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Vardenafil and methylarginines in pulmonary hypertension
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology. Uppsala universitet.
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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1747
Keyword [en]
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
Identifiers
URN: urn:nbn:se:umu:diva-113903ISBN: 978-91-7601-376-2 (print)OAI: oai:DiVA.org:umu-113903DiVA: diva2:891063
Public defence
2016-01-22, Hörsal B, tandläkarhögskolan våning 9, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2016-01-08 Created: 2016-01-05 Last updated: 2016-02-09Bibliographically approved
List of papers
1. Acute haemodynamic response in relation to plasma vardenafil concentrations in patients with pulmonary hypertension
Open this publication in new window or tab >>Acute haemodynamic response in relation to plasma vardenafil concentrations in patients with pulmonary hypertension
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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
Keyword
haemodynamics, pharmacokinetics, phosphodiesterase inhibitor, pulmonary hypertension, right heart catheterization, vardenafil
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-62780 (URN)10.1111/j.1365-2125.2012.04303.x (DOI)000311108800011 ()
Available from: 2013-01-02 Created: 2012-12-18 Last updated: 2016-01-05Bibliographically approved
2. High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension
Open this publication in new window or tab >>High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension
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2013 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 2, 197-207 p.Article in journal (Refereed) Published
Abstract [en]

To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH). Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis. The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C-max) was 21.4 +/- 1.7 mu g/L, (2) the normalized C-max (C-max,C- norm) 79.1 +/- 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 +/- 1.6 mu g center dot h/L and (4) the normalized AUC (AUC(norm)) 261.6 A +/- 1.7 g center dot h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C-max, C-max,C- norm, AUC and AUC(norm). The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.

Keyword
Vardenafil, Population pharmacokinetics, Pulmonary hypertension, Right heart catheterization, Phosphodiesterase type 5 inhibitors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-66639 (URN)10.1007/s00228-012-1323-5 (DOI)000313791600008 ()
Available from: 2013-03-06 Created: 2013-02-26 Last updated: 2016-01-05Bibliographically approved
3. Acute vasodilator response to vardenafil and clinical outcome in patients with pulmonary hypertension
Open this publication in new window or tab >>Acute vasodilator response to vardenafil and clinical outcome in patients with pulmonary hypertension
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2015 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 10, 1165-1173 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: 

Acute vasodilator testing is recommended in patients with pulmonary arterial hypertension to identify individuals who may benefit from long-term treatment with oral calcium channel blockers. The aim of this study was to investigate the use of vardenafil in acute vasoreactivity testing compared to adenosine.

METHODS: 

A total of 20 patients eligible for right heart catheterisation were enrolled. Acute vasoreactivity testing was carried out with intravenous (iv) adenosine (n = 18) followed by oral vardenafil (n = 20). Haemodynamic responses were recorded at baseline and after 60 min (vardenafil). Responders were defined according to consensus guideline criteria.

RESULTS: 

Both vardenafil and adenosine significantly decreased mean pulmonary arterial pressure (mPAP, p < 0.001 and p = 0.026, respectively) and pulmonary vascular resistance (p < 0.001 and p > 0.001, respectively), and significantly increased cardiac output (p = 0.001 and p = 0.005, respectively). Vardenafil reduced mPAP more than adenosine (p = 0.044), while adenosine resulted in higher responses of cardiac index (p = 0.009) and pulmonary arterial oxygen saturation (p = 0.042). Acute adverse reactions were common with adenosine, while no side effects were observed after a single oral dose vardenafil. Vardenafil identified five responders (out of 20), while adenosine identified three responders (out of 18). During a 7-year follow-up, vardenafil responders had significantly lower NT-proBNP levels compared to non-responders.

CONCLUSIONS: 

Vardenafil may be safely used for acute vasoreactivity testing in patients with PH. A single oral dose of vardenafil is better tolerated than iv adenosine and may identify additional responders who could benefit from long-term vasodilator treatment.

Keyword
denosine, Vardenafil, Acute vasodilator test, Haemodynamics, Pulmonary hypertension, Right heart catheterisation
National Category
Cardiac and Cardiovascular Systems Pharmacology and Toxicology
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-108234 (URN)10.1007/s00228-015-1914-z (DOI)000360996300002 ()26242227 (PubMedID)
Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2017-05-23Bibliographically approved
4. Differences in plasma L-arginine and dimethylarginines in diagnosis and treatment of pulmonary arterial hypertension: a prospective observational study
Open this publication in new window or tab >>Differences in plasma L-arginine and dimethylarginines in diagnosis and treatment of pulmonary arterial hypertension: a prospective observational study
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance in vasoactive substances and remodelling of pulmonary vasculature. Asymmetric dimethylarginine (ADMA) inhibits the enzyme nitric oxide synthase, which generates nitric oxide (NO), a molecule causing smooth muscle cell relaxation. Our aim was to investigate the plasma concentrations of ADMA, symmetrical dimethylarginine (SDMA), L-arginine, L-ornithine and L- citrulline at diagnosis and during PAH-specific treatment in patients with PAH compared to patients with left heart failure (LVHF) and healthy subjects.

Methods This is an observational, prospective multicentre study of 21 PAH patients. For comparison 14 patients with LVHF and 27 healthy subjects were investigated. Blood samples were collected and ADMA, SDMA, L-arginine, L-ornithine and L-citrulline were analysed with liquid chromatography – tandem mass spectrometry (LC-MS/MS).

Results Baseline plasma concentrations of ADMA and SDMA were higher whereas the L-arginine concentrations and L-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p<0.001). Patients with PAH had lower L-arginine concentration than patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to L-arginine and L- arginine/ADMA in PAH at baseline (p<0.05). At follow-up, patients on mono- or combination therapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on phosphodiesterase type-5 inhibitors (PDE5-inhibitors) had higher ADMA levels compared to patients without PDE5-inhibitor treatment (p<0.05).

Conclusion Concentrations of L-arginine were decreased and dimethylarginines were increased in PAH compared to healthy subjects. L-arginine was decreased in PAH compared to LVHF. L- arginine/ADMA ratio correlated to WHO functional class and L-arginine and L-arginine/ADMA ratio correlated to 6MWD. PAH-specific treatment influences the levels of L-arginine and dimethylarginines. 

Keyword
pulmonary arterial hypertension, dimethylarginines, L-arginine, haemodynamics, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists
National Category
Cardiac and Cardiovascular Systems Pharmacology and Toxicology
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:umu:diva-113901 (URN)
Available from: 2016-01-05 Created: 2016-01-05 Last updated: 2016-01-05

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