Synthesis and anticancer activity of simplified indenoisoquinoline topoisomerase I inhibitors lacking substituents on the aromatic rings

The indenoisoquinolines are a class of cytotoxic topoisomerase I inhibitors that offer certain advantages over the camptothecins, including the greater stabilities of the compounds themselves, as well as the greater stabilities of their drug-enzyme-DNA cleavage complexes. To investigate the possible biological roles of the di(methoxy) and methylenedioxy substituents present on the aromatic rings of the previously synthesized indenoisoquinoline topoisomerase I inhibitors, a series of compounds lacking these substituents was synthesized and tested for both cytotoxicity in cancer cell cultures and for enzyme inhibitory activity. The results indicate that the aromatic substituents make a small, but consistently observable contribution to the biological activity. Molecular models derived for the binding of the unsubstituted indenoisoquinolines in ternary complex with DNA and topoisomerase I indicate that the substituents on the lactam nitrogen project out of the major groove, and the carbonyl group is directed out of the minor groove, where it is involved in a hydrogen bonding interaction with the side chain guanidine group of Arg364. The DNA cleavage patterns observed in the presence of topoisomerase I and various indenoisoquinolines were similar, although significant differences were detected. There were also variations in the DNA cleavage pattern seen with camptothecin vs the indenoisoquinolines, which indicates that these two classes of topoisomerase I inhibitors are likely to target the cancer cell genome differently, resulting in different spectra of anticancer activity. The most cytotoxic of the presently synthesized indenoisoquinolines has a 4-amino-n-butyl group on the lactam nitrogen.     

Anticardiolipin antibodies as a risk factor for venous thromboembolism in a population-based prospective study

Anticardiolipin antibodies, one of the family of 'antiphospholipid' antibodies, increase the risk of venous thromboembolism in the presence of autoimmune disease. Our objective was to determine prospectively whether there is a positive association between anticardiolipin antibodies and venous thromboembolism in ostensibly healthy adults. We conducted a nested case-control study (n = 317 patients and n = 655 control subjects) in a longitudinal study of over 20 000 participants. Baseline (prediagnosis) anticardiolipin IgG and IgM antibodies were assessed by enzyme-linked immunoassays. Venous thromboembolism was validated using standardized criteria for venous thrombosis and pulmonary embolism. There was no association between anticardiolipin antibodies and subsequent venous thromboembolism occurrence, overall or in any subgroup. For example, the multivariate-adjusted relative risk was 0.88 (95% confidence interval, 0.43, 1.78) for greater than versus less than the 95th percentile of anticardiolipin IgG. In conclusion, in this general population sample, an elevated anticardiolipin antibody level was not a risk factor for venous thromboembolism.     

Two New York City hospitals' surgical response to the September 11, 2001, terrorist attack in New York City

BACKGROUND: We describe the surgical response of two affiliated hospitals during the day of, and week following, the September 11th, 2001 terrorist attack at the World Trade Center in New York City. The city of New York has 18 state designated regional trauma centers that receive major trauma victims. The southern half of Manhattan is served by a burn center, two regional trauma centers, and a community hospital that is an affiliate of one of the regional trauma centers. This report accounts for the surgical response by a regional trauma center (Hospital A, located 2.5 miles from the World Trade Center) and its affiliate hospital (Hospital B, located 5 city blocks from the World Trade Center) on September 11th when two commercial jets crashed into the Twin Towers at the World Trade Center mall. METHODS: Hospital A maintained a concurrent log of patients received during the first 5 hours, the first day, and the first week after the disaster which was kept by the Surgical Triage Officer. The trauma registry completed and verified this data by September 18th. Hospital B collected its data by hand counting and verification by chart review. Both hospitals, A and B, had established disaster plans that were implemented. RESULTS: Nine hundred eleven patients were received by two affiliated hospitals from the World Trade Center attack. Seven hundred seventy six patients (85%) were walking wounded, sustaining mild inhalation and eye irritant injuries. One hundred thirty five (15%) were admitted with 18 (13%) of these undergoing surgery. Twenty two of the 23 transfers were from the community hospital to specialized orthopedic or burn centers. Of the 109 patients admitted to Hospital A, 30 were to the surgical service. The mean ISS score of these patients was 12. There were 4 deaths (within minutes of arrival at the hospital) and 6 delayed deaths (day 1-14). Excluding walking wounded and DOAs, the critical mortality rate was 37.5% overall. CONCLUSION: The September 11th, 2001, terrorist attack in New York City, involving two commercial airliners crashing into the World Trade Center, led to 911 patients received at two affiliated hospitals in lower Manhattan. One hospital is a regional trauma center and one was an affiliate community hospital. Eighty five percent of the patients received were walking wounded. Of the rest, 13% underwent surgical procedures with an overall critical mortality rate of 37.5%.     

Enhanced transport of a novel anti-HIV agent--cosalane and its congeners across human intestinal epithelial (Caco-2) cell monolayers

PURPOSE: Cosalane is a potent inhibitor of HIV replication with activity against a broad range of viral targets. However, oral bioavailability of this highly lipophilic compound is extremely poor (<1%). The purpose of this study is to screen a variety of permeation enhancers (cyclodextrin derivatives, cremophor EL, bile salts and mixed micelles) for their ability to enhance the transport of cosalane and its analogs/prodrugs across Caco-2 cell monolayers. METHODS: Cosalane and its different analogs/prodrugs were synthesized and their physicochemical properties were determined. Caco-2 cells were cultured at a density of 66,000 cells/cm(2) either on collagen coated clear polyester membranes or Transwell inserts. Side-bi-side diffusion cells and Transwell inserts were employed to study for the transport of cosalane and its analogs/prodrugs with various permeation enhancers across Caco-2 cell monolayers. RESULTS: Permeabilities of EH-3-39, EH-3-55 and EH-3-57 significantly improved compared to that of cosalane in the presence of bile salt, sodium desoxycholate. Among the various cyclodextrins studied, hydroxypropyl beta cyclodextrin (HP-beta-CD) and dimethyl beta cyclodextrin (DM-beta-CD) exhibited 22.3-fold and 19-fold permeability enhancement of cosalane respectively across Caco-2 cell monolayers. Sodium desoxycholate (10 mM) also showed a remarkable (105-fold) enhancement on the permeability of cosalane (P(app) 11.72+/-3.31 x 10(-6) cm/s) without causing any measurable cellular damage. Cremophor EL resulted in higher transport of 14C mannitol. The mechanism of enhancement effect can be mainly attributed to the alteration of membrane fluidity by cyclodextrin and opening of tight junctions by cremophor EL. CONCLUSIONS: Among the enhancers tested, 10 mM sodium desoxycholate and HP-beta-CD appear to be viable candidates for further development of an oral formulation of cosalane and its congeners.     

Challenge of managing interventional cardiology patients over a decade

Using an outcomes management approach, St. Luke's Episcopal Hospital has achieved positive outcomes in the interventional cardiology patient population. In this article the authors describe a decade of experiences related to the processes they implemented and the outcomes achieved in this patient population.     

Prostate carcinoma knowledge, attitudes, and screening behavior among African-American men in Central Harlem, New York City

BACKGROUND: Although the benefits of prostate carcinoma screening in reducing mortality rates have not been proven or shown to be cost-effective, screening, particularly using prostate specific antigen (PSA) tests, is widespread. A better understanding of screening behavior, knowledge of prostate carcinoma risk, and attitudes toward screening among men at high risk, such as African-American men, would be valuable. METHODS: A prevalence survey was conducted using 2 samples of African-American men, aged 50-74 years: a clinic sample drawn from all clinics in Central Harlem (n = 404) and a random-digit dial sample from the same geographic region (n = 319). The prevalence of self-reported PSA screening was estimated using a cognitive survey methodology based on the internal consistency of answers to four different questions. Prevalence estimates were adjusted to take into account the high proportion of nontelephone residences. RESULTS: The clinic sample, representing a poorer, more ill population (as determined by MOS Physical Function Scores, was less likely to report PSA screening than the community sample (11.1% in clinic sample vs. 25.5% in community). The prevalence of PSA testing in Central Harlem overall in this age group by using two different techniques was estimated to be 24%. In multiple logistic models, self-reported PSA screening was associated with age, education, favorable attitudes toward screening, and knowing someone who had prostate carcinoma. However, the association between these factors and the likelihood of self-reported PSA screening differed between clinic and community samples. CONCLUSIONS: The prevalence of self-reported PSA screening in Central Harlem was lower than that reported for other populations. These findings may be useful in the design of health education campaigns and for counseling innercity, low-income African-American patients appropriately about the disease.     

Tamoxifen and cardiac risk factors in healthy women: Suggestion of an anti-inflammatory effect

-Tamoxifen reduces the incidence of breast cancer in women at risk for that disease. Because heart disease is the leading cause of death in women and because tamoxifen is also associated with venous thrombosis, an improved understanding of the association of tamoxifen with cardiovascular disease risk factors is required. In 111 healthy women at a single center, who were participating in a randomized double-blind breast cancer prevention trial, the 6-month effects of oral tamoxifen (20 mg/d) compared with placebo on factors related to inflammation, hemostasis, and lipids were studied. Tamoxifen was associated with reductions of 26% in median C-reactive protein, 22% in median fibrinogen, and 9% in cholesterol (all P:<0.01 compared with placebo). There were no differences in treatment effects on factor VII coagulant activity, fragment 1-2, and triglycerides. In secondary analyses, the effect of tamoxifen on C-reactive protein was larger in postmenopausal women and in women with higher waist-to-hip ratios. The effect on fibrinogen was larger in women with higher baseline cholesterol. Tamoxifen demonstrated effects on inflammatory markers that were consistent with reduced cardiovascular risk. These findings are in contrast to recent reports of increased C-reactive protein associated with postmenopausal estrogen. The potential for beneficial cardiovascular effects of tamoxifen in healthy women is suggested.     

Dietary fat, body weight, and cancer: contributions of studies in rodents to understanding these cancer risk factors in humans

Understanding diet and energy balance as risk factors for breast, colon, and other cancers requires information on the contribution of each factor and of interactions among factors to cancer risk. Rodent models for breast cancer provide extensive data on effects of dietary fat and calories, energy balance, body weight gain, and physical activity on tumor development. Analyses of the combined data from many studies have shown clearly that quality and quantity of dietary fat and energy balance contribute independently to increased mammary gland tumorigenesis. These findings were seen in female rats fed diets high in fat (35-40% of calories) compared to rats fed control diets, with approximately 10% of calories as fat (Fay and Freedman, 1997, Breast Cancer Res. Treat. 46, 215-223). The methods used permit comparison of experimental and epidemiological data, and they may be useful in extrapolating between species and developing public health recommendations. In addition to the contributions of lifetime-diet composition, intake, energy balance, and physical activity to cancer risk, there are questions about the timing and duration of alterations in these factors and about the "dose-response" characteristics of cancer risk to the factors. Endocrine mechanisms may be significant in mammary gland tumor risk, but experimental and epidemiological data indicate that cancers at other sites, such as colon and liver, also are influenced by the factors listed. Other diet and lifestyle factors that influence energy, or specifically fat, metabolism may also affect risk for cancers that are promoted by increased intake of fat and calories. Studies of separate and interactive effects of dietary fat, black tea, weight gain, and mammary gland tumorigenesis (Rogers, et al, 1998, Carcinogenesis 19, 1269-1273) have been analyzed. Using adjustment of carcinogenesis endpoints for body weight, tumor burden, and latency, they were found to be related to weight gain within treatment groups in 2 of 3 experiments.