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  • 1
    In: Transplantation, 2000, Vol.69(9), pp.1977-1981
    Description: BACKGROUND.: Prostaglandin E2 (PGE2) is a powerful endogenous immune suppressant and interferes with various T-cell functions. However, it is not known in detail whether immunosuppressive drugs influence the PGE2-driven immune response in transplant patients. Therefore, we investigated the effect of several immunosuppressive compounds, in particular the novel drug mycophenolate mofetil (MMF), on endothelial PGE2 release. METHODS.: Endothelial cells (HUVEC) were activated by either allogeneic CD4 or CD8 T cells, or by the cytokines interleukin-1 or γ-interferon. Using an enzyme-linked immunosorbent assay, we analyzed PGE2 release of the activated HUVEC in the presence of MMF, cyclosporine, or tacrolimus. As verapamil and mibefradil also possess immunosuppressive properties, they were included in the study as well. RESULTS.: Activation of HUVEC with interleukin-1 or T cells resulted in a drastic accumulation of PGE2 in the supernatant. Cyclosporine or tacrolimus had no effect on PGE2 release. However, Ca channel blockers, when applied at higher dosages, caused a significant increase in PGE2. Interestingly, MMF strongly diminished the PGE2 level in the cell culture supernatant in a concentration-dependent manner. CONCLUSION.: The results demonstrate an inhibitory effect of MMF on PGE2 production, which may lower the benefits of the PGE2-triggered immune response after organ transplantation.
    Keywords: Endothelium ; Cytokines ; Lymphocytes T ; Immunosuppression ; Transplantation ; Interleukin 1 ; ^G-Interferon ; Prostaglandin E2 ; Mycophenolate Mofetil ; Clinical ; Man ; Immunology ; Gamma -Interferon ; Immunology ; Man ; Mycophenolate Mofetil ; Prostaglandin E2;
    ISSN: 0041-1337
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  • 2
    In: Transplantation, 2000, Vol.69(4), pp.588-597
    Description: BACKGROUND.: Cyclosporine A (CsA) and tacrolimus prevent proliferation but not transendothelial migration of alloreactive lymphocytes into donor organs. As a result, serious adverse effects, such as nephrotoxicity and neurotoxicity, have been observed under CsA/tacrolimus therapy. The incorporation of new drugs with infiltration blocking properties might enhance the efficacy of the current immunosuppressive protocol, allowing lower CsA/tacrolimus dosage. Because Ca plays a critical role in cell-cell interaction, the Ca-channel blocker verapamil might be a good cany.didate for supporting CsA/tacrolimus-based therap METHODS.: A T-cell endothelial cell coculture model or immobilized immunoglobulin G globulin chimeras were employed to investigate how S- and R- verapamil interfere with the lymphocytic infiltration process. The expression and arrangement of membranous adhesion receptors and cytoskeletal F-actin filaments were analyzed by fluorometric method in the presence of. verapamil. RESULTS.: Both verapamil enantiomers strongly inhibited lymphocyte infiltration. CD4 and CD8 T-cells were influenced to a similar extent with regard to horizontal locomotion (CD4=CD8), but to a different extent with regard to adhesion and penetration (CD4 〉 CD8). Moreover, penetration was blocked to a higher extent than was adhesion. ID50-values were 31 μM (CD4-adhesion) and 11 μM (CD4-penetration). Verapamil reduced P-selectin expression on endothelial cells and effectively down-regulated binding of T-cells to immobilized P-selectin immunoglobulin G globulins (ID50=4.4 μM; CD4). A verapamil-induced reduction of intracellular F-actin in T-lymphocytes was proven to be mainly responsible for diminished cell locomotion. CONCLUSIONS.: The prevention of CD4 T-cell penetration by verapamil might argue for its use as an adjunct to CsA/tacrolimus-based immunosuppressive therapy.
    Keywords: Immunosuppression ; Endothelium ; Lymphocytes T ; Immunosuppressive Agents ; Cell Motility ; Verapamil ; Calcium Channel Blockers ; Experimental ; Function ; Immunology ; Calcium Channel Blockers ; Cell Motility ; Immunology ; Verapamil;
    ISSN: 0041-1337
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  • 3
    Language: English
    In: European Journal of Clinical Pharmacology, 2013, Vol.69(9), pp.1617-1633
    Description: Byline: Sebastian Harder (1,2), Jochen Graff (1) Keywords: Anticoagulant agents; Apixaban; Dabigatran; Rivaroxaban; Thromboembolism Abstract: Background Novel oral anticoagulants are approved in several indications: rivaroxaban, apixaban, and dabigatran for the prevention of venous thromboembolism after elective hip or knee replacement surgery, and edoxaban for hip or knee replacement surgery and hip fracture surgery (in Japan only) rivaroxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE and rivaroxaban, apixaban, and dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. These agents overcome some limitations of traditional anticoagulants, are suggested to have no requirement for routine coagulation monitoring, and are administered orally. Rivaroxaban, apixaban, and dabigatran have different pharmacological characteristics, and guidance is needed on optimum doses and dosing intervals and the effects of renal or hepatic impairment, age, food, and other drugs. Dabigatran has stricter prescribing advice than rivaroxaban or apixaban for patients with moderate-to-severe renal impairment. All three drugs have restrictions on use in patients with hepatic impairment. Apixaban requires twice-daily dosing in all indications, whereas rivaroxaban and dabigatran are dosed once- or twice-daily depending on indication. Although head-to-head comparisons are lacking, the novel oral anticoagulants may show favorable cost--benefit relations compared with traditional vitamin K antagonists or no therapy. Aim This review summarizes the pharmacology of rivaroxaban, apixaban, edoxaban, and dabigatran, and the indications for which they are approved. Issues regarding the optimization of the use of these anticoagulants for the management of thromboembolic disorders will also be discussed. Author Affiliation: (1) Goethe University Frankfurt, Frankfurt am Main, Germany (2) Institute of Clinical Pharmacology, University Hospital, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany Article History: Registration Date: 20/03/2013 Received Date: 17/12/2012 Accepted Date: 19/03/2013 Online Date: 26/04/2013
    Keywords: Anticoagulant agents ; Apixaban ; Dabigatran ; Rivaroxaban ; Thromboembolism
    ISSN: 0031-6970
    E-ISSN: 1432-1041
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  • 4
    Language: English
    In: Thrombosis journal, 2014, Vol.12, pp.22
    Description: Patients with deep vein thrombosis or pulmonary embolism are recommended to receive anticoagulation for acute treatment and secondary prevention of venous thromboembolism (VTE). Fast-acting direct oral anticoagulants, with or without parenteral heparin, have the potential to replace vitamin K antagonists in this setting. Rivaroxaban, a direct Factor Xa inhibitor, is approved in the European Union and the United States for the single-drug treatment of deep vein thrombosis and pulmonary embolism and the secondary prevention of recurrent VTE in adults. The approved rivaroxaban dose schedule (15 mg twice daily for 3 weeks followed by 20 mg once daily) was derived based on pharmacological data from the clinical development programme to achieve a strong antithrombotic effect in the acute treatment phase and address the need to balance efficacy and bleeding risk for long-term treatment with a once-daily dose in the maintenance phase. Data from dose-ranging studies, pharmacokinetic modelling and randomised phase III trials support the use of this regimen. Other direct oral anticoagulants have also shown favourable efficacy and safety compared with standard treatment, and apixaban (European Union) and dabigatran (European Union and United States) have been approved in this indication. There are practical aspects to rivaroxaban use that must be considered, such as treatment of patients with renal and hepatic impairment, drug-drug interactions, monitoring of effect and management of bleeding. This review discusses the derivation of the VTE treatment regimen for rivaroxaban, summarises the clinical data for rivaroxaban and other direct oral anticoagulants in VTE treatment, and considers the practical aspects of rivaroxaban use in this setting.
    Keywords: Dosing ; Pharmacokinetics ; Rivaroxaban ; Venous Thromboembolism Treatment
    ISSN: 1477-9560
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  • 5
    Language: English
    In: Clinical pharmacokinetics, April 2013, Vol.52(4), pp.243-54
    Description: The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration-time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels 〉2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (〉2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.
    Keywords: Factor Xa Inhibitors ; Anticoagulants -- Pharmacokinetics ; Liver Diseases -- Complications ; Thrombin -- Antagonists & Inhibitors
    ISSN: 03125963
    E-ISSN: 1179-1926
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  • 6
    Language: English
    In: 2012, Vol.7(12), p.e50847
    Description: The coral genus Pocillopora is one of the few to include some species that broadcast spawn gametes and some species that brood larvae, although reports of reproductive mode and timing vary within and among species across their range. Notably, the ubiquitous Pocillopora damicornis has been described as both a brooder and spawner, although evidence of broadcast spawning is rare. Here, we report observations of broadcast-spawning in four species of Pocillopora on the Great Barrier Reef (GBR), including P. damicornis. All species spawned predictably during the early morning, two days following the full moon, and spawning was observed in multiple months over the summer period (November to February). Eggs and sperm were free-spawned concurrently. Eggs were negatively buoyant and contained Symbiodinium . This newfound knowledge on the mode, timing and regularity of broadcast spawning in Pocillopora spp. on the GBR brings us one step closer to elucidating the complex reproductive ecology of these species.
    Keywords: Research Article ; Biology ; Veterinary Science ; Physiology ; Marine And Aquatic Sciences ; Neuroscience
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Clinical Pharmacokinetics, 2013, Vol.52(4), pp.243-254
    Description: The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration–time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels 〉2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (〉2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.
    ISSN: 0312-5963
    E-ISSN: 1179-1926
    Source: Springer Science & Business Media B.V.
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  • 8
    Language: English
    In: International journal of clinical pharmacology and therapeutics, August 2017, Vol.55(8), pp.639-642
    Description: Peer reviewers and authors of clinical pharmacology manuscripts need to meet the standards for Evidence-Based Medicine (EBM) and Good Publication Practices (GPP), and editors of clinical pharmacology journals have to maintain an overview of the peer review process. The peer review process can be monitored and facilitated using the 10-D assessment, which comprises peer review criteria to determine if: 1. design of the study, 2. diagnoses employed, 3. drug molecules involved, 4. dosages applied, 5. data collected, 6. discussion of the findings, 7. deductions made, 8. documentation, 9. declarations, and 10. dHS (drug hypersensitivity syndrome) risk assessment is in accord with the objectives of the study and meet the requirements of EBM and GPP. The 10-D assessment tool, although easy to apply, requires a high level of clinical pharmacology expertise, especially in the fields of drug disposition, pharmacokinetics, and drug action. Its application will facilitate the peer review of clinical research and clinical trial reports and thus promote safety in drug development and pharmacotherapy and meet the needs of Good Publication Practices.
.
    Keywords: Evidence-Based Medicine -- Methods ; Peer Review, Research -- Methods ; Pharmacology, Clinical -- Methods
    ISSN: 0946-1965
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  • 9
    Language: English
    In: Physical review letters, 21 December 2018, Vol.121(25), pp.257402
    Description: Two-dimensional electronic materials such as graphene and transition metal dichalgenides feature unique electrical and optical properties due to the conspirative effect of band structure, orbital coupling, and crystal symmetry. Synthetic matter, as accomplished by artificial lattice arrangements of cold atoms, molecules, electron patterning, and optical cavities, has emerged to provide manifold intriguing frameworks to likewise realize such scenarios. Exciton polaritons have recently been added to the list of promising candidates for the emulation of system Hamiltonians on a semiconductor platform, offering versatile tools to engineer the potential landscape and to access the nonlinear electro-optical regime. In this work, we introduce an electronically driven square and honeycomb lattice of exciton polaritons, paving the way towards real world devices based on polariton lattices for on-chip applications. Our platform exhibits laserlike emission from high-symmetry points under direct current injection, hinting at the prospect of electrically driven polariton lasers with possibly topologically nontrivial properties.
    Keywords: Physics - Optics ; Physics - Applied Physics;
    ISSN: 00319007
    E-ISSN: 1079-7114
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  • 10
    In: PLoS ONE, 2013, Vol.8(3)
    Description: Pocillopora damicornis (Linnaeus, 1758; Scleractinia, Pocilloporidae) has recently been found to comprise at least five distinct genetic lineages in Eastern Australia, some of which likely represent cryptic species. Due to similar and plastic gross morphology of these lineages, field identification is often difficult. Here we present a quick, cost effective genetic assay as well as three novel microsatellite markers that distinguish the two most common lineages found on the Great Barrier Reef. The assay is based on PCR amplification of two regions within the mitochondrial putative control region, which show consistent and easily identifiable fragment size differences for the two genetic lineages after Alu1 restriction enzyme digestion of the amplicons.
    Keywords: Research Article ; Biology
    E-ISSN: 1932-6203
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