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141.
Allon Nechmad Rachel Maayan Baruch Spivak Edward Ramadan Michael Poyurovsky Abraham Weizman 《European neuropsychopharmacology》2003,13(5):327-332
Although it is known that selective serotonin reuptake inhibitors (SSRIs), as other antidepressants, elevate mood only after 3-4 weeks of treatment, the mechanism responsible for this delay is not understood. SSRIs have been demonstrated to alter the levels of neurosteroids such as allopregnanolone (THP) which possess anxiolytic and mood-elevating properties. We compared the effect of 9 and 21 days i.p. administration of paroxetine, a potent SSRI, on the synthesis of THP and its precursor, 5alpha-dihydroprogesterone (DHP), in the mouse cortex, hypothalamus and olfactory bulb. Cortex, olfactory bulb and hypothalamus synthesized levels of DHP were significantly raised after 9 days of paroxetine administration, whereas a significant rise in the THP synthesized level was observed only after 21 days of treatment. Peripheral synthesis of DHP, measured by the level in serum, significantly increased after 9 days, but reverted to normal values after 21 days. No increase was detected in serum THP levels either after 9 or 21 days treatment. Differences in peripheral and brain synthesis indicates independence in brain synthesis. The data indicate that paroxetine administration differentially increases [3H]DHP and [3H]THP content, depending on the duration of the treatment. Our results suggest that brain THP may be involved in the antidepressive and anxiolytic activity of paroxetine. 相似文献
142.
Michael H Abraham Mostafa Hassanisadi Mehdi Jalali-Heravi Taravat Ghafourian William S Cain J Enrique Cometto-Muniz 《Toxicological sciences》2003,76(2):384-391
Draize rabbit eye test scores, as modified maximum average score (MMAS), for 68 pure bulk liquids were adjusted by the liquid-saturated vapor pressure P. These 68 adjusted scores, as log (MMAS/P), were shown to be completely equivalent to eye irritation thresholds (EIT), expressed as log (1/EIT), for 23 compounds in humans. Thus, for the first time the Draize eye test in rabbits for pure bulk liquids is shown to be perfectly compatible with eye irritation thresholds in humans. The total data set for 91 compounds was analyzed by the general solvation equation of Abraham. Values of log (MMAS/P) or log (1/EIT) could be fitted to a five-parameter equation with R2 = 0.936, SD = 0.433, AD = 0.000, and AAD = 0.340 over a range of 9.6 log units. When divided into a training set of 45 compounds, the corresponding equation could be used to predict the remaining 46 compounds in a test set with AD = -0.037 and AAD = 0.345 log units. Thus, the 91-compound equation can now be used to predict further EIT values to around 0.4 log units. It is suggested that the mechanism of action in the Draize test and in the human EIT involves passive transfer of the compound to a biophase that is quite polar, is a strong hydrogen bond base, a moderate hydrogen bond acid, and quite hydrophobic. The biophase does not resemble water or plasma, but resembles an organic solvent such as N-methylformamide. 相似文献
143.
Urmila P Kodavanti Carolyn F Moyer Allen D Ledbetter Mette C Schladweiler Daniel L Costa Russ Hauser David C Christiani Abraham Nyska 《Toxicological sciences》2003,71(2):237-245
Epidemiologists have associated particulate matter (PM) air pollution with cardiovascular morbidity and premature mortality worldwide. However, experimental evidence demonstrating causality and pathogenesis of particulate matter (PM)-induced cardiovascular damage has been insufficient. We hypothesized that protracted, repeated inhalation by rats of oil combustion-derived, fugitive emission PM (EPM), similar in metal composition to selected sources of urban air PM, causes exposure duration- and dose-dependent myocardial injury in susceptible rat strains. Zinc was the only primary water-leachable/bioavailable element of this EPM. Male Sprague-Dawley (SD), Wistar Kyoto (WKY), and spontaneously hypertensive (SH) rats were exposed nose-only to EPM (2, 5, or 10 mg/m(3), 6 h/day for 4 consecutive days or 10 mg/m(3), 6 h/day, 1 day/week for 4 or 16 consecutive weeks). Two days following the last EPM exposure, cardiac and pulmonary tissues were examined histologically. The results showed that particle-laden alveolar macrophages were the only pulmonary lesions observed in all three rat strains. However, WKY rats exposed to EPM (10 mg/m(3) 6 h/day, 1 day/week for 16 weeks) demonstrated cardiac lesions with inflammation and degeneration. To further characterize the nature of EPM-associated lesions, more rigorous histopathological and histochemical techniques were employed for WKY and SD rats. We examined the hearts for myocardial degeneration, inflammation, fibrosis, calcium deposits, apoptosis, and the presence of mast cells. Decreased numbers of granulated mast cells, and multifocal myocardial degeneration, chronic-active inflammation, and fibrosis were present in 5 of 6 WKY rats exposed to EPM for 16 weeks. None of these lesions were present in WKY exposed to clean air. EPM-related cardiac lesions were indistinguishable from air-exposed controls in SD and SH rats. This study demonstrates that long-term inhalation exposures to environmentally relevant PM containing bioavailable zinc can cause myocardial injury in sensitive rats. These findings provide supportive evidence for the epidemiological associations of cardiovascular morbidity and ambient PM. 相似文献
144.
Approval summary: Docetaxel in combination with prednisone for the treatment of androgen-independent hormone-refractory prostate cancer. 总被引:1,自引:0,他引:1
Ramzi Dagher Ning Li Sophia Abraham Atiqur Rahman Raji Sridhara Richard Pazdur 《Clinical cancer research》2004,10(24):8147-8151
PURPOSE: Docetaxel, a taxane previously approved for the treatment of breast cancer and non-small cell lung cancer, was approved by the United States Food and Drug Administration on May 19, 2004 for use in combination with prednisone for the treatment of metastatic androgen-independent (hormone-refractory) prostate cancer. The purpose of this summary is to review the database supporting this approval. EXPERIMENTAL DESIGN: In a randomized, global study enrolling 1,006 patients, two schedules of docetaxel were compared with mitoxantrone + prednisone as follows: MTZ q 3w, mitoxantrone 12 mg/m2 every 21 days + prednisone 5 mg twice a day for a total of 10 cycles; TXT q 3w, docetaxel 75 mg/m2 every 21 days + prednisone 5 mg twice a day for a total of 10 cycles; and TXT qw, docetaxel 30 mg/m2 days 1, 8, 15, 22, and 29 every 6 weeks + prednisone 5 mg twice a day for a total of 5 cycles. RESULTS: There was a statistically significant overall survival advantage shown for the TXT q 3w arm over MTZ q 3w (median survival 18.9 months versus 16.5 months, P = 0.0094). No overall survival advantage was shown for TXT qw compared with MTZ q 3w. The most commonly occurring adverse events included anemia, neutropenia, infection, nausea, sensory neuropathy, fluid retention, alopecia, nail changes, diarrhea, and fatigue. CONCLUSIONS: This report describes the Food and Drug Administration review supporting this first approval of a combination therapy for hormone-refractory prostate cancer based on demonstration of a survival benefit. 相似文献
145.
Abraham SC Ravich WJ Anhalt GJ Yardley JH Wu TT 《The American journal of surgical pathology》2000,24(12):1678-1682
Involvement of the esophagus by lichen planus is a rarely reported condition. The histologic features of esophageal lichen planus, which may differ from those of cutaneous disease, have only rarely been illustrated. We describe a 58-year-old woman with skin and oral lichen planus who presented with dysphagia and an esophageal stricture that were ultimately diagnosed as esophageal lichen planus. Multiple esophageal biopsies demonstrated a lichenoid, T cell-rich lymphocytic infiltrate, along with degeneration of the basal epithelium and Civatte bodies. Correct diagnosis of esophageal lichen planus is critical because of its prognostic and therapeutic distinction from other more common causes of esophagitis and stricture formation. 相似文献
146.
Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. 总被引:4,自引:0,他引:4
Jame Abraham Manish Agrawal Susan Bakke Ann Rutt Maureen Edgerly Frank M Balis Brigitte Widemann Louis Davis Bharat Damle Daryl Sonnichsen David Lebwohl Susan Bates Herb Kotz Tito Fojo 《Journal of clinical oncology》2003,21(9):1866-1873
PURPOSE: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. PATIENTS AND METHODS: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. RESULTS: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. CONCLUSION: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting. 相似文献
147.
Therapy of heart failure 总被引:2,自引:0,他引:2
The incidence and prevalence of heart failure is on the rise. It has become the single most expensive health care item in the United States and the number one discharge diagnosis in the elderly. The goals of therapy include both prevention and treatment of heart failure. In recent years research studies and randomized clinical trials have revolutionized the understanding of the pathophysiology and treatment of this disease. This article focuses on the medical management of chronic systolic heart failure based on the pathophysiology of the disease. Systolic heart failure is characterized by a decrease in left ventricular function and cardiac output, which results in activation of several neurohormonal compensatory systems. The long term effects of this neurohormonal activation leads to further deterioration of cardiac function. The use of hydralazine and nitrates to reduce the systemic vascular resistance was the first to show an improvement in mortality and morbidity. Then angiotensin converting enzyme inhibitors, by inhibiting the renin angiotensin system, demonstrated a greater improvement in mortality and morbidity. More recently the inhibition of the sympathetic stimulation with beta-blockers has been shown to have an additive effect on morbidity and mortality in combination with angiotensin-converting enzyme inhibitors. Digoxin and diuretics remain important for improving symptoms and decreasing hospitalizations but have not been shown to decrease mortality. The most recent advance in the treatment of cardiac failure is the demonstration that the aldosterone antagonists, spironolactone decreases morbidity and mortality. 相似文献
148.
149.
Abraham Benshushan Orly Shoshani Ora Paltiel Joseph G. Schenker Aby Lewin 《Journal of assisted reproduction and genetics》1997,14(6):347-353
Purpose: Our purpose was to measure changes in semen quality and quantity in young healthy sperm donors in Jerusalem over time.
Methods: A retrospective analysis of semen parameters over 15 years using linear regression analysis, in a single sperm bank in a
tertiary university center. Study population consisted of 188 young, healthy medical students, aged 20 to 30 years, who donated
sperm samples for Artificial insemination between 1980 and 1995.
Results: There were no statistically significant changes in semen concentration and motility during the study period. The mean semen
volume increased by 0.1 ml (5.1%) per year (P < 0.0001), with a concomitant mean rise of 5.8 × 106 (7.7%) per year in total motile sperm count. The percentage normal morphology decreased by a mean of 1.04% per year during
the entire period (P < 0.0001).
Conclusions: During the past 15 years, there has been an increase in total motile sperm count, secondary to an increase in semen volume,
and a decline in normal morphology that are independent of the age and the duration of abstinence in fertile men. 相似文献
150.
Garth Powis Alfred Gallegos Robert T. Abraham Curtis L. Ashendel Loen H. Zalkow Robert Dorr Katerina Dvorakova Sydney Salmon Steadman Harrison John Worzalla 《Cancer chemotherapy and pharmacology》1997,41(1):22-28
Purpose: Studies were conducted on oryzalin (3,5-dinitro-N,N-di(n-propyl)sulfanilamide), a widely used dinitroaniline sulfonamide herbicide, which was identified from plant extracts as an
inhibitor of mitogen- and growth factor-mediated intracellular free Ca2+ ([Ca2+]i) signalling in mammalian cells. Methods and Results: Oryzalin inhibited vasopressin, bradykinin and platelet-derived growth factor [Ca2+]i signalling in Swiss 3T3 fibroblasts with IC50 values of 14, 16 and 18 μM, respectively. 45Ca2+ uptake into nonmitochondrial stores of saponin-permeabilized Swiss 3T3 cells was inhibited by oryzalin with an IC50 of 34 μM. Oryzalin inhibited colony formation of HT-29 colon carcinoma cells with an IC50 of 8 μM and inhibited the growth of a number of other cancer cell lines and primary human tumors in vitro with IC50 values in the range 3 to 22 μM. A number of oryzalin analogues were studied and an association was found between the ability to inhibit [Ca2+]i signalling and inhibition of the growth of HT-29 human colon cancer cells (P=0.001) and of CCRF-CEM human leukemia cells (P=0.016). Oryzalin at doses up to 600 mg/kg administered orally or subcutaneously daily to mice for 3 to 10 days beginning
a day after tumor inoculation inhibited the growth of murine B16 melanoma by 63% but showed no appreciable activity when administered
subcutaneously or intraperitoneally to mice beginning a number of days after tumor inoculation against a variety of human
tumor xenografts. The peak plasma concentration of oryzalin following repeated subcutaneous administration of oryzalin at
600 mg/kg per day to mice was 37 μM and of its major metabolite N-depropyl oryzalin was 53 μM. Conclusion: It is unlikely that the absence of significant antitumor activity of oryzalin is a result of the inability to achieve adequate
plasma concentrations.
Received: 24 December 1996 / Accepted: 20 March 1997 相似文献