9 results on '"Landskroner K"'
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2. Enhanced factor VIII activity measurements using ROTEG and factor VIII–/– mice whole blood
- Author
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LANDSKRONER, K. A., OLSON, N. C., and JESMOK, G. J.
- Published
- 2004
3. SITE-SPECIFIC PEGYLATION OF RFVIII RESULTS IN PROLONGED IN VIVO EFFICACY
- Author
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Murphy, J.E., primary, Pan, C., additional, Barnett, T., additional, Mei, B., additional, Strauss, J., additional, Tjandra, H., additional, Tang, L., additional, Esmon, P., additional, Newgren, J., additional, Landskroner, K., additional, Parmathi, M., additional, Severs, J., additional, Teare, J., additional, Jiang, H., additional, Devens, B., additional, Pierce, G., additional, Konstantinov, K., additional, and Fournel, M., additional
- Published
- 2007
- Full Text
- View/download PDF
4. Identification of Patient Needs and Preferences in Pigmented Villonodular Synovitis (PVNS) Using a Qualitative Online Bulletin Board Study.
- Author
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Cook NS, Landskroner K, Shah B, Walda S, Weiss O, and Pallapotu V
- Subjects
- Adult, Canada epidemiology, Female, Humans, Male, Middle Aged, Qualitative Research, Synovitis, Pigmented Villonodular epidemiology, United Kingdom epidemiology, United States epidemiology, Neoplasm Recurrence, Local psychology, Neoplasm Recurrence, Local therapy, Patient Preference psychology, Patient Preference statistics & numerical data, Patient Satisfaction statistics & numerical data, Synovitis, Pigmented Villonodular psychology, Synovitis, Pigmented Villonodular therapy
- Abstract
Introduction: Pigmented villonodular synovitis (PVNS), also known as giant-cell tumour of the tendon sheath (GCTT), is a rare, benign proliferative tumour affecting the inner lining of synovial joints and tendon sheets. Information on treatment needs of PVNS patients to inform drug development is currently scarce. We conducted an exploratory qualitative study with PVNS patients to generate insights into the objective and emotional aspects related to their medical journey and experiences of living with this disease., Methods: A 4-day study using an online bulletin board (OBB), an asynchronous, online qualitative research platform, was conducted with patients recruited via physician referral who underwent screening questions to ensure eligibility for the study and willingness to participate. The discussion was moderated, was structured and allowed open answers in response to other participants' posts., Results: Eleven patients (4 from the USA, 4 from the UK and 3 from Canada; 45% female), aged 28-57 years, suffering from PVNS for 2-27 years participated in the study. Key patient insights from the study were: (1) pain was the topmost, spontaneous thought that the participants associated with PVNS, constituting a significant emotional and psychological burden; (2) surgery (arthroscopy) did not completely ameliorate symptoms associated with PVNS, as the relapse rate was high in these patients; (3) PVNS has a substantial negative financial impact on patients, their families and the healthcare system; (4) orthopaedic specialists/surgeons predominantly managed PVNS, as surgery is currently the only therapeutic option., Conclusion: PVNS patients expressed an urgent need for a medical drug treatment, which can reduce pain, avoid relapses and provide an alternative to surgery, the current standard of care.
- Published
- 2020
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- View/download PDF
5. Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension.
- Author
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Iglarz M, Landskroner K, Bauer Y, Vercauteren M, Rey M, Renault B, Studer R, Vezzali E, Freti D, Hadana H, Schläpfer M, Cattaneo C, Bortolamiol C, Weber E, Whitby BR, Delahaye S, Wanner D, Steiner P, Nayler O, Hess P, and Clozel M
- Subjects
- Animals, Bleomycin, Bosentan, Disease Models, Animal, Gene Expression Regulation, Heart Ventricles metabolism, Heart Ventricles physiopathology, Hypertension, Pulmonary chemically induced, Hypertension, Pulmonary genetics, Hypertension, Pulmonary metabolism, Hypertension, Pulmonary physiopathology, Hypertrophy, Right Ventricular chemically induced, Hypertrophy, Right Ventricular genetics, Hypertrophy, Right Ventricular metabolism, Hypertrophy, Right Ventricular physiopathology, Male, Pulmonary Artery drug effects, Pulmonary Artery metabolism, Pulmonary Artery physiopathology, Rats, Wistar, Time Factors, Vascular Remodeling drug effects, Endothelin Receptor Antagonists pharmacology, Heart Ventricles drug effects, Hypertension, Pulmonary drug therapy, Hypertrophy, Right Ventricular prevention & control, Pyrimidines pharmacology, Sulfonamides pharmacology, Ventricular Function, Right drug effects, Ventricular Remodeling drug effects
- Abstract
Aims: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling., Methods and Results: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg(-1)·d(-1)), but not bosentan (300 mg·kg(-1)·d(-1)), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue., Conclusions: Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan.
- Published
- 2015
- Full Text
- View/download PDF
6. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist.
- Author
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Bruderer S, Aänismaa P, Homery MC, Häusler S, Landskroner K, Sidharta PN, Treiber A, and Dingemanse J
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- Adult, Animals, Area Under Curve, CHO Cells, Cricetinae, Cricetulus, Cross-Over Studies, Cyclosporine administration & dosage, Drug Interactions, Endothelin A Receptor Antagonists, Endothelin B Receptor Antagonists, Humans, Male, Organic Anion Transporters metabolism, Pyrimidines administration & dosage, Rifampin administration & dosage, Sulfonamides administration & dosage, Young Adult, Cyclosporine pharmacology, Pyrimidines pharmacokinetics, Rifampin pharmacology, Sulfonamides pharmacokinetics
- Abstract
Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration-time profiles during a dose interval (AUC(τ)) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC(τ) of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC(τ) between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent.
- Published
- 2012
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7. Surgical and pharmacological animal models used in drug metabolism and pharmacokinetics.
- Author
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Landskroner KA, Hess P, and Treiber A
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- Animals, Cytochrome P-450 Enzyme System metabolism, Drug Discovery, Humans, Models, Anatomic, Surgical Procedures, Operative, Models, Animal, Pharmaceutical Preparations metabolism, Pharmacokinetics
- Abstract
Mechanistic approaches in drug metabolism and pharmacokinetics during drug discovery depend upon animal models to increase the understanding of the absorption and disposition of new compounds. These animal models are also important to understand the complex interplay of biochemical and physiological events, and for the ability to answer questions in a reasonable time frame while interrogating numerous chemical structures. Many animal models have been described for understanding absorption, distribution, metabolism, and excretion and this review attempts to summarise some of these models. The focus is primarily on surgical and pharmacological models for pharmacokinetic studies in rodents with special emphasis on descriptive methodologies for researchers embarking on in vivo studies. In this review, the surgical approaches include the mechanical instrumentation of anatomical structures, e.g. abdominal cavity, marginal ear vein, while pharmacological models are restricted to chemical inhibition of the cytochrome P450 enzymes and P-gp to understand hepatic metabolism or brain penetration and intestinal absorption, respectively. The purpose of this review is not to exhaustively characterise each model but to serve as a general resource for investigators interested in performing these models.
- Published
- 2011
- Full Text
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8. Cross-species pharmacologic evaluation of plasmin as a direct-acting thrombolytic agent: ex vivo evaluation for large animal model development.
- Author
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Landskroner K, Olson N, and Jesmok G
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- Analysis of Variance, Animals, Cattle, Humans, Microscopy, Electron, Sheep, Species Specificity, Swine, Tissue Plasminogen Activator pharmacology, Fibrinolysin pharmacology, Fibrinolytic Agents pharmacology
- Abstract
Purpose: Human plasma-derived plasmin has been developed for the treatment of thrombosed hemodialysis arteriovenous grafts and vascular occlusive diseases. To further investigate this drug in large animal models and derive preliminary dosing estimates, the authors compared plasmin's relative lytic potential in four species, including man. The goal was to find which species' whole blood clots best compared to human clots in terms of lysis with plasmin. The results from these studies will serve to guide species selection for large animal experimentation., Materials and Methods: Clotted blood from human, pig, sheep, and bovine subjects were treated with saline solution control, plasmin, or tissue plasminogen activator. Electron microscopy (EM) techniques were used to investigate the effects of clot size and fragmentation on plasmin lysis, the effects of intrathrombic infusion by injection of plasmin directly into whole blood clots, and species fibrin structural differences., Results: Under static conditions, plasmin efficiently lysed clots from all species studied at an optimal dose of 4-5 mg per 4-5 g of clot. With fragmented human clots, plasmin (5 mg)-induced lysis was 80% +/- 2% at 60 minutes. Porcine clots were more resistant to plasmin lysis compared with human, ovine, and bovine clots. Percent lysis at 60 minutes with plasmin for ovine clots was 72% +/- 3% (4-mg dose), compared with 50% +/- 4% for porcine clots (5-mg dose; P < .05). EM of porcine clots showed a compact fibrin network that appeared more dense than that in human or sheep clots, which may account for the decreased lytic rate., Conclusions: Human plasmin is an effective direct-acting thrombolytic agent that is capable of lysing fibrin from several species. Ex vivo lysis studies were used to investigate the most appropriate large animal model that best approximates plasmin lysis with human clots under certain conditions. It was determined that ovine clots treated with plasmin most closely resemble the lysis observed with human clots.
- Published
- 2005
- Full Text
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9. Plasmin induces local thrombolysis without causing hemorrhage: a comparison with tissue plasminogen activator in the rabbit.
- Author
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Marder VJ, Landskroner K, Novokhatny V, Zimmerman TP, Kong M, Kanouse JJ, and Jesmok G
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- Animals, Aorta, Abdominal, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Ear, Fibrinolysin pharmacology, Fibrinolytic Agents pharmacology, Hemorrhage chemically induced, Infusions, Intra-Arterial, Rabbits, Recurrence, Safety, Tissue Plasminogen Activator pharmacology, Aortic Diseases drug therapy, Fibrinolysin therapeutic use, Fibrinolysis drug effects, Fibrinolytic Agents therapeutic use, Hemorrhage prevention & control, Thrombolytic Therapy adverse effects, Thrombosis drug therapy, Tissue Plasminogen Activator therapeutic use
- Abstract
The direct fibrinolytic enzyme, plasmin, was compared with tissue plasminogen activator (TPA) in rabbit models of local thrombolysis and fibrinolytic hemorrhage. Plasmin was produced by solid-phase urokinase activation of plasminogen and purified on benzamidine Sepharose. Applied as an intra-arterial infusion into the thrombosed abdominal aorta under conditions of unimpeded blood flow, plasmin (4 mg/kg) and TPA (2 mg/kg) achieved equivalent clot dissolution and flow restoration. Using the model of restricted blood flow into the thrombosed aorta, which limits local plasminogen supply, plasmin was superior to TPA in clot lysis and vascular reperfusion. Using similar dosages of plasmin (2 or 4 mg/kg) and TPA (1 or 2 mg/kg) in the earpuncture rebleed model. TPA induced rebleeding in a dose-dependent manner from prior puncture sites in 9 of 10 animals, while none of the 10 animals exposed to plasmin rebled from these sites. These results suggest that plasmin is an effective, unique thrombolytic agent, distinguished from the plasminogen activators in current usage by its striking safety profile.
- Published
- 2001
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