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61.
Summary Estrogen has an important role in stimulating the growth of breast carcinomas. Inhibition of estrogen production is therefore a logical treatment strategy. A number of selective inhibitors have been developed against aromatase, a cytochrome P-450 enzyme which catalyzes the rate limiting step in the biosynthesis of estrogens. The mechanisms of the aromatase reaction, current knowledge of the enzyme, and regulation of its expression are discussed as the basis for inhibitor development. Two classes of aromatase inhibitors, steroidal and non-steroidal compounds, are now coming into use. Among the steroid substrate analogues, 4-hydroxyandrostenedione (4-OHA) has been shown to be effective in breast cancer patients with advanced disease and was recently approved for treatment in the United Kingdom. Several different classes of compounds which act as aromatase inhibitors are currently in clinical trials and should provide breast cancer patients with a number of treatment options. Among these are highly potent and selective non-steroidal inhibitors which have recently been found to suppress plasma and urinary estrogens over 95% in breast cancer patients. The potency of these newer aromatase inhibitors provides the opportunity to determine whether complete suppression of estrogen production and action will result in enhanced tumor regression. 相似文献
62.
Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration‐dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B‐containing lipoproteins into plasma. Avasimibe induced cholesterol 7α‐hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol‐fed as well as in non‐cholesterol‐fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non‐HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50–500 mg/day, significantly reduced plasma total triglyceride and VLDL‐cholesterol. Although total cholesterol, LDL‐cholesterol, and HDL‐cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol‐lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol. 相似文献
63.
K. Iwatsuki L-M. Ren S. Chiba 《Clinical and experimental pharmacology & physiology》1994,21(9):701-707
1. The effects of the cyclic nucleotide phosphodiesterase (PDE) inhibitors, Ro20,1724, 3-isobutyl-1-methylxanthine (IBMX), trifluoperazine (TFP) and amrinone on pancreatic exocrine secretion were investigated in anaesthetized dogs in comparison with those of secretin and cholecystokinin octapeptide (CCK-8). 2. Ro20,1724 (1–30 nmol/kg), IBMX (3–30 nmol/kg), secretin (0.01–0.1 pmol/kg) or CCK-8 (0.1–1 pmol/kg) injected i.a. elicited a dose-dependent increase in the secretion of pancreatic juice, but TFP and amrinone (up to 1 μmol/ kg) did not. 3. The bicarbonate concentration in pancreatic juice was increased and the protein concentration was decreased by Ro20,1724, IBMX and secretin. Cholecystokinin octapeptide increased the protein concentration but did not alter the bicarbonate concentration. 4. Ro20,1724 and IBMX elicited more than the respective additive secretory response when added together with secretin, although the stimulatory effects of CCK-8 with Ro20,1724 and IBMX were additive. 5. Ro20,1724 and IBMX increased cyclic AMP concentration but did not affect cyclic GMP concentration. 6. These results suggest that Ro20,1724 and IBMX have secretory properties on pancreatic exocrine glands of the dog, which may be mediated through an increase in cyclic AMP subsequent to inhibition of PDE activity. Furthermore, pancreatic PDE enzymes in the dog may be mainly type IV. 相似文献
64.
The question whether the benzodiazepine receptor site in astrocytes or in neurons might be identical to the adenosine uptake site was studied by determining pharmacological profiles, inhibition types, and the effects of benzodiazepine antagonsts in primary cultures of either astrocytes or neurons. Fourteen different benzodiazepines and five different adenosine uptake inhibitors displaced [3H] diazepam and inhibited adenosine uptake in both astrocytes and neurons. However, the rank orders (determined as IC50 values) with which these two parameters were affected were profoundly different, indicating dissimilarities between these two sites. For several of the compounds a difference in inhibition type (competitive vs. noncompetitive) was observed between the benzodiazepine-binding site and the adenosine uptake site in astrocytes and/or neurons, which further corroborated the conclusion of a difference between the benzodiazepine-binding site and the adenosine uptake site. Finally, the neuronal benzodiazepine antagonists RO 15-1788 and CGS-8216 and the astrocytic benzodiazepine antagonist PK 11195, which reverse the action of benzodiazepines, were not able to reverse inhibition of adenosine uptake by diazepam but exerted an inhibitory effect of their own. 相似文献
65.
Persisting cough developed in three children treated with converting enzyme inhibitors. The symptoms disappeared within 3–7 days after withdrawing medication. These observations in children complement previous reports in adults and indicate that cough may be induced by treatment with these agents. 相似文献
66.
Cheryce M. Poon M.D. Robert A. Koenigsberg D.O. Betsy A. Izes M.D. 《Emergency radiology》1997,4(5):264-267
Angioedema of the oropharynx and hypopharynx due to oral angiotensin-converting enzyme (ACE) inhibitors is a potentially life-threatening event and has not been well described in the radiology literature. A retrospective review of the clinical and radiologic findings in three patients with angioedema due to ACE inhibitor use was performed.Our subgroup of patients treated with ACE inhibitors presented with varying degrees of dysphagia, dyspnea, and facial swelling. Plain radiographic findings included enlargement of the epiglottis, aryepiglottic folds, and prevertebral and submental soft tissue. Computed tomography confirmed extensive retropharyngeal and subcutaneous edema. Clinical symptoms resolved in each case in 24–48 hours with cessation of the ACE inhibitor and concomitant steriod therapy.Our cases demonstrate the typical clinical and radiographic presentation of neck angioedema in the setting of ACE inhibitor use. As ACE inhibitors are increasingly being used as first-line agents in the treatment of hypertension, we caution that neck angioedema may be encountered with increased frequency in adults. Early recognition and immediate intervention result in rapid resolution of this potentially life-threatening event. 相似文献
67.
Tang Jian汤健 Wang Yu王瑜 Zkang Chenhui张晨晖 E. Costa Institute of Cardiovascular Research Beijing Medical University 《北京大学学报(医学版)》1994,(Z1)
THECLONINGOFNa ̄+/Ca ̄(2+)EXCHANGERGENEANDITSEXPRESSIONINBRAINISCHEMIATangJian汤健,WangYu王瑜,ZkangChenhui张晨晖,E.CostaInstituteofCar... 相似文献
68.
GP SCHWAB AL BLUM E BODNER B DALLEMAGNE K GLASER H KOOP F PACE W RÖSCH JR SIEWERT G WETSCHER 《Journal of gastroenterology and hepatology》1997,12(12):785-789
Gastroesophageal reflux disease (GERD) is the most common disease of the upper gastrointestinal tract. With the introduction of proton pump inhibitors medical treatment of GERD has been significantly improved. However, the development of laparoscopic antireflux surgery resulted in an increasing interest of surgeons in this disease. An interactive meeting was organized in order to develop an agreement between gastoenterologists and surgeons regarding therapeutic decisions and this is the main topic of this paper. 相似文献
69.
F. BRUNET J. P. MIRA C. CERF M. BELGHITH O. SOUBRANE J. L. TERMIGNON† B. RENAUD L. FIEROBE I. HAMY M. MONCHI E. DESLANDE A. BRUSSET† J. F. DHAINAUT 《Artificial organs》1994,18(11):826-832
Abstract: This open clinical study was aimed at testing the hypothesis that an intravascular oxygenator (IVOX) may help to perform permissive hypoventilation in 10 patients with severe ARDS. After initial evaluation, we tried to reduce ventilator settings before and after IVOX implantation. Before IVOX, poor clinical tolerance and worsening oxygenation did not allow for a significant decrease in ventilator settings. With IVOX, peak inspiratory pressure (PIP) was reduced from 47 to 39 cm H2 O (p = 0. 005) and minute ventilation from 13 ± 3. 5 to 11 ± 3 L/min. CO2 removal by IVOX allowed a significant decrease in Paco2 from 66 ± 15 to 59 ± 13 mm Hg. Improvement of oxygenation with IVOX was not signify cant. Furthermore, interruption of oxygen flow through IVOX did not change oxygenation variables. Tolerance of the IVOX device was good, but insertion of the device was followed by a significant decrease in both cardiac index and pulmonary wedge pressure. In conclusion, IVOX improves tolerance of hypoventilation by limiting hypercapnia in ARDS patients. These preliminary results must be confirmed by a randomized controlled study 相似文献
70.
Activated prothrombin complex concentrate (FEIBA® ) treatment during surgery in patients with inhibitors to FVIII/IX 总被引:1,自引:0,他引:1
Non-activated and activated prothrombin complex concentrates (PCC/aPCC) have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX (FVIII/IX) concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 14 minor and five major surgical and invasive diagnostic procedures in eight patients with congenital haemophilia A and inhibitors and in two patients with acquired haemophilia. When a loading dose of 100 U kg-1 of FEIBA was given followed by 200 U kg-1 day-1 in three divided doses every 8 h for 3 days, and then, when the daily dose was tapered to 100-150 U kg-1, no severe or unexpected bleeding complications were observed. However, one adverse event was observed. A 69-year-old man who suffered a myocardial infarction the third postoperative day following sigmoidectomy was managed safely with opiate analgesia, nitrates and diuretics, and the continued use of FEIBA(R). 相似文献