tbuckley/cabot-search huggingface dataset:
Abstract 3676: Influence of early toxicology assessment on the selection of azd9291
Authors: Mark J. Anderton, Richard A. Ward, Paula Daunt, Anne Galer, Darren A. E. Cross, Louise Marks, M. Raymond V. Finlay
Journal: Cancer Research (2014)

Abstract Discovery toxicology is the concept of evaluating the safety of molecules early in the drug development process when there is chemical scope to refine candidate drug quality. The aim is to identify and mitigate safety liabilities to maximize the chance of clinical success. This poster describes the impact of discovery toxicology on the selection of AZD9291, an irreversible inhibitor of both EGFR-TKI sensitising and resistance mutations. Although, maintaining a margin of selectivity to wild type EGFR was a key medicinal chemistry goal, early in vitro selectivity evaluation of the lead series compounds revealed significant off-target inhibition against the insulin and insulin-like growth factor receptors (IR/IGFR). Further exploration of this liability in a rat in vivo study revealed that our early lead compound (Cmpd 1) was associated with severe hyperglycemia, rapid body weight loss and evidence of reduced gastric emptying. The reduction in bodyweight and the inhibition of gastric emptying was dose limiting and we hypothesized this was caused by the hyperglycaemia. A broader selection of compounds based on the same scaffold was tested both in vitro and in vivo in the hope of identifying one or more compounds without this liability. Compounds were tested in a modified single dose rat study, exploring insulin and glucose homeostasis and effects on gastric emptying. Compounds within the shortlist caused increases in insulin of up to 80-fold, 3-fold increases in glucose and up to a 60% reduction in gastric emptying. There was a clear link between in vitro IR/IGF inhibition, hyperinsulinemia and inhibition of gastric emptying. One of the shortlisted candidates (now selected as AZD9291), had up to a 30 fold improvement in in vitro IGFR cellular potency compared to previous candidates and had no effect on insulin/glucose homeostasis in vivo. AZD9291 has demonstrated tumor shrinkage in patients at doses that have been very well tolerated and to date, no effect on glucose homeostasis has been reported. Cmpd 1Cmpd 2Cmpd 3Cmpd 4Cmpd 5 (AZD9291)EGFRm+sensitising mutationcell IC50 (pEGF μM)0.390.0160.0210.0020.017EGFRm+/T790Mdouble mutationcell IC50 (pEGF μM)0.0910.0020.0040.00070.015EGFR wildtypecell IC50 (pEGF μM)23.00.360.940.150.48IGFRcell IC50 (pIGF μM)0.0990.160.490.103.3SM/IGFR selectivity0.25102348194 Citation Format: Mark J. Anderton, Richard A. Ward, Paula Daunt, Anne Galer, Darren A. E. Cross, Louise Marks, M. Raymond V. Finlay. Influence of early toxicology assessment on the selection of azd9291. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3676. doi:10.1158/1538-7445.AM2014-3676
Abstract 1398: Effects Of Cardioprotective Drugs On Mitochondrial Functions During Myocardial Ischemia/reperfusion Revealed By Real-time Two-photon Imaging Of Perfused Rat Hearts.
Authors: Masaharu Akao, Madoka Matsumoto-Ida, Masashi Kato, Moritake Iguchi, Toshihiro Takeda, Toru Kita
Journal: Circulation (2007)

Background: We recently established a real-time imaging system to monitor the mitochondrial functions in perfused hearts subjected to ischemia/reperfusion, using two-photon laser scanning microscopy. The opening of the mitochondrial permeability transition pore (MPTP), which leads to loss of mitochondrial membrane potential (ΔΨ m ) and mitochondrial dysfunction, is a critical step in cardiomyocyte death during ischemia/reperfusion. We tested the effects of various drugs on Δ Ψ m loss in perfused rat hearts using this novel system. Methods and Results: Langendorff-perfused rat hearts were loaded with a fluorescent indicator of ΔΨ m , tetramethylrhodamine ethyl-ester, and was pretreated with the drugs for 30 minutes. The spatio-temporal changes of ΔΨ m in response to ischemia/reperfusion were monitored at a subcellular level, under excitation with a two-photon laser. Ischemia/reperfusion elicits stereotyped responses in cardiomyocytes; cells maintained a constant ΔΨ m for the cell-to-cell specific period of latency, followed by a rapid and irreversible ΔΨ m depolarization and subsequent cytolysis. The mitochondrial ATP-sensitive potassium channel opener diazoxide (100 μmol/L) and the mitochondrial peripheral benzodiazepine receptor ligand 4′-chlorodiazepam (50 μmol/L) markedly suppressed the latency and thus decreased the likelihood that cells would undergo ΔΨ m depolarization; they not only decreased the number of cells undergoing ΔΨ m loss but also delayed the onset of ΔΨ m loss, whereas it did not change the duration of depolarization in unprotected cells. While this mimicked the effects of ischemic preconditioning to suppress latency, it did not reflect that of cyclosporin A, a MPTP blocker which rather slowed the process of depolarization. In addition, neither a free radical scavenger 2-mercaptopropionyl glycine nor an iron chelator desferroxamine, which reduces the generation of hydroxyl radical through inhibiting the iron-mediated Fenton reaction, was protective. Simply scavenging oxygen radicals or reducing radical generation may not be a feasible strategy to achieve cardioprotection. Conclusions: This novel two-photon imaging provides deeper insight into anti-ischemia/reperfusion therapy targeting mitochondria.
Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease
Authors: Shawn D. Aaron, Katherine L. Vandemheen, Dean Fergusson, Jean Bourbeau, Roger Goldstein, Meyer Balter, Andrew McIvor, Sat Sharma, Graham Bishop, John Anthony, Robert Cowie, Stephen Field, Andrew Hirsch, Paul Hernandez, Robert Rivington, Jeremy Road, Victor Hoffstein, Richard Hodder, Darcy Marciniuk, David McCormack, George Fox, Gerard Cox, Henry B. Prins, Gordon Ford, Dominique Bleskie, Steve Doucette, Irvin Mayers, Kenneth Chapman, Noe Zamel, Mark FitzGerald
Journal: Annals of Internal Medicine (2020)

Scant evidence supports prescribing combinations of inhaled corticosteroids and long-acting β-agonists and anticholinergic bronchodilators for chronic obstructive pulmonary disease (COPD). Investig...
Medical Laboratory Haematology.
Authors: Hall, Roger, Fimls, Robert G. Malia
Journal: Annals of Internal Medicine (1985)

Haemopoiesis physiology of the blood basic haematological practice quality control preparation, staining and examination of blood films bone-marrow biopsy erythrocyte sedimentation rate and plasma viscosity automated blood-cell analysis anaemias I microcytic anaemias anaemias II macrocytosis and the macrocytic anaemias anaemias III haemolytic anaemias anaemias IV refractory anaemias the proliferative disorders haematology of infections disorders of the haemostatic mechanism antithrombotic therapy methods for the investigation of haemostatic disorders.
TB Gene Code Revealed
Authors: Rebecca Voelker
Journal: JAMA (1998)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Self-care 3 months after COPD patient education: A qualitative descriptive analysis
Authors: Camilla Askov Mousing, Kirsten Lomborg
Journal: European Respiratory Journal (2012)

Introduction:  The literature indicates a conflict between the documented effect of COPD patient education and the patients9 own experiences of the benefit in their everyday life.   Aim:  To explore from the patients9 perspective how group patient education influences their self-care three months after attending the program.   Methods:  In the  2009-2010, eleven patients diagnosed with COPD completed an 8-week group education program in a Danish community health center. The patients were interviewed 3 months after completion of the program.   Results:  Patients reported that their knowledge of COPD had increased, that they had acquired tools to handle their symptoms; and that the social aspect of patient education had motivated them to utilize their new habits after finishing the course. The data indicate that patients need a ripening period to integrate new habits and competencies into everyday life. As a side effect of the study it appeared that the research interview focused the patients9 attention on their newly acquired skills and made them more aware of their enhanced self-care.   Conclusions:  Patients9 self-care may be enhanced through group education, even though the patients are not always able to see the immediate outcome. Some patients may require professional help to implement their newly acquired knowledge and skills in everyday life. A planned dialogue concentrating on self-care in everyday life 3 months after finishing the course may enhance patients9 awareness and appraisal of their acquired competencies.
The Cerebral Cortex of Man: A Clinical Study of Localization of Function
Authors: Wilder Penfield, Theodore Rasmussen
Journal: JAMA (1968)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract P187: Intake of Plant Sterols from Natural Sources and Risk of Cardiovascular Disease in the EPIC-NL Population
Authors: Rouyanne T Ras, Yvonne T van der Schouw, Elke A Trautwein, Isabelle Sioen, W. Monique M Verschuren, Jolanda M Boer, Geertje W Dalmeijer, Inge Huybrechts, Peter L Zock, Joline W Beulens
Journal: Circulation (2014)

Background: Plant sterols (PS) are known to lower low-density lipoprotein (LDL-)cholesterol, which is an established risk factor for cardiovascular disease (CVD). Whether a high intake of PS indeed reduces the risk of CVD is unknown. This study aimed to investigate the relations of dietary intake of naturally occurring PS with blood lipids and CVD risk. Methods: The study included 35,597 Dutch men and women, aged 20-70 years, participating in the European Prospective Investigation into Cancer (EPIC-NL) study. Intakes of PS were estimated with a validated food frequency questionnaire (correlation of 0.59 for energy adjusted PS intake against 12 24-hour recalls). Occurrence of CVD was determined through linkage with registries. Blood lipids were measured at baseline. Associations with cardiovascular endpoints were analyzed prospectively using Cox proportional hazard models; this was done for total CVD, total coronary heart disease (CHD) and myocardial infarction (MI). Associations with blood lipids were analyzed cross-sectionally using regression models in a random sample of the baseline cohort (n=2417). Results: Average energy-adjusted PS intake was 295.8 ±49 mg/d (mean ±SD) and ranged from 231.3 ±22.0 to 366.0 ±34.9 mg/d between the lowest and highest quintiles. During follow-up, 3047 CVD cases were documented, including 1807 cases of CHD and 606 cases of MI. Adjusted for CVD risk factors, lifestyle and dietary factors, naturally occurring PS intake was not associated with risk of CVD, CHD or MI (P-value trend &gt;0.05). However, PS intake was associated with a lower risk of CHD in the second (HR: 0.83; 95%CI: 0.72; 0.97) and third (0.84; 0.72; 0.98) quintiles vs. the lowest quintile of PS intake, but not in the fourth (0.90; 0.76-1.06) and fifth quintile (0.84; 0.70-1.01). Higher PS intake was associated with lower total cholesterol (-0.06 mmol/L; P-value 0.038) and lower LDL-cholesterol (-0.07 mmol/L; P-value 0.007) per 50 mg/d incremental PS intake. These associations were stronger in men than in women. Conclusions: In this population with a relatively narrow and low range of naturally occurring PS intake, PS intake was not associated with a reduced cardiovascular risk, although total- and LDL-cholesterol concentrations were lower in people with higher intakes of PS. Future studies should preferably investigate the association between PS intake and CVD risk in populations with higher PS intakes .
PRIMARY PULMONARY HYPERTENSION: REPORT OF SIX CASES AND REVIEW OF LITERATURE
Authors: P N YU
Journal: Annals of Internal Medicine (1958)

ExcerptWith few exceptions, the diagnosis of primary pulmonary hypertension was made only at necropsy prior to the introduction of cardiac catheterization. Pathologists referred to this condition as primary pulmonary arteriosclerosis,1 right ventricular hypertrophy of unknown origin,2 primary pulmonary vascular sclerosis,3, 4 and obliterative pulmonary arteriosclerosis.5 The disease was thought to be rare. In 1931 McCallum5 reported only one instance of obliterative pulmonary arteriosclerosis in 12,000 autopsies. In 1954 Goodale and Thomas,6 in 10,000 autopsies, found two cases which fulfilled their criteria for the diagnosis of primary pulmonary arteriosclerosis.Clinical and pathologic studies of this disease with extensive reviews of the...
Understanding the variation in response to methotrexate
Authors: G. Becher, A.D. Burden
Journal: British Journal of Dermatology (2012)

ORIGINAL ARTICLE, p 165 Methotrexate (MTX) has been used in the management of psoriasis since the 1960s and despite the increasing use and success of newer biologic agents, it remains a first‐line treatment in patients with moderate to severe psoriasis, due to its efficacy and cost‐effectiveness.1 It is used as a standard comparator in randomized controlled trials of biologic agents in psoriasis. However, a significant number of patients on MTX do not experience benefit and up to 30% of patients are unable to tolerate the drug because of toxicity including nausea, myelosuppression or hepatotoxicity.2 Reasons for this inter‐individual variability in both toxicity and response are partially unknown but may include demographic factors (such as patient age and weight), external or environmental influences (for instance adherence to treatment, drug dosage), and genetic variation in pharmacokinetics (for instance, drug metabolizing enzymes) or pharmacodynamics (drug targets). Pharmacogenetics is the study of those inherited factors that influence the inter‐individual variability in response to drugs and is a rapidly developing field. The pharmacokinetics and pharmacodynamics of MTX, as have recently been unravelled, have proved to be complicated, and early attempts at pharmacogenetic studies in both rheumatology and dermatology using a candidate gene approach have not been definitive. MTX is a pro‐drug which is actively transported into the cell via a transmembrane reduced folate carrier protein (SLC19A1) and actively exported from the cell by ATP‐binding cassette transporters ABCC1 and ABCG2. Polymorphisms in ABCC1 and ABCG2 have been found to correlate with a better response to MTX (with odds ratios of about 2) and polymorphisms in SLC19A1 and ABCC1 have been associated with MTX toxicity. Within the cell, MTX is activated by the sequential addition of between two and seven glutamic acid residues under the action of the enzyme folylpolyglutamate synthetase, thus converting the parent drug to the active and more stable polyglutamated form. MTX polyglutamates (MTXPGs) persist intracellularly, exerting a sustained effect which allows for its once‐weekly administration.3 Some studies of patients with rheumatoid arthritis have shown a correlation between intracellular MTXPG levels and MTX treatment efficacy.4, 5
Abstract 16147: Risk Stratification of ICD Patients With Ischemic Cardiomyopathy: Do Clinical Trial Results Apply in the ”Real World”?
Authors: Naga V Garikipati, Vijaya Praveena Paruchuri, Mehul Adhaduk, Prakash Verma, Akshay Avula, Ganesh Kamath, Suneet Mittal, Jonathan S Steinberg
Journal: Circulation (2010)

Introduction: ICDs reduce mortality in pts with ischemic cardiomyopathy (EF ≤ 30%). However, clinical factors other than EF alone influence mortality. The MADIT II investigators have proposed a ris...
Universal Consent for Invasive Procedures in the Intensive Care Unit
Authors: Don Milmore
Journal: JAMA (2003)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
464. Severe Pulmonary Pathology after Intravenous Administration of Adenovirus Vectors in Cirrhotic Rats
Authors: Jeffrey S. Smith, Jie Tian, Jay N. Lozier, Andrew P. Byrnes
Journal: Molecular Therapy (2004)

Normally, when adenoviral vectors (AdVs) are administered by intravascular injection, the majority of the vector is rapidly cleared from the circulation by the reticuloendothelial system (RES), primarily by Kupffer cells (KCs), specialized macrophages that reside in liver sinusoids. This results in a rapid innate immune response and subsequent liver pathology. In cirrhotic animals, however, we have previously shown that the biodistribution of intravenously administered AdVs is altered due to the presence of pulmonary intravascular macrophages (PIMs), which cause a shift in RES vector uptake from the liver to the lungs. We report here that this is correlated with fatal pulmonary hemorrhagic edema.
Impact of mometasone furoate nasal spray on individual ocular symptoms of allergic rhinitis: a meta-analysis
Authors: L. Bielory, Y. Chun, B. P. Bielory, G. W. Canonica
Journal: Allergy (2011)

To cite this article: Bielory L, Chun Y, Bielory BP, Canonica GW. Impact of mometasone furoate nasal spray on individual ocular symptoms of allergic rhinitis: a meta-analysis. Allergy 2011; 66: 686–693. Abstract Background: Intranasal corticosteroids (INSs) are a mainstay of treatment of allergic rhinitis (AR) nasal symptoms. The INS mometasone furoate nasal spray (MFNS) has well-documented efficacy and safety for the treatment and prophylaxis of nasal symptoms of seasonal AR (SAR) and for the treatment of nasal symptoms of perennial AR (PAR). Increasing interest has focused on whether INSs, including MFNS, may have beneficial effects on the ocular symptoms frequently associated with AR. Methods: We performed a meta-analysis of 10 randomized, placebo-controlled trials of the efficacy of MFNS 200 mcg daily in relieving ocular allergy symptoms, including itching/burning, redness, and tearing/watering in both SAR and PAR. Four PAR studies and six SAR studies are included in the analysis. A fixed-effect inverse variance model was used to calculate weighted mean differences, 95% confidence intervals (CIs) for each comparison, and a combined overall treatment effect (Z) with P-value. Results: In both analyses of SAR and PAR studies, including 3132 patients, all individual ocular symptoms were reduced in patients treated with MFNS. Overall treatment effect was significant for all three individual ocular symptoms in the SAR studies (Z = 9.18 for tearing, Z = 10.15 for itching, and Z = 8.88 for redness; P < 0.00001 for all) and in the PAR studies (Z = 5.94, P < 0.00001 for tearing; Z = 2.43, P = 0.02 for itching; and Z = 2.42, P = 0.02 for redness). Conclusions: Our findings add to the growing body of literature supporting the positive class effect of INSs, including MFNS, on ocular symptoms associated with SAR and PAR.