tbuckley/cabot-search huggingface dataset:
Abstract 12150: Dronedarone is a Potent Cardiac and Hepatic CPT-1 Inhibitor
Authors: Cher-Rin Chong, Giovanni Licari, Ian Westley, John D Horowitz, Benedetta C Sallustio
Journal: Circulation (2014)

Purpose: Dronedarone was developed on the basis that it would represent a class III anti-arrhythmic devoid of “amiodarone-like” adverse effects. Indeed, photosensitization and iodine-related thyroid toxicity do not occur with dronedarone. However, a number of other adverse effects have emerged. We tested the hypothesis that, like amiodarone, dronedarone modifies cellular metabolism by inhibiting mitochondrial fatty acid uptake via the carnitine shuttle. Methods: We compared the efficacy of dronedarone as an inhibitor of cardiac and hepatic carnitine palmitoyl transferase-1 (CPT-1) with that of the known CPT-1 inhibitors perhexiline and amiodarone. Male 6-week old Sprague-Dawley rats were euthanized under 2% isoflurane. Hearts and livers were rapidly removed, homogenised and placed on ice. CPT-1 activity was measured by the formation of palmitoyl-carnitine, as previously described1. Samples were ultracentrifuged and supernatants were injected for detection by liquid-chromatography/mass-spectometry. Dronedarone (5, 10, 50, 100 and 500μM) was compared to amiodarone (100, 200 and 500μM), perhexiline (20, 50, 100, 150 and 200μM), and the physiological inhibitor of CPT-1, malonyl-CoA (1μM). Concentration-response curves were expressed via log(inhibitor) vs normalized responses. Results: (1) Malonyl-CoA inhibited CPT-1 by &gt;90% in both heart and liver, while perhexiline was more potent than amiodarone as CPT-1 inhibitor (Table). (2) Dronedarone was equipotent (IC50 approximately 40μM) in both heart and liver, and approximately 3-fold more potent than amiodarone. Conclusion: Dronedarone, like amiodarone and perhexiline, inhibits cardiac and hepatic CPT-1. This has potential advantages regarding haemodynamic stability in atrial fibrillation, but may predispose to eventual hepato- and cardiotoxic effects. Ref: 1. Kennedy JA, Unger S, Horowitz JD. Biochem Pharmacology 1996, 52, p273-280.
Abstract 2026: Atrial Fibrillation Predicts Ventricular Arrhythmogenicity In Heart Failure
Authors: Kristina Lemola, Razi Khan, Stanley Nattel, Sakari Lemola, Peter G Guerra, Laurent Macle, Marc Dubuc, Mario Talajic, Elena Popescu, Fadi Mansour, Frederic Dumont, Grigorios Katsouras, Bernard Thibault, Pierre Gagne, Denis Roy, Paul Khairy
Journal: Circulation (2007)

Background: Atrial fibrillation (AF) is associated with appropriate ICD discharges in patients with primary prevention indications. We explored potential effect modifiers impacting on ventricular arrhythmogenic risk associated with AF. Methods and Results: A retrospective cohort study was conducted on 215 consecutive patients with ICDs for primary prevention having a left ventricular ejection fraction (LVEF) &lt; &lt;26&gt;35% and followed for 1.3±0.7 years. Mean age was 61.0±0.7 years and 17% were women. Cox regression models were explored in subgroups of patients stratified by demographic parameters, prior medical and surgical history, physical exam features, laboratory findings, and results of diagnostic tests. Appropriate ICD discharges were received by 10% of patients. AF was associated with a 3.5 fold increased risk [95% CI (1,5, 8.1), P=0.005]. Effect modifiers for the relationship between AF and appropriate ICD discharges included QRS duration and QTc. In patients with a QRS&gt;130 msec (N=93), 6 of 33 (18%) patients with AF received appropriate ICD discharges versus 2 of 60 (3%) without AF (P=0.03). In this subgroup, AF was associated with a hazard ratio of 5.1 (P=0.049). Among individuals with a QTc &gt;440 msec (N=93), 6 of 32 (19%) AF patients received appropriate ICD discharges versus 1 of 61 (2%) without AF (P=0.01). AF was associated with a hazard ratio of 10.3 (P=0.031). Five of 28 patients (18%) with both prolonged QRS and QTc duration (N=77) that also having AF received appropriate ICD discharges compared to 0 of 49 of patients without AF (P=0.005). After adjusting for medical therapy, AF independently predicted appropriate ICD discharges in subgroups with and without QRS and QTc increase. Conclusion: AF portends increased risk for ventricular tachyarrhythmias in patients with heart failure, particularly when associated with conduction and/or repolarization abnormalities. This finding may reflect common depolarization and repolarization defects associated with the arrhythmic milieu contributing to AF and ventricular arrhythmias, or adverse consequences of AF on the complex neurohumoral/electrophysiological substrate underlying ventricular arrhythmogenesis in heart failure.
Abstract 8625: Impact of Red Blood Cell Distribution Width on Mortality in Diabetic Patients After Percutaneous Coronary Intervention
Authors: Shuta Tsuboi, Katsumi Miyauchi, Tomotaka Dohi, Manabu Ogita, Tadashi Miyazaki, Akihisa Nishino, Ken Yokoyama, Takeshi Kurata, Takayuki Yokoyama, Hiroyuki Daida
Journal: Circulation (2011)

Background: A high red blood cell distribution width (RDW) has been identified as a novel prognostic marker in patients with heart failure. RDW, a measurement of the variability in size of circulating erythrocytes, is obtained routinely by standard blood cell count and used in the differential diagnosis of anemia. But little is known about correlates of RDW with long-term outcomes in diabetic patients with coronary artery disease (CAD). Therefore, we investigated that RDW would be predictive value of prognosis in diabetic patients with CAD treated with percutaneous coronary intervention (PCI). Method and Results: Five hundred ninety-two patients (mean age 66.5±9.0 years, male 80%) with stable CAD who underwent elective PCI were enrolled and followed up for a mean of 4.2 years. Primary endpoint was all cause mortality. Patients were divided into two groups as high or low RDW according to the mean baseline RDW (13.3%). Patients with higher RDW values were significantly older and lower ejection fraction and hemoglobin level. Patients with high RDW (mean 14.0 ± 1.2%) had higher mortality than those with low RDW (mean 12.6 ± 0.3%); (Kaplan Meier, log-rank p=0.01). After adjustment for baseline characteristics using multivariate Cox regression analysis high RDW was an independent predictor of death with a HR of 2.40 (95%CI 1.13-5.31, p=0.02) after adjustment of age, gender, ejection fraction, hemoglobin and serum creatinine. Conclusion: High RDW levels strongly associated with increased risk for long term mortality in diabetic patients undergoing coronary intervension.
Insoluble drug delivery strategies: review of recent advances and business prospects
Authors: Sandeep Kalepu, Vijaykumar Nekkanti
Journal: Acta Pharmaceutica Sinica B (2015)

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects.
Abstract 3724: A One-Step Statin Titration Process Moves Large Numbers of Patients to LDL-C Goal
Authors: Victor M Benson
Journal: Circulation (2007)

Introduction.  Although compelling evidence supports the concept that people at high CVD risk should have LDL-C   99 even though on statin treatment. This has been attributed to inadequate or absent medication titration. This project’s purpose is to lower LDL-C in a large population of high risk people by a centralized pharmacy-mediated medication efficacy increase process that involves minimal physician time.   Methods.  Diabetes or CVD patients on a statin and with an LDL > 99 were selected (N > 3000). Because by design there was minimal physician or pharmacist contact with patients, for safety extensive exclusion criteria were applied. Prescribing physicians were asked via a web-based “eApproval” message to approve or disapprove each patient’s inclusion in the project. Pharmacists increased approved patients’ statin efficacy via a titration algorithm designed to lower LDL-C to    Results.  Most (88%) panel-carrying physicians responded to the eApproval request, approving 92% of their patients. In 6 days, 2 pharmacists increased the medication efficacy for 787 patients. At an average of 52 days (range 1–153) after titration, 75% of patients had filled their new prescription and 62% of those had done a subsequent LDL-C test. LDL-C was reduced by 27 from a baseline mean of 118 to a post-titration mean of 91 mg/dL, a 23% reduction. LDL-C    Conclusions:   A large number of high risk patients are on inadequate statin therapy.  A sizeable percentage of this population can be brought to LDL-C goal by a 1-step, pharmacy-mediated intervention that requires minimal physician involvement.  The medication titration algorithm is effective in reducing LDL-C the expected amount.  Widespread implementation of this process would be expected to prevent a substantial amount of CVD morbidity and mortality.
Phase I dose-escalation and pharmacokinetic (PK) study of a(6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) in patients with advanced cancers
Authors: J. Drevs, K. Mross, F. Kratz, M. Medinger, C. Unger
Journal: Journal of Clinical Oncology (2004)

2125 Background: The anthracyclines are among the most useful agents in the treatment of solid malignancies and exhibit a wide range of antitumor activity. Adriamycin is most commonly used, but therapy is associated with significant bone marrow and organ toxicities. Therefore, an albumin-binding prodrug of adriamycin with acid-sensitive properties, i.e. (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), was developed that binds to circulating albumin with high affinity after intravenous application in a first step thus preventing rapid diffusion of adriamycin into healthy tissue. Due to a passive accumulation of albumin in solid tumors, DOXO-EMCH is targeted to the tumor and releases adriamycin in the acidic environment of tumor tissue. DOXO-EMCH has shown superior antitumor efficacy and an improved toxicity profile in various animal models compared to adriamycin. The objectives of this phase I trial is to evaluate the safety profile and pharmacokinetics of DOXO-EMCH in order to assess the maximum tolerated dose (MTD), evaluate dose-limiting toxicity (DLT), and to preliminarily assess the antitumor activity of intravenous single dosing in 3 week intervals in patients with advanced cancer. Methods: Cohorts of 3 patients with advanced cancer disease were treated with an intravenous infusion of DOXO-EMCH over 30 minutes once every 3 weeks at dose levels 27 mg/m2 (20 mg/m2 adriamycin equivalent), 54 mg/m2 (40 mg/m2 adriamycin equivalent) and 108 m2 (80 mg/m2 adriamycin equivalent) so far. Blood sampling for of PK analysis was performed. Results: 10 patients (6 female, 4 male) were treated with DOXO-EMCH so far, median age was 55.8 years. Treatment with DOXO-EMCH was well tolerated up to 40 mg/m2 adriamycin equivalent, whereas treatment with 54mg/m2 adriamycin equivalent was still ongoing. The MTD was not established. One out of 3 patients evaluable for response had a minor response after 2 cycles of DOXO-EMCH dosed with 27 mg/m2. Conclusions: Intravenous infusion once every 3 weeks of DOXO-EMCH was well tolerated and showed potential antitumor activity. The study is ongoing. No significant financial relationships to disclose.
Abstract 5038: Role of the short isoform of the progesterone receptor in hormone-regulated invasiveness of breast cancer cells at pre- and post-menopausal levels of estrogen and progesterone
Authors: Thomas B. McFall, Mugdha Patki, Rayna Rosati, Manohar Ratnam
Journal: Cancer Research (2015)

Abstract Introduction: High expression of the progesterone receptor (PR) isoform A, relative to PR isoform B, is clinically associated with progression to invasiveness in estrogen receptor (ER)-positive breast cancer and lower disease free survival. This is apparently at odds with in vitro studies implicating PR-B in mediating progestin-induced invasiveness. As the in vitro studies were conducted in the absence of estrogen (E2) signaling, we considered the possibility that modulation of E2 action may comprise a distinct aspect of the regulation of invasiveness by progestins. Methods: Standard ER+/PR+ and ER+/PR+/HER2+ breast cancer cell line models were studied, as well as recombinant cells expressing a single PR isoform. For the progestin hyper-sensitization studies, PR-A was over-expressed by lentiviral infection. Hormonal influence on invasiveness was studied using the Boyden chamber assay. Gene expression was examined by Illumina DNA microarray analysis and by Taq-Man real time RT-PCR assays. Results: E2 strongly suppressed invasiveness of ER+ breast cancer cells at concentrations below 0.01nM. At low (&amp;lt; 1 nM) concentrations, progesterone, R5020 and medroxyprogesterone acetate completely abrogated the inhibition of invasiveness by E2. It was only in a higher (5nM - 50 nM) concentration range that progestins induced invasiveness in the absence of E2. The ability of progestins to rescue invasiveness from E2 regulation was exclusively mediated by PR-A whereas PR-B mediated the E2-independent component of progestin-induced invasiveness. Overexpression of PR-A in PR-A+/PR-B+ cells lowered the progestin concentration needed to completely rescue invasiveness (to &amp;lt; 0.2 nM). Progesterone opposed E2 regulation of a distinctive set of genes, exclusively through PR-A. Conclusion: At relatively low concentrations, progesterone influences breast cancer cell invasiveness by rescuing it from E2 regulation via PR-A, whereas at higher concentrations the hormone also induces invasiveness independent of E2 signaling, through PR-B. The findings establish a direct functional link between PR-A and progression of luminal breast cancer in the context of the entire range of pre- and post-menopausal plasma and breast tissue estrogen and progesterone levels. Citation Format: Thomas B. McFall, Mugdha Patki, Rayna Rosati, Manohar Ratnam. Role of the short isoform of the progesterone receptor in hormone-regulated invasiveness of breast cancer cells at pre- and post-menopausal levels of estrogen and progesterone. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5038. doi:10.1158/1538-7445.AM2015-5038
Abstract 2206: Exercise Capacity and Quality of Life late after Fontan Surgery.
Authors: Yves d’Udekem, Michael H Cheung, Stella Setyapranata, Ajay J Iyengar, Melissa Newton, Patricia Kelly, Naomi Buckland, Leeanne Grigg, Robert G Weintraub, Andrew D Cochrane, Alasdair Vance, Christian P Brizard, Dan J Penny
Journal: Circulation (2007)

Objectives. Determine the exercise capacity and quality of life in a longitudinal cohort of Fontan patients and identify parameters influencing these outcomes. Methods and Results. Fontan survivors operated in our institution and living in the same state were invited to participate in the study if they were aged more than 10 years, and free of arrhythmias. Thirty-six patients, 23 with a classical atrio-pulmonary connection (AP) and 13 with a lateral tunnel operation (LT) underwent transthoracic echocardiography, a cycloergometer exercise study, were tested for resting ANP and BNP levels, and completed the following quality of life measures: Short Form-36 Questionnaire, the Hopkins Symptom Checklist, the Dyadic Adjustment Scale and the Family Assessment Device. A mean of 17±4 years after Fontan, VO2max ranged between 14 and 34 ml/kg/min and anaerobic threshold (AT) between 11 and 34 ml/kg/min. Diastolic dysfunction was identified in 23 pts (E wave velocity z-score &lt;−2: 17/23 pts with AP vs 6/13 pts with LT, p=0.1). ANP and BNP levels were elevated in AP Fontan and normal in LT (p0.1). The only factor predicting worse exercise capacity was the type of Fontan performed, with patients with lateral tunnel having better exercise capacity than those with atrio-pulmonary connections (percentage of predicted AT: 88±14% vs 72±14%, p&lt;0.005; percentage of predicted VO2max: 62±8% vs 54±7%, p&lt;0.005). Responses from quality of life measures placed our Fontan cohort within the normal population range. None of the pre and postoperative variables adversely affected patients’ quality of life. Conclusion: Optimal blood streaming seems to be the most important determinant of exercise capacity late after Fontan surgery. Patients with lateral tunnel performed better than those with atrio-pulmonary connections. Despite limited exercise capacity, Fontan patients appear to have a normal quality of life, reflected in their reports of psychiatric symptoms and family relationships.
Precursor insulin-like growth factor-II (proIGF-II) and mature IGF-II differentially mediate resveratrol-induced downregulation of survivin and apoptosis of MCF-7 breast cancer cells
Authors: Sharda Vyas, Frankis Almaguel, Dafne Moretta, Marino De Leon, Daisy De Leon
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4394 

Insulin-like growth factor II (IGF-II) is a potent mitogen associated with cell proliferation, inhibition of apoptosis and induction of malignant transformation. Precursor IGF-II (proIGF-II) is the predominant form secreted by most tumors and is biologically active. Since resveratrol regulates IGF-II expression, we hypothesize that IGF-II mediates RSV effects on genes involved in apoptosis of breast cancer cells. This study examines whether: 1) IGF-II mediates RSV effect on survivin protein and mRNA levels; 2) proIGF-II and mature IGF-II differentially block RSV inhibition of survivin; and 3) proIGF-II and mature IGF-II differentially modulate survivin subcellular localization and mitochondrial membrane potential status. Our results show that treatment of MCF-7 cells with RSV (10-4 M) induced a decrease of survivin protein and mRNA levels. In addition, RSV increased caspase -7 cleavage and activation. These effects were blocked by IGF-II. ProIGF-II produced a more potent effect on survivin expression and nuclear/organelle localization than mature IGF-II. MCF-7 cells transfected with proIGF-II were protected from RSV-induced apoptosis, while mIGF-II transfected cells were less protected. RSV (10-4)did not change survivin levels in proIGF-II transfected cells.

In summary, our studies show that IGF-II mediates RSV effects on cell survival and apoptosis of MCF-7 breast cancer cells in part by regulating survivin expression.
The implications of outlawing age discrimination
Authors: R. A Fisken
Journal: BMJ (2000)

Editor—All over the country health services are groaning under the weight of increasing workloads, pushed upwards in many instances by skyrocketing public expectations fuelled by the utterances of self seeking politicians. Levels of stress among health professionals are ratcheted up even further by demands for more accountability, publication of audit data, clinical governance, the ever expanding “blame culture,” and so on, all in an environment where resources are nowhere near adequate to deal with the workload that we already bear. Now we are being told by Rivlin that it would be a great idea to make age discrimination in health care illegal.1 I am sure none of us would disagree with the principle behind his argument, but does he have any idea what a can of worms he is opening? The problems which he dismisses so breezily as “grey areas” could, in fact, result in a large number of legal actions against doctors who are simply trying to do an extremely difficult job in balancing the countless demands on our services. It's no good saying that if a doctor acts properly and in good faith any legal action against him or her is likely to fail: does Rivlin have any idea how stressful defending such an action could be even if the doctor were acquitted?

Can we please try first of all to get a grip on this extraordinary cloud-cuckoo-land vision of the NHS which people are being sold by politicians—that is, that they can have whatever they want, when they want it, but without the patient or the taxpayer putting up any more money? Until we do that we will never be in a position to make a sensible exploration of ideas like Rivlin's.
Abstract 1219: Counterregulatory Roles of TGF-{beta} and ANP Signaling in Pressure Overload-Induced Cardiac Remodeling and Fibrosis
Authors: Jason Lucas, Yun Zhang, Peng Li, Bryan Wells, Bryan Cogar, Richard Hsiung, Suzanne Oparil, Yiu-Fai Chen
Journal: Circulation (2007)
Arson: an unforeseen sequela of deinstitutionalization
Authors: J Geller
Journal: American Journal of Psychiatry (1984)

Did the shift from institutional to community-based services brought about by deinstitutionalization affect the nature or function of pathological fire setting? The author studied admissions to a state hospital that were precipitated by arson. During a 200-day period, 14 patients accounted for 16 admissions and 17 fires. The data indicate that fires are set by consumers of public sector mental health services to communicate a wish or a need for a change in location of those services. Communicative arson has caused property damage, personal injury, and death and has resulted in a backlash against community alternatives for psychiatric treatment.
Pituitary-adrenocortical hyperfunction and intolerance to fluvoxamine, a selective serotonin uptake inhibitor
Authors: W A Brown, M Arato, R Shrivastava
Journal: American Journal of Psychiatry (1986)

Of nine nonsuppressors on the dexamethasone suppression test (DST), five (56%) developed intolerable side effects during treatment with fluvoxamine, a new serotonin uptake inhibiting antidepressant, compared with three of 24 suppressors (13%).
Abstract 8731: Ventricular Tachycardias in Compensated Hypertrophic Rats Are Polymorphic: Strong Evidence of Increased Spatial Heterogeneity of Non-phosphorylated Cx43 as Part of the Arrhythmogenic Substrate
Authors: Mohamed Boulaksil, Marti F Bierhuizen, Markus A Engelen, Mèra Stein, Toon A van Veen, Bart Kok, Marc A Vos, Jacques M de Bakker, Harold V van Rijen
Journal: Circulation (2010)

Introduction: Hypertrophic remodeling is known to increase the propensity of ventricular tachyarrhythmias leading to sudden death in patients. To study the mechanism underlying these fatal arrhythm...