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PubMed1992

Elevated 4-hydroxylation of estradiol by hamster kidney microsomes: a potential pathway of metabolic activation of estrogens.

Characterization of enzymes mediating the formation of catecholestrogens (CE) by hamster kidney is of importance because of the proposed role of CE in renal cancer induced in this species by estrogens. We have reexamined the potential of hamster kidney to convert estradiol (E2) to 2- and 4-hydroxylated CE because of recent evidence of the limitations of assays used in previous studies, in particular in measuring 4-hydroxylation of estrogens. Under conditions optimized for NADPH-dependent activity, hamster kidney microsomes exhibited high levels of both E2-2- and E2-4-hydroxylase activities. Evidence that the two activities depend on different forms of cytochrome P-450 was obtained by the demonstration that 2- and 4-hydroxylation of E2 were affected differentially 1) by chronic treatment of hamsters with E2 and 2) by fadrozole hydrochloride, a selective cytochrome P-450 inhibitor. NADPH-dependent 2-hydroxylation of E2 from control and E2-treated hamsters, measured by a direct product isolation assay, was 1 order of magnitude higher (apparent maximum velocity, 24-32 and 6-12.5 pmol/mg protein.min in control and E2-treated hamsters, respectively) than that reported previously using radioenzymatic assays. NADPH-dependent 4-hydroxylation of E2 in controls approached and in E2-treated hamsters exceeded 2-hydroxylation of E2 (apparent maximum velocity, 17-21 and 7.5-19 pmol/mg protein.min in control and E2-treated hamsters, respectively). Thus, estrogen treatment reversed the ratios of NADPH-dependent E2-2-/4-hydroxylase activities by causing a much greater decline in 2- than 4-hydroxylation of E2 (P less than 0.007, by analysis of variance). Fadrozole hydrochloride caused a marked dose-dependent decrease in 2-hydroxylation of E2, in contrast to a small nondose-dependent inhibition of 4-hydroxylation. Under conditions optimized for peroxidatic organic hydroperoxide-dependent activity, hamster kidney microsomes generated 2- and 4-hydroxylated CE in similar amounts. The amounts of the two CE and, consequently, the ratios remained unaffected by estrogen treatment (1:0.9 and 1:1.0 in control and E2-treated hamsters, respectively). Thus, this study establishes that CE can be generated in the same tissue by three different pathways, i.e. NADPH-dependent E2-2-hydroxylase, NADPH-dependent E2-4-hydroxylase, and organic hydroperoxide-dependent E2-2/4-hydroxylase activities. We also show that these three activities can be regulated differentially and are, thus, probably mediated by different forms of cytochrome P-450. In hamster kidney, the potential to generate 4-hydroxylated CE metabolites with distinct properties could be a factor in this tissue's vulnerability to estrogen-induced carcinogenesis.

Animals↗
PubMed2006

Predictors of lower endoscopy use among patients at three inner-city neighborhood health centers.

Although colorectal cancer (CRC) is the second leading cause of cancer death in the U.S., screening rates are low. Understanding the predictors of CRC screening is needed. In 2003, a random sample of patients aged 50 and over from three inner-city health centers was surveyed by computer-assisted telephone interview concerning CRC screening. The questionnaire was based on the Transtheoretical Model and the Theory of Reasoned Action. Factor analysis with Varimax rotation and logistic regression analyses were conducted. Of 319 surveys with data about endoscopy, 148 (46%) met guidelines (19 reported sigmoidoscopy within 5 years, 105 reported colonoscopy within 10 years, and 24 reported both within 5 years). Factor analysis identified three factors associated with increased likelihood of lower endoscopy within guidelines: Social Influence for CRC Screening (Eigenvalue 1.73), Barriers to Lower Endoscopy (Eigenvalue 2.00), and Lower Endoscopy Benefit/Ease (Eigenvalue 1.19). Variables in logistic regression associated with a lower rate of endoscopy include being African American (Odds Ratio (OR) = 0.35, 95% confidence interval = 0.13-0.96), being a current smoker (OR = 0.13, CI = 0.03-0.60), and having a higher score on the Barriers to Lower Endoscopy factor (i.e., viewed the inconvenience and unpleasant aspects as more troubling, OR = 0.33, CI = 0.18-0.60). The perceived inconvenience and unpleasant aspects of lower endoscopy are substantial barriers to screening. Advances in colon preparation procedures and better educational campaigns might lessen this perceived barrier and may be particularly important in disadvantaged and African American communities.

Black or African American↗
PubMed2006

Evaluation of an intervention to increase screening colonoscopy in an urban public hospital setting.

Only 50% of New Yorkers aged 50 and over reported ever being screened for colorectal cancer by any modality according to a recent household survey. The objective of this investigation was to assess the impact of a hospital-based intervention aimed at eliminating health care system barriers to timely colorectal cancer screening at Lincoln Medical Center, a large, urban public hospital in one of the nation's poorest census tracts. We conducted a retrospective analysis of all colonoscopies performed over an 11-month period, during which a multi-pronged intervention to increase the number of screening colonoscopies took place. Two "patient navigators" were hired during the study period to provide continuity for colonoscopy patients. A Direct Endoscopic Referral System (DERS) was also implemented. Enhancements to the gastrointestinal (GI) suite were also made to improve operational efficiency. Immediately following the introduction of the patient navigators, there was a dramatic and sustained decline in the broken appointment rates for both screening and diagnostic colonoscopy (from 67% in May of 2003 to 5% in June of 2003). The likelihood of keeping the appointment for colonoscopy after the patient navigator intervention increased by nearly 3-fold (relative risk = 2.6, 95% CI 2.2-3.0). The rate of screening colonoscopies increased from 56.8 per month to 119 per month. The screening colonoscopy coverage provided by this facility among persons aged 50 and over in surrounding Zip codes increased from 5.2 to 15.6% (RR 3.0, 95% CI 1.9-4.7). Efforts to increase the number of screening colonoscopies were highly successful, due in large part to the influence of patient navigators, a streamlined referral system, and GI suite enhancements. These findings suggest that there are significant health-care system barriers to colonoscopy that, when addressed, could have a significant impact on screening colonoscopy rates in the general population.

Adult↗
PubMed2005

What happens when GPs proactively prescribe NRT patches in a disadvantaged community.

BACKGROUND AND AIMS: The high prevalence of smoking in disadvantaged communities gives serious cause for concern in terms of adverse effects on health and social outcomes. In Scotland, smoking -related lung cancer rates are particularly high and compare less favourably with the rest of the U.K. and Europe. GPs are increasingly being recognised as having an important role in smoking cessation and are allowed to prescribe NRT to those on a low income. This study aimed to follow up a group patientsfrom a disadvantaged area who had been prescribed nicotine patches by their GP. METHODS: An initial self-complete questionnaire gathered details on age, sex, motivation, marital status, employment history, contact with other smokers, concern about weight gain, and nicotine dependence. (Nicotine dependence was assessed by using the Fagerstrom Test). Follow up was carried out at three months after commencing NRT prescription. Data was also gathered from patient case notes as to whether the participant had a smoking-related diagnosis, periods of depression, drug and/or alcohol problems. Outcome was measured in terms of "smoke the same", "smoke less" and "stopped". The statistical methods used for testing each factor against smoking were Spearman rank correlation, chi-squared test for trend and Kruskal-Wallis test. Basic descriptive statistics were used to report general outcomes of the study. RESULTS: The study enrolled 120 patients but 19 were lost to follow up. Out of 101 who used their prescription, 35 were smoking the same, 46 were smoking less and 20 had stopped. The variables most strongly affecting outcome were age, with older smokers having more success (p < 0.001), and those who had a diagnosis of depression having a worse outcome in terms of smoking cessation (p < 0.05). CONCLUSION: This study's findings indicate that encouraging GPs to take a proactive approach in prescribing NRT is effective, even in an area of socio-economic deprivation, and particularly with older smokers.

Administration, Cutaneous↗
PubMed2004

Gadofosveset: MS 325, MS 32520, Vasovist, ZK 236018.

Gadofosveset [MS 325, MS 32520, Vasovist, ZK 236018], a gadolinium-based chelate, is an injectable angiography imaging agent for use in magnetic resonance imaging (MRI) scans. The agent is being developed by EPIX Medical (formerly Metasyn) for diagnostic imaging of blood vessels of the cardiovascular system. Gadofosveset has potential as an alternative to the range of x-ray, invasive, catheter-based angiograms and thallium stress tests currently used in the diagnosis of coronary artery disease. The agent may also have applications in the diagnosis of peripheral vascular disease, thrombosis and breast cancer. Unlike conventional MRI contrast agents, gadofosveset binds to serum albumin in the blood and moves with the blood through the arteries and veins for an extended period of time before being excreted by the kidneys. The MRI with gadofosveset allows 3D images of the whole body to be accessed in one imaging session. Moreover, it makes it possible to view vessel structures.EPIX Medical has acquired an exclusive licence from the Massachusetts General Hospital to a certain technology, including patents and patent applications, that relates to the company's product candidates such as gadofosveset.EPIX Medical, Mallinckrodt (Tyco International) and Schering AG signed several agreements to develop, manufacture and market gadofosveset (formerly known as Mallinckrodt's AngioMARK). Initially, in June 2000 Schering AG acquired worldwide exclusive rights (except for Japan) from EPIX Medical to develop and market gadofosveset. Under the terms of the agreement, EPIX Medical is responsible for the completion of clinical trials and filing for approval in the US, while Schering AG undertakes responsibility for clinical investigation of gadofosveset outside the US. Mallinckrodt is responsible and will undertake a long-term supply contract for gadofosveset for clinical development and sales. Schering's subsidiary Berlex will market the product in the US after the approval via its 100 sales representatives. In January 2001, EPIX Medical reacquired the Japanese rights for gadofosveset from Daiichi Radioisotope Laboratories and exclusively licensed them to Schering AG. With this agreement, Schering AG has worldwide rights for gadofosveset. The financial terms of the Japanese rights agreement included a US$3 million upfront fee, and additional milestone payments from Schering AG to EPIX Medical. On 16 December 2003, EPIX announced that it submitted an NDA to the US FDA for gadofosveset for vascular imaging using magnetic resonance angio-graphy (MRA). This is the first NDA filed for approval with the FDA for a MR contrast agent for the primary indication of MRA. The NDA is based on the results of 18 clinical trials in 1438 patients who received gadofosveset. In February 2004, EPIX Medical announced that the NDA for gadofosveset was accepted for filing by the FDA and would proceed through a standard review cycle. The approval for gadofosveset is expected at the end of 2004. In January 2004, Schering reported at the JP Morgan Healthcare Conference that it plans a product launch in the US sometime in 2005.EPIX and Schering have completed four phase III studies in patients with suspected atherosclerotic disease in the aortoilliac, pedal and renal arteries for inclusion in the NDA submission. These trials were conducted at 86 clinical sites and involved 782 patients. The blinded reading of almost 4000 vessels showed that gadofosveset improved diagnostic accuracy of MRA compared with non-contrast MRA. The diagnostic efficacy of gadofosveset-enhanced MRA was comparable to that of x-ray angiography. These trials were initiated in accordance with the recommendations of the FDA to expand gadofosveset's target indication of aortoiliac occlusive disease to a broader peripheral vascular disease indication. In July 2004, EPIX Medical initiated a multicentre, post-NDA trial with gadofosveset for use in high-resolution vessel imaging for the characterisation of vascular wall structures and vulnerable plaque. The trial will investigate whether gadofosveset has an extended imaging window above and beyond that which was demonstrated in phase III studies. In June 2004, Schering submitted gadofosveset for approval in Europe for use as a conrast agent for MRA. The launch in Europe is projected for 2006 (Schering, Annual Report 2003). Schering has initiated its first feasibility, multicentre (Europe, US), phase III clinical trial with gadofosveset for the imaging of coronary artery disease in approximately 50 patients. This trial follows a successful completion of phase II feasibility studies with gadofosveset in the imaging of coronary artery disease and breast tumour imaging. In July 2004, EPIX announced that it initiated a multicentre phase IIa feasibility clinical trial with gadofosveset in the imaging of both the coronary arteries and myocardial perfusion.EPIX Medical is conducting preclinical investigation with gadofosveset for myocardial perfusion and rheumatoid arthritis.EPIX Medical, Mallinckrodt and Pfizer have announced a collaboration to investigate MRI imaging with gadofosveset in the diagnosis and monitoring of female sexual arousal dysfunction (FSAG). EPIX Medical completed enrolment in a phase II clinical feasibility trial using gadofosveset for this indication. It is estimated that more than 10 million women in the US suffer from FSAD.EPIX Medical was granted a US patent No. 6,676,929 covering composition-of-matter claims for the chemical structure of gadofosveset. The patent is entitled "Diagnostic Imaging Contrast Agents With Extended Blood Retention". Its expiry date is August 2015. However, under provision of the Hatch-Waxman Act, the terms of the patent may be extended following FDA approval. In its 2002 Annual Report, Schering predicted that gadofosveset has the potential to reach peak sales of EUR100 million, 3 years after launch - at the time, launch in the US was anticipated in 2005. Earlier, at an analyst presentation in Berlin in March 2002, the company stated that launch in the US was planned for 2004.

Clinical Trials, Phase II as Topic↗
PubMedDate not supplied

[Hepatitis C, interferon a and depression: main physiopathologic hypothesis].

UNLABELLED: Imputability of thymic disorders caused by IFNalpha during the chronic Hepatitis C treatment -- hepatitis C and depression -- the infection by the hepatitis C virus (HCV) is a major public health concern since it affects 1.2% in the French population. Eighty percent of those contaminated by HCV keep bearing the virus chronically although they remain asymptomatic during many years. HCV infection is associated with psychiatric symptoms like depression. Together with other factors (eg the severity of hepatic condition), depression may induce significant impairment in quality of life. Conversely, some psychiatric conditions may increase the risk of HCV infection. In drug-addicted subjects using intravenous route, HCV contamination rate ranges from 74 to 100%. Compared with general population, a higher HCV contamination rate has also been noticed in some other subgroups of subjects (patients with alcohol abuse or dependence, with alcohol-induced hepatic disease and psychiatric inpatients). However, no valid explanation to this phenomenon has been established. Interferon alpha and depression - Interferons are a variety of cytokines naturally produced by human tissues and have also been synthesized for therapeutic purposes (treatment of a variety of cancers and viral infections). Many psychobehavioural symptoms are observed under IFNalpha treatment. Among them, mood disorders are known to occur early after entry into treatment and to be within the reach of preventive measures. The reported frequency of depression during IFNalpha treatment ranges from 0 to 37%. This variation reflects either methodological biases (eg differences in psychiatric assessment) or the heterogeneity of the population of patients accepted in therapeutic protocols. Note that the adjunction of ribavirine to IFNalpha in therapeutic protocols has not brought any changes in the depression frequency. The causal relationship between IFNalpha administration and the occurrence of mood disorders has been tackled by various recent research works focusing on the importance of the immune system in the pathophysiology of depression. Miscellaneous pathophysiological hypotheses -- nature of the psychobehavioural symptomatology -- in addition to depressive symptoms, IFNalpha treatment also induces various cognitive impairments and disruptions in EEG patterns. These symptoms are consistent with a mild subcortical dementia. Data resulting from pharmacological trials in humans and in animals are controversial (eg IFNalpha-induced symptoms being alleviated by both immune and antidepressant therapies). However, the debate about the nature of the psychobehavioural disorders observed under IFNalpha treatment might be no longer relevant in the light of recent theories which regard depression as a maladaptive response to a particular form of stress, namely a deep and diffuse feeling of sickness ("malaise"). These theoretical views ascribe the production of depressive symptoms to a disruption in the immune function, mediated by the variety of cytokines. The therapeutic effects of anti-depressive drugs are thus attributed to their analgesic properties, reducing the "malaise" feeling underlying depressive symptoms. Necessity of a second messanger -- accordingly to current pathophysiological theories, depression results from disorders of various CNS functions, mainly limbic, monaminergic and neuroendocrinal systems. Though, exogenous IFNalpha does not cross the blood-brain barrier when unscathed and an intermediary mechanism is necessary. First to be addressed is the cytokines system itself since it is composed of numerous different molecules interacting in an infinite number of possible combinations. Some of these cytokines (eg some interleukins) both are activated by IFNalpha and can reach CNS; they are good candidates for the role of second messenger mediating the induction of psychobehavioural disorders. Second, keeping in mind that serotonin is a monoaminergic neurotransmitter classically involved in depression pathophysiology, other works have demonstrated that IFNalpha modulates the peripheral activity of indolamine-dioxygenase -- a regulating enzyme of serotonin metabolism -- possibly through lymphocyte T CD4 activation. Third, other authors have postulated an immune-induced vagal mechanism to explain depression caused by IFNalpha. Action of IFNalpha on the neuroendocrine and on neuromodulating functions: monoaminergic hypothesis -- cytokines could have an influence on the mood through their modulating role on the serotoninergic system. IFNalpha treatment is reported to produce: 1) a decrease in tryptophan availability for serotonin synthesis, 2) a decrease in the 5-HIAA level in the LCR, and 3) a modification of the central serotoninergic receptors. Moreover, selective inhibitors of serotonin transporters are effective to treat or prevent depression caused by IFNalpha. Many studies support the serotonin-transporter hypothesis: in vitro, both IFNalpha and interleukine 4 (IL-4) increases the expression of serotonin transporter gene, IFNalpha increases in the production of IL-4 by mononucleus cells (not found in vivo). Serotoninergic system can also be altered by a peripheral action of IFNalpha on trytophan catabolism by activating a concurrent pathway (known as "kynurenine pathway") to serotonin synthesis. Finally, serotonin-mediated vulnerability to the psychobehavioural effects of IFNalpha could be underlain by a polymorphism of serotonin transporter gene. Concerning the other monoaminergic systems, IFNalpha seems to have an amphetamine-like effect at its first administration, followed by a decrease in dopaminergic tone with chronic administration. Dopaminergic depletion, subsequent to psychostimulant abuse for instance, results in severe depressive syndromes. Interactions between IFNalpha and noradrenergic system have also been reported. Neuroendocrinian hypothesis -- when administered through central or peripheral way, IFNalpha simulates/inhibits the corticotrope axis and alters endorphin system as shown by the induction of analgesia, catatonia and behavioural slowdown that can be suppressed by opioid antagonists. IFNalpha neurotoxic effects are successfully treated by naltrexone. Lastly, IFNalpha is known to cause disorders in thyroid function that are likely to contribute to the production or aggravation of mood disorders. CONCLUSION: A better understanding of pathophysiologic mechanisms underlying psychiatric side-effects of IFNalpha is essential to extend access to treatment to some categories of patients that remain excluded from the protocols. A better management of those psychiatric side effects should help the clinician not to draw aside patients at risk, ie patients with depression, drug and alcohol addiction. Treating them in a pragmatic and careful way is a major issue, since this population represents a high percentage of the potential candidates for interferon therapy.

Antiviral Agents↗