actual frequency of various clinical features. 相似文献
57.
Burger A Li H Panayiotakis A Salesiotis A Seth A 《International journal of oncology》1996,8(2):395-400
A number of genes differentially expressed in breast cancer were isolated using a subtractive cloning technique. DNA sequence analysis and GenBank searches of T4F10, T2H7, and T2E5 cDNA clones found them to be identical with E2A, MSS1, and SEC13R genes. Their expression in a variety of primary breast tumor and cancer cell lines was compared with c-ERB-B2 and pS2 by Northern blot analysis. In breast cancer cell lines, the genes that we isolated are more frequently expressed than the previously described c-ERB-B2 and pS2. 相似文献
58.
Deletions in the ligand for CD40 in X-linked immunoglobulin deficiency with normal or elevated IgM (HIGMX-1) 总被引:10,自引:0,他引:10
Ramesh Narayanaswamy; Fuleihan Ramsay; Ramesh Vijaya; Lederman Seth; Yellin Michael J.; Sharma Sunita; Chess Leonard; Rosen Fred S. 《International immunology》1993,5(7):769-773
Patients with X-linked Ig deficiency with normal or elevatedIgM (HIGMX-1) fail to switch from IgM/IgD to other Ig isotypes.Interaction between the B cell antigen CD40 and the CD40 ligandexpressed on activated T cells is critical for T cell drivenisotype switching. We have reported that T lymphocytes fromthree unrelated male patients with HIGMX-1 failed to expressCD40 ligand on their surface, but the mRNA for CD40 ligand wasof an apparently normal size and level. Analysis of CD40 ligandcDNA from two of the patients revealed deletions that alterthe reading frame. Patient 1 displayed two mutations: a C Atransversion at nucleotide 590 and the deletion of an adjacentC nucleotide. The second patient had a 58 bp deletion from nucleotides289–346. Furthermore, neither patient expressed a proteinproduct detectable by the CD40L mAb, 5c8. 相似文献
59.
Glutathione-S-transferase activity has been demonstrated in the brain of rabbit, guinea pig, rat, mouse, and pigeon. The activity was in the following order: rabbit > (guinea pig = mouse) > rat > pigeon. The activity of brain was about 1/3 to 1/9 of that present in liver depending upon the species. In the rat brain glutathione-S-transferase activity was found to be distributed equally in cerebrum, cerebellum, and brain stem and localized mainly in the organelle-free cytosol fraction. 相似文献
60.
Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy. 总被引:4,自引:0,他引:4
Jennifer A Low Arlene W Berman Seth M Steinberg David N Danforth Marc E Lippman Sandra M Swain 《Journal of clinical oncology》2004,22(20):4067-4074
PURPOSE: To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy. PATIENTS AND METHODS: Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy. RESULTS: OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients. CONCLUSION: Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook. 相似文献