259 results match your criteria emax slope

5-HT receptor- and M muscarinic acetylcholine receptor-mediated activation of Gα in postmortem dorsolateral prefrontal cortex of opiate addicts.

Pharmacol Rep 2021 Apr 9. Epub 2021 Apr 9.

Laboratory of Neuropharmacology, IUNICS/IdISPa, University of the Balearic Islands (UIB), Palma de Mallorca, Spain.

Background: Chronic exposure to opiates causes the development of tolerance and physical dependence as well as persistent brain neuroplasticity. Despite a wealth of postmortem human studies for opiate addicts, little direct information regarding the functional status of serotonergic and cholinergic receptor-mediated signaling pathways in the human brain of opiate addicts is yet available.

Methods: Functional activation of Gα proteins coupled to 5-HT and M type muscarinic acetylcholine receptor (mAChR) was assessed by using the method named [S]GTPγS binding/immunoprecipitation in frontal cortical membrane preparations from postmortem human brains obtained from opiate addicts and matched controls. Read More

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Understanding Exposure-Receptor Occupancy Relationships for Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators across a Range of Preclinical and Clinical Studies.

J Pharmacol Exp Ther 2021 04 4;377(1):157-168. Epub 2021 Feb 4.

Sosei Heptares, Cambridge, CB21 6DG, United Kingdom.

The metabotropic glutamate receptor 5 (mGlu) is a recognized central nervous system therapeutic target for which several negative allosteric modulator (NAM) drug candidates have or are continuing to be investigated for various disease indications in clinical development. Direct measurement of target receptor occupancy (RO) is extremely useful to help design and interpret efficacy and safety in nonclinical and clinical studies. In the mGlu field, this has been successfully achieved by monitoring displacement of radiolabeled ligands, specifically binding to the mGlu receptor, in the presence of an mGlu NAM using in vivo and ex vivo binding in rodents and positron emission tomography imaging in cynomolgus monkeys and humans. Read More

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Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Guidelines on Model Fitting and Recommendations on Time Course for In Vitro Cytochrome P450 Induction Studies Including Impact on Drug Interaction Risk Assessment.

Drug Metab Dispos 2021 Jan 2;49(1):94-110. Epub 2020 Nov 2.

Genentech, South San Francisco, California (S.G.W.); Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Janssen R&D, Spring House, Pennsylvania (S.D.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); Pfizer Global Research and Development, Groton, Connecticut (T.C.G.); Pfizer Global Research and Development, Cambridge, Massachusetts (P.D.Y.); Eisai, Cambridge, Massachusetts (Y.A.S.); Corning Life Sciences, Woburn, Massachusetts (G.Z.); Merck & Co., Inc., Kenilworth, New Jersey (D.T., J.P.); and AstraZeneca, Cambridge, Cambridgeshire, United Kingdom (B.J.).

Translational and ADME Sciences Leadership Group Induction Working Group (IWG) presents an analysis on the time course for cytochrome P450 induction in primary human hepatocytes. Induction of CYP1A2, CYP2B6, and CYP3A4 was evaluated by seven IWG laboratories after incubation with prototypical inducers (omeprazole, phenobarbital, rifampicin, or efavirenz) for 6-72 hours. The effect of incubation duration and model-fitting approaches on induction parameters (E and EC) and drug-drug interaction (DDI) risk assessment was determined. Read More

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January 2021

5-HT receptor-mediated Gα activation in psychiatric disorders: A postmortem study.

World J Biol Psychiatry 2020 Nov 9:1-11. Epub 2020 Nov 9.

Laboratory of Neuropharmacology, IUNICS/IdISPa, University of the Balearic Islands (UIB), Palma de Mallorca, Spain.

Objectives: Serotonin-2A (5-HT) receptors play an important role in the regulation of many brain functions that are disturbed in patients with such psychiatric diseases as mood disorders and schizophrenia. The objective of this study was to evaluate 5-HT receptor-mediated signalling pathway through Gα activation in psychiatric patients by using post-mortem brain samples.

Methods: Functional activation of Gα proteins coupled to 5-HT receptors was determined by means of [S]GTPγS binding/immunoprecipitation assay in post-mortem prefrontal cortex of psychiatric patients diagnosed as bipolar disorder (BP), major depressive disorder (MDD), and schizophrenia, and individually matched controls. Read More

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November 2020

Development and Verification of a Body Weight-Directed Disease Trial Model for Glucose Homeostasis.

J Clin Pharmacol 2021 02 7;61(2):234-243. Epub 2020 Sep 7.

Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Weight loss has been associated with improvement in insulin sensitivity. It is consequently a cornerstone in the management of type 2 diabetes mellitus (T2DM). However, the strictly quantitative relationship between weight loss, insulin sensitivity, and clinically relevant glucose homeostasis biomarkers as well as changes therein as T2DM progresses is not yet fully understood. Read More

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February 2021

Experimental validation of the prestretch-strain relationship as a non-invasive index of left ventricular myocardial contractility.

PLoS One 2020 26;15(2):e0228027. Epub 2020 Feb 26.

Department of Cardiovascular Imaging and Dynamics, University of Leuven (KU Leuven), Leuven, Belgium.

Background: The slope of the relationship between segmental PreS and total systolic shortening (S) has been proposed as a non-invasive index of left ventricular contractility. The aim of this study was to correlate this novel parameter to invasive gold standard measurements of contractility and to investigate how it is influenced by afterload.

Methods: In domestic pigs, afterload was increased by either balloon inflation in the aorta or by administration of phenylephrine while contractility was increased by dobutamine infusion. Read More

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Exposure-response modelling approaches for determining optimal dosing rules in children.

Stat Methods Med Res 2020 09 13;29(9):2583-2602. Epub 2020 Feb 13.

Department of Mathematics & Statistics, Fylde College, Lancaster University, Lancaster, UK.

Within paediatric populations, there may be distinct age groups characterised by different exposure-response relationships. Several regulatory guidance documents have suggested general age groupings. However, it is not clear whether these categorisations will be suitable for all new medicines and in all disease areas. Read More

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September 2020

Functional coupling of M muscarinic acetylcholine receptor to Gα in dorsolateral prefrontal cortex from patients with psychiatric disorders: a postmortem study.

Eur Arch Psychiatry Clin Neurosci 2020 Oct 5;270(7):869-880. Epub 2019 Dec 5.

Laboratory of Neuropharmacology, IUNICS/IdISPa, University of the Balearic Islands (UIB), Palma de Mallorca, Spain.

Accumulating studies have implicated intracellular signaling through muscarinic acetylcholine receptors (mAChRs) in psychiatric illness. In the present study, carbamylcholine chloride (carbachol)-induced Gα and Gα activation was identified in postmortem human prefrontal cortical membranes. The following two sample cohorts were used: subjects [1], consisting of 40 controls without neuropsychiatric disorders, and subjects [2], consisting of 20 with bipolar disorder (BP), 20 major depressive disorder (MDD), 20 schizophrenia, and 20 controls, strictly sex- and age-matched. Read More

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October 2020

Exposure-Response Analyses of the Effects of Venetoclax, a Selective BCL-2 Inhibitor, on B-Lymphocyte and Total Lymphocyte Counts in Women with Systemic Lupus Erythematosus.

Clin Pharmacokinet 2020 03;59(3):335-347

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.

Background: Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the development of various autoimmune diseases including systemic lupus erythematosus. The aim of these analyses was to quantify the exposure-response relationship for venetoclax effects on B-lymphocyte and total lymphocyte counts as pharmacodynamic markers of efficacy and safety, respectively, in women with systemic lupus erythematosus. The developed modeling framework was also used to evaluate venetoclax effects following cyclic, continuous, or induction/maintenance dosing paradigms as potential dosing alternatives in systemic lupus erythematosus. Read More

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Methods for the Preparation of an Excised, Cross-Circulated Rat Heart.

Methods Mol Biol 2018 ;1816:117-132

Department of Physiology, Gifu University Graduate School of Medicine, Gifu, Japan.

The Emax-Pressure-Volume Area (PVA)-VO framework proposed by Dr. Suga for canine hearts has dramatically advanced the field of cardiac mechanical work and energetics, i.e. Read More

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In vitro and in vivo activity of iclaprim, a diaminopyrimidine compound and potential therapeutic alternative against Pneumocystis pneumonia.

Eur J Clin Microbiol Infect Dis 2018 Mar 12;37(3):409-415. Epub 2018 Jan 12.

Motif BioSciences, 125th Park Avenue, 25th Floor, New York, NY, 10017, USA.

Pneumocystis pneumonia is a serious complication that may affect immunosuppressed patients. The absence of reliable and safe therapeutic alternatives to trimethoprim-sulfamethoxazole (TMP/SMX) justifies the search for more effective and less toxic agents. In this study, the in vitro and in vivo anti-Pneumocystis jirovecii activity of iclaprim, a diaminopyrimidine compound that exerts its antimicrobial activity through the inhibition of dihydrofolate reductase (DHFR), as does TMP, was evaluated alone or in combination with SMX. Read More

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Pharmacodynamics of fosfomycin against ESBL- and/or carbapenemase-producing Enterobacteriaceae.

J Antimicrob Chemother 2017 Dec;72(12):3374-3381

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: The increase in antibiotic resistance in Gram-negative bacteria and the limited therapeutic options due to the shortage of new antibiotics have increased the interest of the 'old' antibiotic fosfomycin in the treatment of infections. However, there are contradictory reports on the pharmacodynamics of and emergence of resistance to fosfomycin.

Methods: Time-kill assays were performed with 11 ESBL-positive and 3 ESBL-negative strains, exposing the bacteria to 2-fold static concentrations from 0. Read More

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December 2017

Understanding MCP-MOD dose finding as a method based on linear regression.

Neal Thomas

Stat Med 2017 Nov 6;36(27):4401-4413. Epub 2017 Sep 6.

Pfizer, Inc, Inc 445 Eastern Point Road MS 8260-2270 Groton, CT 06340.

MCP-MOD is a testing and model selection approach for clinical dose finding studies. During testing, contrasts of dose group means are derived from candidate dose response models. A multiple-comparison procedure is applied that controls the alpha level for the family of null hypotheses associated with the contrasts. Read More

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November 2017

The role of MRI in predicting Ki-67 in breast cancer: preliminary results from a prospective study.

Tumori 2018 12 8;104(6):438-443. Epub 2018 May 8.

2 Department of Clinical Medicine and Surgery, Breast Unit, University of Naples Federico II, Naples - Italy.

Purpose: In the last decade contrast-enhanced magnetic resonance imaging (MRI) has gained a growing role as a complementary tool for breast cancer diagnosis. Currently the relationship between the kinetic features of a breast lesion and pathologic prognostic factors has become a popular field of research. Our aim is to verify whether breast MRI could be considered a useful tool to predict Ki-67 score, thus resulting as a breast cancer prognosis indicator. Read More

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December 2018

In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects.

Neuropharmacology 2017 05 22;117:171-181. Epub 2017 Jan 22.

Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. Electronic address:

Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of cAMP and cGMP and signaling within the basal ganglia. This study with PDE10A radioligand [F]MNI-659 was designed to measure the enzyme occupancy of PF-02545920 in 8 healthy male volunteers (48 ± 4 years) after a single oral dose (10 mg or 20 mg) and to evaluate safety and tolerability. Read More

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Population Pharmacokinetic-Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects.

Clin Ther 2016 Dec;38(12):2610-2621

Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea. Electronic address:

Purpose: The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences.

Methods: This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Read More

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December 2016

Multiple comparison procedure and modeling: a versatile tool for evaluating dose-response relationships in veterinary pharmacology - a case study with furosemide.

J Vet Pharmacol Ther 2016 Dec 11;39(6):539-546. Epub 2016 May 11.

Department of Pharmacometrics, Biostatistical Sciences & Pharmacometrics, Novartis Pharma AG, Basel, Switzerland.

Congestive heart failure (CHF) is a leading cause of mortality with an increasing prevalence in human and canine populations. While furosemide is a loop diuretic prescribed for the majority of CHF patients to reduce fluid retention, it also activates the renin-angiotensin aldosterone system (RAAS) which further contributes to the accelerated progression of heart failure. Our objective was to quantify the effect of furosemide on diuresis, renin activity (RA), and aldosterone (AL) in dogs, using a combined multiple comparisons and model-based approach (MCP-Mod). Read More

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December 2016

[Value of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Evaluating Diffuse Tumor Infiltration of Bone Marrow in Patients with Acute Leukemia].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2016 Oct;24(5):1365-1368

Department of Hematology, The First Affiliated Hospital of Xiamen Univetsity, Xiamen 361000, Fujian Province, China.

Objective: To analyze the value of dynamic contrast-enhanced magnetic resonance imaging (CEMRI) for evaluating diffuse tumor infiltration of bone marrow in patients with acute leukemia (AL).

Methods: From January 2010 to February 2016, 80 AL patients admitted in our hospital were chosen as AL patient group, 100 healthy people were chosen as control group, and all subjects were diagnosed with MRI and CEMRI. The Emax and Slope of ilium and vertebra lumbalis were compared between AI patient and control groups. Read More

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October 2016

Left ventricular function: time-varying elastance and left ventricular aortic coupling.

Keith R Walley

Crit Care 2016 09 10;20:270. Epub 2016 Sep 10.

Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.

Many aspects of left ventricular function are explained by considering ventricular pressure-volume characteristics. Contractility is best measured by the slope, Emax, of the end-systolic pressure-volume relationship. Ventricular systole is usefully characterized by a time-varying elastance (ΔP/ΔV). Read More

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September 2016

Likelihood ratio tests for a dose-response effect using multiple nonlinear regression models.

Biometrics 2017 03 11;73(1):197-205. Epub 2016 Jul 11.

Biostatistical Sciences and Pharmacometrics, Novartis Pharma AG, Basel, Switzerland.

We consider the problem of testing for a dose-related effect based on a candidate set of (typically nonlinear) dose-response models using likelihood-ratio tests. For the considered models this reduces to assessing whether the slope parameter in these nonlinear regression models is zero or not. A technical problem is that the null distribution (when the slope is zero) depends on non-identifiable parameters, so that standard asymptotic results on the distribution of the likelihood-ratio test no longer apply. Read More

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Pharmacodynamics and differential activity of nitrofurantoin against ESBL-positive pathogens involved in urinary tract infections.

J Antimicrob Chemother 2016 10 7;71(10):2883-9. Epub 2016 Jun 7.

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: Although nitrofurantoin has been used for >60 years for the treatment of uncomplicated urinary tract infections, its pharmacodynamic properties are not fully explored. Use is increasing because of increasing resistance to other antimicrobials due to ESBLs.

Methods: We tested nine ESBL+ and two ESBL- strains in time-kill assays. Read More

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October 2016

Population pharmacokinetic/pharmacodynamic modelling of the effects of axomadol and its O-demethyl metabolite on pupil diameter and nociception in healthy subjects.

Br J Clin Pharmacol 2016 07 14;82(1):92-107. Epub 2016 Apr 14.

Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.

Aim: The aim of the present study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) properties of the active components of axomadol and to quantify their contribution to observed the pupillometric and analgesic (measured through the cold pressor test) effects linking the PD engagement biomarker with clinical response.

Methods: Healthy subjects (n = 74) received either placebo or axomadol orally at doses ranging from 66 mg to 225 mg following multiple dosing regimens in two separate clinical trials. Plasma concentrations of the two enantiomers of axomadol and their metabolites, and PD responses were measured at specific times. Read More

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Relating Doses of Contrast Agent Administered to TIC and Semi-Quantitative Parameters on DCE-MRI: Based on a Murine Breast Tumor Model.

PLoS One 2016 22;11(2):e0149279. Epub 2016 Feb 22.

Radiology department, Second Hospital of Tianjin Medical University, Hexi District, Tianjin, China.

Objective: To explore the changes in the time-signal intensity curve(TIC) type and semi-quantitative parameters of dynamic contrast-enhanced(DCE)imaging in relation to variations in the contrast agent(CA) dosage in the Walker 256 murine breast tumor model, and to determine the appropriate parameters for the evaluation ofneoadjuvantchemotherapy(NAC)response.

Materials And Methods: Walker 256 breast tumor models were established in 21 rats, which were randomly divided into three groups of7rats each. Routine scanning and DCE-magnetic resonance imaging (MRI) of the rats were performed using a 7T MR scanner. Read More

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Hemodynamics during Rotary Blood Pump support with speed synchronization in heart failure condition: A modelling study.

Annu Int Conf IEEE Eng Med Biol Soc 2015 ;2015:3307-10

The aim of this work is to study the hemodynamic changes in the cardiovascular system under different modes of Rotary Blood Pump (RBP) support. Continuous mode (constant pump speed) and co-pulse mode (increased pump speed in systole) are studied. Computer simulation studies have been conducted to evaluate the performances of these two modes under normal and pathological conditions. Read More

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October 2016

Reverse fiber type disproportion: A distinct metabolic myopathy.

Muscle Nerve 2016 06 15;54(1):86-93. Epub 2016 Mar 15.

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

Introduction: In this investigation we characterized the physiological and metabolic responses to incremental exercise in 13 subjects with a predominance of type II fibers on muscle biopsy.

Methods: Subjects underwent incremental exercise testing with measures of maximum oxygen uptake ( V˙O2 max), maximum heart rate (fc max), chronotropic index (fc / V˙O2 slope), maximum ventilation ( V˙emax), blood lactate, ammonia, and creatine kinase (CK) levels. Muscle fiber type was determined by myosin ATPase histochemistry. Read More

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A hemodynamic model to guide blood pressure control during deliberate hypotension with sodium nitroprusside in children.

Front Pharmacol 2015 28;6:151. Epub 2015 Jul 28.

Duke Clinical Research Institute, Duke University Medical Center Durham, NC, USA.

Sodium nitroprusside (SNP) has been widely used to control blood pressure in infants and children. The goals of this analysis were to develop models that describe the hemodynamic response to SNP dosing in pediatric patients; examine sources of variation in dose-response, defining age, and size dependencies; and determine vulnerable populations or patient subtypes that may elicit dosing modifications. A multi-center, randomized, double-blinded, parallel-group, dose-ranging, effect-controlled study, followed by an open-label dose titration of an intravenous infusion of SNP was undertaken in 203 pediatric subjects, who required deliberate hypotension or controlled normotension during anesthesia. Read More

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Dynamic contrast-enhanced imaging of the wrist in rheumatoid arthritis: dedicated low-field (0.25-T) versus high-field (3.0-T) MRI.

Skeletal Radiol 2015 Aug 27;44(8):1095-101. Epub 2015 Feb 27.

Department of Imaging and Interventional Radiology, Prince Of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, China.

Objective: To compare the assessment of wrist synovitis severity, synovial volume and synovial perfusion parameters on a dedicated low-field (0.25-T) to that of a high-field (3-T) whole-body MR system in patients with rheumatoid arthritis (RA).

Methods: Twenty-one patients (mean age 50. Read More

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M2 Subtype preferring dibenzodiazepinone-type muscarinic receptor ligands: Effect of chemical homo-dimerization on orthosteric (and allosteric?) binding.

Bioorg Med Chem 2015 Jul 14;23(14):3970-90. Epub 2015 Jan 14.

School of Chemistry, University of New South Wales, UNSW Sydney NSW 2052, Australia. Electronic address:

A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [(3)H]N-methylscopolamine ([(3)H]NMS) at the muscarinic receptor subtype M2, and seven selected compounds were additionally investigated at M1, M3, M4 and M5 with respect to receptor subtype selectivity. The side chain of the known M2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Read More

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Short- and long-term effects of brain death on post-transplant graft function in a rodent model.

Interact Cardiovasc Thorac Surg 2015 Mar 11;20(3):379-86. Epub 2014 Dec 11.

Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.

Objectives: Heart transplantation has become the most effective treatment for end-stage heart failure. Donors after brain death (BD) are currently the only reliable source for cardiac transplants. However, haemodynamic instability and cardiac dysfunction have been demonstrated in brain-dead donors and this could therefore also affect post-transplant graft function. Read More

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Low birth weight followed by postnatal over-nutrition in the guinea pig exposes a predominant player in the development of vascular dysfunction.

J Physiol 2014 Dec 31;592(24):5429-43. Epub 2014 Oct 31.

Department of Physiology and Pharmacology, The University of Western London, Ontario, Canada Department of Obstetrics and Gynaecology, The University of Western London, Ontario, Canada Lawson Health Research Institute, The University of Western London, Ontario, Canada Children's Health Research Institute, The University of Western London, Ontario, Canada.

The association between intrauterine growth restriction (IUGR) and hypertension is well established, yet the interaction between IUGR and other pathogenic contributors remains ill-defined. This study examined the independent and interactive effects of fetal growth reduction resulting in low birth weight (LBW), and postnatal Western diet (WD) on vascular function. Growth reduction was induced in pregnant guinea pigs by uterine artery ablation. Read More

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December 2014