Karin Wåhlander - Academia.edu (original) (raw)

Papers by Karin Wåhlander

European Heart Journal, 2003

Circulation. Heart failure, May 1, 2016

Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement i... more Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability ...

Thrombosis Research, 2011

Thrombosis and Haemostasis, 2010

SummaryAZD0837 is an investigational oral anticoagulant which is converted to the active form, AR... more SummaryAZD0837 is an investigational oral anticoagulant which is converted to the active form, AR-H067637, a selective direct thrombin inhibitor. The present study, a multicentre, randomised, parallel-group, dose-guiding study, assessed the safety and tolerability of an immediate-release formulation of AZD0837 compared with dose-adjusted warfarin in the prevention of stroke and systemic embolic events in atrial fibrillation (AF) patients. Two hundred fifty AF patients with at least one additional risk factor for stroke were randomised to receive either immediate-release AZD0837 (150 mg twice daily [bid] or 350 mg bid, blinded treatment) or dose-adjusted warfarin (international normalised ratio 2.0–3.0, open treatment) for three months. The safety and tolerability of 150 mg bid AZD0837 appeared to be as good as that of warfarin. Total bleeding events were six with 150 mg bid AZD0837, 15 with 350 mg bid AZD0837 and eight with warfarin. Alanine aminotransferase elevations (> 3 x upp...

Clinical Pharmacokinetics, 2003

anticoagulant currently in clinical development for the prevention and treatment of thromboemboli... more anticoagulant currently in clinical development for the prevention and treatment of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form melagatran. Objective: To investigate the influence of mild-to-moderate hepatic impairment on the pharmacokinetic and pharmacodynamic properties of ximelagatran. Study design: Nonblinded, nonrandomised study. Participants: Twelve volunteers with mild-to-moderate hepatic impairment (classified as Child-Pugh A or B) and 12 age-, weight-, and sex-matched control volunteers with normal hepatic function. Methods: Volunteers received a single oral dose of ximelagatran 24mg. Plasma and urine samples were collected for pharmacokinetic and pharmacodynamic analyses. Results: The absorption and bioconversion of ximelagatran to melagatran were rapid in both groups. The maximum plasma concentration of melagatran (Cmax) was achieved 2-3 hours after administration; the mean elimination half-life (t 1 /2z) was 3.6 hours for hepatically impaired volunteers and 3.1 hours for the control volunteers. The area under the plasma concentration-time curve (AUC) and Cmax of melagatran in volunteers with hepatic impairment were 11 and 25% lower than in control volunteers, respectively. However, after correcting for the higher renal function (i.e. higher calculated creatinine clearance) in the hepatically impaired volunteers, the ratio of melagatran AUC for hepatically impaired/control volunteers was 0.98 (90% CI 0.80, 1.22), suggesting that mild-to-moderate hepatic impairment had no influence on the pharmacokinetics of ximelagatran. Melagatran was the predominant compound in urine, accounting for 13-14% of the ximelagatran dose. Renal clearance of melagatran was 13% higher in hepatically impaired than in control volunteers. There were no significant differences

Thrombosis and Haemostasis, 2004

SummaryThe objectives were to investigate whether activation of the extrinsic coagulation cascade... more SummaryThe objectives were to investigate whether activation of the extrinsic coagulation cascade by recombinant factor VIIa (rFVIIa) reverses the inhibition of thrombin generation and platelet activation by melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. In a single-blind, randomized, parallel-group study, volunteers (20 per group) received a 5-hour intravenous (iv) infusion to achieve steadystate melagatran plasma concentrations of approximately 0.5 µmol/L, with a single iv bolus of rFVIIa (90 µg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-antithrombin complex, fibrinopeptide A, β-thromboglobulin, and thrombin-activatable fibrinolysis inhibitor were quantified for venous and shed blood. Activated partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin potential, thrombus precursor protein (TpP), and plasmin-α2-antiplasmin complex concentrations were determined in venous blood. Shed blood volume was measure...

Thrombosis and Haemostasis, 2005

The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significant... more The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in the THRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initial VTE event, and history of previous VTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49,4.17), and in patients with one or more than one previous VTE event (HR: 1.73,95% CI 1.00, 2.99). There was a high...

Journal of Pharmacology and Experimental Therapeutics

Fewer new medicines have become available to patients during the last decades. Clinical efficacy ... more Fewer new medicines have become available to patients during the last decades. Clinical efficacy failures in late-phase development have been identified as a common cause of this decline. Improved ways to ensure early selection of the right drug targets when it comes to efficacy is therefore a highly desirable goal. The aim of this work was to develop a strategy to facilitate selection of novel targets already in the discovery phase that later on in clinical development would demonstrate efficacy. A crossfunctional team at AstraZeneca with extensive experience in drug discovery and development participated in several workshops to identify the critical elements that contribute to building human target validation [(HTV); the relevance of the target from a human perspective]. The elements were consolidated into a 10-point HTV classification system that was ranked from lowest to highest in terms of perceived impact on future clinical efficacy. Using 50 years of legacy research and development data, the ability of the 10-point HTV classification to predict future clinical efficacy was evaluated. Drug targets were classified as having low, medium, or high HTV at the time of candidate drug selection. Comparing this HTV classification with later clinical development efficacy data showed that HTV classification was highly predictive of future clinical efficacy success. This new strategy for HTV assessment provides a novel approach to early prediction of clinical efficacy and a better understanding of portfolio risk.

Galanin, 1991

We have investigated the mechanisms underlying galanin-induced inhibition of electrical activity ... more We have investigated the mechanisms underlying galanin-induced inhibition of electrical activity in normal pancreatic β-cells. By applying the perforated-patch whole-cell recording method (nystatin technique) to cultured mouse β-cells, it was possible to demonstrate that galanin repolarized the β-cell and inhibited glucose-induced electrical activity. The action of galanin was abolished by pretreatment of the cells with pertussis toxin suggesting the participation of an inhibitory G-protein. Furthermore, the repolarization persisted in the presence of a high concentration of the hypoglycaemic sulphonylurea glibene1amide, an inhibitor of the ATP-regulated K+-channels. Somatostatin and the α2-adrenergic agonist clonidine produced effects similar to those of galanin. It is suggested that the hormone and the neurotrans-mitters interact with the β-cell electrical activity by activating a low-conductance, sulphonylurea-insensitive and G-protein-regulated K+-channel distinct from the ATP-regulated K+-channel.

Ximelagatran in extended secondary prevention of venous thromboembolism: Pharmacokinetics, pharma... more Ximelagatran in extended secondary prevention of venous thromboembolism: Pharmacokinetics, pharmacodynamics and relationships to clinical events

Cardiovascular diabetology, Jan 19, 2016

Patients with angina-like symptoms without myocardial perfusion scintigram (MPS)-verified abnorma... more Patients with angina-like symptoms without myocardial perfusion scintigram (MPS)-verified abnormality may still be at risk for cardiovascular events. We hypothesized that insulin resistance could play a role in this population even without diagnosed diabetes. We further explored physiological and blood biomarkers, as well as global gene expression patterns that could be closely related to impaired glucose homeostasis to deepen our mechanistic understanding. A total of 365 non-diabetic patients with suspected myocardial ischemia referred to MPS were enrolled and followed up regarding event-free survival with a median time of 5.1 years. All patients underwent endothelial function assessment by reactive hyperemic index (RHI) using EndoPAT and extensive biomarker analysis. Whole blood global gene expression pathway analysis was performed in a subset of patients. Homeostasis model assessment of insulin resistance (HOMA-IR) added independent prognostic value in patients without myocardial...

British journal of clinical pharmacology, Jan 14, 2015

AZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in p... more AZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR-H067637, a potent, specific and reversible thrombin inhibitor. A population pharmacokinetic (PK) analysis was performed and the effect of AZD0837 therapy on fibrin D-dimer levels was correlated to the PK exposure of AR-H067637, as well as the effect on thrombin generation measured ex vivo, to guide selection of the effective dose regimen for a confirmatory efficacy study in AF patients. Blood samples were obtained from 601 AF patients randomized to receive 1 of 4 doses of AZD0837 (blinded treatment) or dose-adjusted vitamin K antagonists (VKA, open treatment) for 3-9 months. A pharmacodynamic model was developed to describe time course of the AR-H067637 exposure dependent effects and the effect of VKA on fibrin D-dimer. The concentration-effect relationship for thrombin generation measured ex vivo in venous ...

Thrombosis and haemostasis, 2002

Patients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee su... more Patients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee surgery, were screened for Factor V Leiden and prothrombin gene G20210A mutations, found in 5.5% and 2.9% of the populations, respectively. All patients underwent prophylactic treatment with one of four doses of melagatran and ximelagatran or dalteparin, starting pre-operatively. Bilateral ascending venography was performed on study day 8-11. The patients were subsequently treated according to local routines and followed for 4-6 weeks postoperatively. The composite endpoint of screened deep vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) during prophylaxis did not differ significantly between patients with or without these mutations. Symptomatic venous thromboembolism (VTE) during prophylaxis and follow-up (1.9%) was significantly over-represented among patients with the prothrombin gene G20210A mutation (p = 0.0002). A tendency towards increased risk of VTE was found with th...

Thrombosis and haemostasis, 2001

Prothrombin time (PT) assays are clotting methods that measure the activity of vitamin K-dependen... more Prothrombin time (PT) assays are clotting methods that measure the activity of vitamin K-dependent coagulation factors (F) II, VII, and X. There are three main types of PT assays in general usage, namely the Quick assay, Owren's assay and PT dry chemistry test cards. PT assays were initially developed to monitor dose-adjustments of vitamin K antagonists such as warfarin. The aim of the present study was to investigate whether commercially available PT assays are suitable for evaluating the anticoagulant activity of direct thrombin inhibitors. Melagatran, a reversible direct thrombin inhibitor, was added to human plasma at concentrations ranging from 0.1 to 2.0 micromol/l. Seventeen different commercially available PT kits were used, including thirteen Quick reagents, two Owren reagents and two PT test cards. The sensitivity of the different reagents, expressed as the concentration of melagatran that doubled the prothrombin time (IC50) varied widely, with Thromboplastin S and Thr...