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Acute haemodynamic response in relation to plasma vardenafil concentrations in patients with pulmonary hypertension
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
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2012 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 74, no 6, 990-998 p.Article in journal (Refereed) Published
Abstract [en]

AIMS To evaluate the acute haemodynamic effects of a single oral dose of vardenafil and to study the drug concentration in relation to haemodynamic effects in patients with pulmonary hypertension (PH). METHODS Sixteen patients with PH (aged 29-85\ years), received one single oral dose of vardenafil (5, 10 or 20 mg). The haemodynamic effect was assessed over a 60 min period. Vardenafil plasma concentrations were measured after 15, 30, 45 and 60 min using liquid chromatography-tandem mass spectrometry. RESULTS At 60 min a reduction in mPAP with a median % decrease of -20.3% (range -48.3 to 3.0; P < 0.001) and an increase in cardiac output and the cardiac index with a median % change of 10.6% (range -25.0 to 88.1; P = 0.015) and 12.1% (range -24.0 to 94.4; P = 0.01) respectively was observed. The pulmonary vascular resistance (PVR) was reduced with a median % decrease of -28.9% (range -61.5 to -5.9; P < 0.001), and pulmonary selectivity was reflected by a median percent reduction of -16.9% (range -49.0 to 16.5; P = 0.002; n = 14) in the PVR/ systemic vascular resistance ratio. There was a correlation between the plasma concentrations of vardenafil and change in mPAP (r = -0.579, P = 0.019) and between vardenafil concentrations and change in PVR (r = -0.662, P = 0.005). CONCLUSIONS Vardenafil causes rapid changes in cardiopulmonary haemodynamics and there is a correlation between plasma vardenafil drug concentration and the acute changes in mPAP as well as PVR in patients with PH.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012. Vol. 74, no 6, 990-998 p.
Keyword [en]
haemodynamics, pharmacokinetics, phosphodiesterase inhibitor, pulmonary hypertension, right heart catheterization, vardenafil
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:umu:diva-62780DOI: 10.1111/j.1365-2125.2012.04303.xISI: 000311108800011OAI: diva2:581595
Available from: 2013-01-02 Created: 2012-12-18 Last updated: 2016-01-05Bibliographically approved
In thesis
1. Vardenafil and methylarginines in pulmonary hypertension
Open this publication in new window or tab >>Vardenafil and methylarginines in pulmonary hypertension
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Pulmonary hypertension (PH) is a rare condition characterized by endothelial dysfunction and vascular remodelling, leading to increased pulmonary vascular resistance (PVR) and right ventricular heart failure. Endothelial dysfunction is associated with an imbalance between vasoconstrictor compounds, such as endothelin and thromboxane A2, and vasodilator compounds, such as prostacyclin and nitric oxide (NO). Asymmetric dimethylarginine (ADMA), a methyl derivate of L-arginine, inhibits synthesis of NO. Vardenafil, a phosphodiesterase type 5 inhibitor (PDE5-inhibitors), causes vasodilation through the NO/cGMP pathway.

Aim: This thesis investigates the pharmacological effects and diagnostic utility of vardenafil in PH patients. In addition, to evaluate the change of L-arginine and dimethylarginines before and during PAHspecific therapy in PAH patients compared to patients with left ventricular heart failure (LVHF) and healthy subjects.

Methods: The pharmacokinetics and hemodynamic effects of vardenafil were examined during right heart catheterization (RHC) in 16 PH patients and plasma concentrations were measured for up to nine hours after oral administration. In 20 PH patients, acute vasoreactivity test with vardenafil was performed during RHC. Hemodynamic responses were recorded, responders were defined and followed for up to seven years. Additionally, plasma ADMA, symmetric dimethylarginine (SDMA), L-arginine, L-citrulline and L-ornithine levels before and after PAH drug treatment were monitored in 21 PAH patients and compared to values measured in 14 LVHF patients and 27 healthy subjects.

Results: Vardenafil concentrations increased rapidly to maximum plasma concentration (tmax 1h) and elimination half-life was 3.4 h. Patients co-medicated with bosentan had reduced vardenafil concentration. Significant acute hemodynamic responses were observed for mean pulmonary artery pressure (mPAP) (p<0.001), pulmonary vascular resistance (PVR) (p<0.001), cardiac output (CO) (p=0.015), cardiac index (CI) (p=0.010), systemic vascular resistance (SVR) (p<0.001) and PVR/SVR (p=0.002) and were related to plasma vardenafil concentrations. PAH patients had significantly higher ADMA and SDMA levels and significantly lower L-arginine levels and L-arginine/ADMA ratio compared with healthy subjects (p<0.001). L-arginine was also lower in PAH patients compared to patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to Larginine and L-arginine/ADMA ratio in PAH at baseline (p<0.05). At follow-up, patients on mono- or combinationtherapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on PDE5-inhibitors had higher ADMA levels compared to patients without PDE5-inhibitors (p<0.05).

Conclusion: Vardenafil is safe in acute vasoreactivity test in PH patients. Cardiopulmonary hemodynamic response was related to plasma drug concentrations. There was a high inter-individual variability of vardenafil pharmacokinetics and co-medication with bosentan caused a pharmacokinetic drug interaction. Baseline L-arginine and dimethylarginines levels were different in PAH patients compared to LVHF patients and healthy controls. PAH-specific treatment influenced L-arginine and dimethylarginines. Our data suggest that L-arginine might be useful for differentiating PAH from LVHF, and L-arginine/ADMA ratios were related to the severity of PAH and might be useful for follow-up evaluations of PAH patients.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. 73 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1747
vardenafil, pulmonary hypertension, pharmacokinetics, haemodynamics, right heart catheterization, adenosine, dimethylarginines, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists
National Category
Pharmacology and Toxicology Cardiac and Cardiovascular Systems
Research subject
Clinical Pharmacology
urn:nbn:se:umu:diva-113903 (URN)978-91-7601-376-2 (ISBN)
Public defence
2016-01-22, Hörsal B, tandläkarhögskolan våning 9, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Available from: 2016-01-08 Created: 2016-01-05 Last updated: 2016-02-09Bibliographically approved

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