Thromboxane synthetase inhibitors and antihypertensive agents. 3. N-[(1H-imidazol-1-yl)alkyl]heteroaryl amides as potent enzyme inhibitors

The title compounds were prepared as the heterocyclic analogues of thromboxane (TX) synthetase inhibitors and antihypertensive agents previously reported from our laboratories. These compounds were at least as active TX synthetase inhibitors as their benzene isosteres with the indole derivatives 50-55 having the most potent enzyme inhibiting activity measured to date in our laboratories. The best compound, 54, is more than 200-fold more potent than the standard, dazoxiben. In contrast, the antihypertensive activity of these series of compounds was no better than their benzene counterparts and is far lower than the isoindoledione derivatives prepared in a related series. The structure-activity relationship results from this study were similar to our previous observations and include the fact that the amide moiety effectively replaces a carboxylic acid for potent TX synthetase inhibition and that a four to six methylene unit separation (approximately 8.5 A) between amide and imidazole moieties achieves maximal activity.     

Autoimmune Pancreatitis in an Asian-dominant American Population

Autoimmune pancreatitis is a rare type of chronic pancreatitis that occurs predominantly in males and was first described in the Asian population. The following study seeks to characterize autoimmune pancreatitis in Hawai‘i''s Asian-dominant population through a retrospective review of 65 pancreaticoduodenectomy cases performed between 2000 and 2010. Three of the 65 pancreaticoduodenectomies were diagnosed with autoimmune pancreatitis, and 3 additional cases were diagnosed prior to surgery. All six patients were males and presented with obstructive jaundice, 5 with weight loss, and 4 with epigastric pain and elevated serum lipase. All six patients showed elevated serum IgG4. Imaging revealed findings typical of pancreatic malignancy: distal bile duct stricture and pancreatic head mass. However, no nodal involvement and vascular invasion were found. In conclusion, autoimmune pancreatitis should be considered in patients presenting with obstructive jaundice. Elevated serum IgG4, normal serum carbohydrate antigen CA19-9, a benign fine needle aspiration/core biopsy, and a therapeutic response to corticosteroid are typical findings of autoimmune pancreatitis. Serum IgG4 measurement is a useful tool to help differentiate autoimmune pancreatitis from most pancreatic cancers. It is important to consider autoimmune pancreatitis as a differential diagnosis of pancreatic malignancy to avoid unnecessary surgery.     

Breast cancer risk and ovariectomy, hysterectomy, and tubal sterilization in the women's contraceptive and reproductive experiences study

Removal or impairment of ovaries before menopause may affect a woman's breast cancer risk by altering her cumulative exposure to ovarian hormones. The Women's Contraceptive and Reproductive Experiences Study, a population-based, multicenter case-control study of incident invasive breast cancer, recruited women aged 35-64 years (4,490 cases and 4,611 controls) who provided data on ovariectomy, hysterectomy, and tubal sterilization during in-person interviews. Controls were frequency-matched to cases by age, race, and study site. Unconditional logistic regression analysis was used. Women who had not undergone premenopausal reproductive surgery were the referent group. Bilateral ovariectomy was associated with reduced breast cancer risk overall (odds ratio (OR) = 0.59, 95% confidence interval (CI): 0.50, 0.69) and among women <45 years of age (ORs ranged from 0.31 to 0.52), but not among those who were older at surgery. It was also associated with a reduced risk for estrogen and progesterone receptor-positive tumors (OR = 0.63, 95% CI: 0.52, 0.75) but not receptor-negative tumors. Hysterectomy with ovarian conservation (OR = 0.83, 95% CI: 0.72, 0.96) and hysterectomy with partial ovary removal (OR = 0.73, 95% CI: 0.59, 0.91) were also associated with lower risk. No association with breast cancer risk was observed with tubal sterilization only or partial ovariectomy without hysterectomy. Reproductive organ surgeries may alter ovarian hormone levels, thereby affecting breast cancer risk.     

Flexible limited sampling model for monitoring tacrolimus in stable patients having undergone liver transplantation with samples 4 to 6 hours after dosing is superior to trough concentration

Trough (C0) monitoring is not optimal for therapeutic drug monitoring of tacrolimus. To better estimate systemic exposure of tacrolimus and achieve clinical benefit, an improved therapeutic drug monitoring strategy should be developed. The authors examined which single and combination of time points best estimated the empiric "gold standard" AUC0-12h and developed and validated a new, flexible, and accurate limited sampling model for monitoring tacrolimus in patients having undergone liver transplantation. Twenty-three stable patients with full AUC0-12h were divided into two groups based on area under the concentration-time curve/dose. With multiple regression analysis, limited sampling formulae were derived and population-pharmacokinetic-based limited sampling models were developed and validated. A regression analysis was performed between either area under the concentration-time curves calculated with formulae or models with the reference trapezoidal AUC0-12h. Both formulae and models based on single samples C4-C6 (r2 = 0.94 [MPE/MAPE 0/7]-0.90 [2/8] and 0.97 [0/7]-0.97 [1/5]) showed excellent performance. The calculated area under the concentration-time curve target range for tacrolimus was 90 to 130 h*microg/L. Multiple point sampling performed better, especially when using models (r2 > 0.94). C0 was a less precise predictor of AUC0-12h compared with both formulae and models (r2's 0.68 [5/17] and 0.87 [2/14]). In conclusion, trough concentration monitoring is not an accurate method for assessing systemic exposure to tacrolimus in stable patients having undergone liver transplantation. This new limited sampling model, based on single time points C4-C6, shows excellent performance in estimating the AUC0-12h.     

Phase II study of ifosfamide and etoposide chemotherapy for extensive-disease small-cell lung cancer

We conducted a phase II study of ifosfamide and etoposide chemotherapy in patients with untreated extensive-disease small-cell lung cancer to assess response and toxicity. Between January 1994 and December 1995, 16 patients were treated. Ifosfamide and etoposide doses were ifosfamide 2 g/m2, with mesna, i.v. infusion over 30 minutes on days 1-3 and etoposide 80 mg/m2 i.v. over 120 minutes on days 1-3 every 4 weeks for up to six cycles. All patients were evaluable for toxicity profile and treatment response. As expected, the major toxicity was myelosuppression. With one exception, grade 3 or 4 leukopenia occurred in all patients during treatment, and 48.7% of the total courses had grade 3 or 4 leukopenia. Nine of 16 patients (56.3%) experienced episodes of febrile neutropenia. One toxic death due to febrile neutropenia with sepsis was documented. Toxicities other than leukopenia were few and mild in severity. After two cycles of treatment, the overall response rate was 81.3% (95% confidence interval 62.2-100) in this study. The median duration of response was 8 months and median survival was 11 months. In conclusion, ifosfamide and etoposide is an active combination regimen with acceptable toxicity profile in Chinese patients with extensive-disease small-cell lung cancer.      

The risk of angiosarcoma following primary breast cancer.

Lymphangiosarcoma of the upper extremity is a rare and aggressive tumour reported to occur following post-mastectomy lymphoedema (Stewart-Treves syndrome). Haemangiosarcoma, a related rare tumour, has occasionally been reported to occur in the breast following irradiation. We conducted a case-control study using the University of Southern California-Cancer Surveillance Program, the population-based cancer registry for Los Angeles County, to evaluate the relationship between invasive female breast cancer and subsequent upper extremity or chest lymphangiosarcoma and haemangiosarcoma together referred to as angiosarcoma. Cases were females diagnosed between 1972 and 1995 with angiosarcoma of the upper extremity (n = 20) or chest (n = 48) who were 25 years of age or older and residing in Los Angeles County when diagnosed. Other sarcomas at the same anatomic sites were also studied. Controls were females diagnosed with cancers other than sarcoma during the same time period (n = 266,444). Cases and controls were then compared with respect to history of a prior invasive epithelial breast cancer. A history of breast cancer increased the risk of upper extremity angiosarcoma by more than 59-fold (odds ratio [OR] = 59.3, 95% confidence interval [95% CI] = 21.9-152.8). A strong increase in risk after breast cancer was also observed for angiosarcoma of the chest and breast (OR = 11.6, 95% CI = 4.3-26.1) and for other sarcomas of the chest and breast (OR = 3.3, 95% CI = 1.1-1.7).     

Glomus tumour in a child

Glomus tumours are uncommon neoplasms. Very rarely do they present in the paediatric age group. We describe a case of bilateral glomus tumours in a 13‐year‐old girl that were successfully treated with radiotherapy. The patient remains well 8 years after completion of treatment.     

生物组织膜细胞色素C电极的研究

本文以猪肾组织膜偶合氧电极制成了生物组织膜细胞色素C电极,测试了电极的响应特性,在0.01～0.227mg/ml细胞色素C浓度范围内,该电极的动力学响应与细胞色素C浓度的对数间呈线性关系,相关系数为-0.9949。研究了缓冲剂、pH条件、温度、切片厚度和防腐剂等因素对电极性能的影响,并试验了组织膜的有效活性周期,采用动力学方法测定了一些样品的平均回收率为98.8%,标准偏差为3.4%。     

Use of CT in the evaluation of cochlear otosclerosis

Otosclerosis (otospongiosis) occurs when the hard endochondral bone of the otic capsule is replaced by spongy vascular foci of haversian bone. Using computed tomography (CT), we studied the ears of 32 selected patients with mixed or sensorineural hearing loss (one patient had normal hearing); 24 were suspected of having otosclerosis. CT proved valuable in detecting cochlear otosclerosis, foci of demineralization, and changes in bony texture and enables the easy recognition of subtle radiographic findings. Our paper also reports the CT findings of temporal bones in osteogenesis imperfecta and Paget disease.