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  • 1.
    Gillespie, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alassaad, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Morlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Effects of Pharmacists' Interventions on Appropriateness of Prescribing and Evaluation of the Instruments' (MAI, STOPP and STARTs') Ability to Predict Hospitalization-Analyses from a Randomized Controlled Trial2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e62401-Article in journal (Refereed)
    Abstract [en]

    Background: Appropriateness of prescribing can be assessed by various measures and screening instruments. The aims of this study were to investigate the effects of pharmacists' interventions on appropriateness of prescribing in elderly patients, and to explore the relationship between these results and hospital care utilization during a 12-month follow-up period. Methods: The study population from a previous randomized controlled study, in which the effects of a comprehensive pharmacist intervention on re-hospitalization was investigated, was used. The criteria from the instruments MAI, STOPP and START were applied retrospectively to the 368 study patients (intervention group (I) n = 182, control group (C) n = 186). The assessments were done on admission and at discharge to detect differences over time and between the groups. Hospital care consumption was recorded and the association between scores for appropriateness, and hospitalization was analysed. Results: The number of Potentially Inappropriate Medicines (PIMs) per patient as identified by STOPP was reduced for I but not for C (1.42 to 0.93 vs. 1.46 to 1.66 respectively, p<0.01). The number of Potential Prescription Omissions (PPOs) per patient as identified by START was reduced for I but not for C (0.36 to 0.09 vs. 0.42 to 0.45 respectively, p<0.001). The summated score for MAI was reduced for I but not for C (8.5 to 5.0 and 8.7 to 10.0 respectively, p<0.001). There was a positive association between scores for MAI and STOPP and drug-related readmissions (RR 8-9% and 30-34% respectively). No association was detected between the scores of the tools and total re-visits to hospital. Conclusion: The interventions significantly improved the appropriateness of prescribing for patients in the intervention group as evaluated by the instruments MAI, STOPP and START. High scores in MAI and STOPP were associated with a higher number of drug-related readmissions.

  • 2.
    Gillespie, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alassaad, Anna
    Hospital Pharmacy, University Hospital of Uppsala, Sweden.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Garmo, Hans
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Toss, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Kettis-Lindblad, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Mörlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    A comprehensive pharmacist intervention to reduce morbidity in patients 80 years or older: a randomized controlled trial2009In: Archives of Internal Medicine, ISSN 0003-9926, E-ISSN 1538-3679, Vol. 169, no 9, p. 894-900Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Patients 80 years or older are underrepresented in scientific studies. The objective of this study was to investigate the effectiveness of interventions performed by ward-based pharmacists in reducing morbidity and use of hospital care among older patients.

    METHODS

    A randomized controlled study of patients 80 years or older was conducted at the University Hospital of Uppsala, Uppsala, Sweden. Four hundred patients were recruited consecutively between October 1, 2005, and June 30, 2006, and were randomized to control (n = 201) and intervention (n = 199) groups. The interventions were performed by ward-based pharmacists. The control group received standard care without direct involvement of pharmacists at the ward level. The primary outcome measure was the frequency of hospital visits (emergency department and readmissions [total and drug-related]) during the 12-month follow-up period.

    RESULTS

    Three hundred sixty-eight patients (182 in the intervention group and 186 in the control group) were analyzed. For the intervention group, there was a 16% reduction in all visits to the hospital (quotient, 1.88 vs 2.24; estimate, 0.84; 95% confidence interval [CI], 0.72-0.99) and a 47% reduction in visits to the emergency department (quotient, 0.35 vs 0.66; estimate, 0.53; 95% CI, 0.37-0.75). Drug-related readmissions were reduced by 80% (quotient, 0.06 vs 0.32; estimate, 0.20; 95% CI, 0.10-0.41). After inclusion of the intervention costs, the total cost per patient in the intervention group was $230 lower than that in the control group.

    CONCLUSION

    If implemented on a population basis, the addition of pharmacists to health care teams would lead to major reductions in morbidity and health care costs.

  • 3.
    Gillespie, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alassaad, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Mörlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of pharmacists’ interventions on appropriateness of prescribing for elderly and exploration of a possible correlation between scores for appropriateness and clinical outcomes: analyses from a randomized controlled trialManuscript (preprint) (Other academic)
    Abstract [en]

    Background:

    Inappropriate prescribing can cause substantial morbidity and represents a clinical and economic burden for patients and society. Appropriateness of prescribing can be assessed by various measures and screening tools, however, for a tool to be valid there should be casual links to important clinical health outcomes. The aim of this study was to investigate the effect of a pharmacist intervention on appropriateness of prescribing, and to explore the relationship between these results and clinical health outcomes defined as re-visits to hospital.

    Methods:

    The study population from a previous randomized controlled study, in which the effects of a comprehensive pharmacist intervention on re-hospitalisation was investigated, was used. The criteria from the validated instruments STOPP, START and MAI were applied retrospectively to the study patients (368 patients; intervention group n=182, control group n=186). The quality assessments were done on admission and at discharge to detect differences over time between the control- and the intervention group. Hospital care consumption one year after admission was recorded and the correlation between scores for appropriateness, as well as number of drugs at discharge, and hospital visits was analysed.

    Results:

    The number of Potentially Inappropriate Medicines (PIMs) per patient as identified by STOPP was reduced for the intervention group but not for the control group (1.42 and 0.93 vs. 1.46 and 1.66 respectively, p<0.01) The number of Potential Prescription Omissions (PPOs) per patient as identified by START was reduced for the intervention group but not for the control group (0.36 and 0.09 vs. 0.42 and 0.45 respectively, p<0.001). The summated score for MAI was reduced for the intervention group but not for the control group (8.5 to 5.0 and 8.7 to 10.0 respectively, p< 0.001). There was no correlation between the scores of the tools and total visits to hospital. Number of drugs (unadjusted) correlated with visits to hospital and the rate ratio was 4%. For readmissions to hospital, MAI (unadjusted) and the number of drugs showed a positive correlation. There was a correlation between MAI and STOPP and drug-related readmissions (RR 8-9% and 30-34% respectively).

    Conclusion:

    The addition of a comprehensive pharmacist service to standard care significantly improved the appropriateness of prescribing for patients in the intervention group that participated in the randomized controlled trial, as evaluated by all three instruments used; STOPP, START and MAI. However, the results on correlation between the tools and re-visits to hospital were inconclusive.

  • 4.
    Henrohn, D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Björkstrand, Kristoffer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lundberg, Jon
    Granstam, Sven-Olof
    Baron, Tomasz
    Ingimarsdottir, Inga
    Hedenström, Hans
    Malinovschi, Andrei
    Wernroth, Mona-Lisa
    Jansson, Martin
    Hedeland, Mikael
    Wikström, Gerhard
    Effects of oral supplementation with nitrate-rich beetroot juice in patients with pulmonary arterial hypertension – results from BEET-PAH a randomised, double-blind, placebo-controlled crossover studyIn: Article in journal (Refereed)
  • 5.
    Henrohn, D
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Le, Greves P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, F
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Morphine alters the levels of growth hormone receptor-mRNA and [I-125]growth hormone binding in human IM-9 lymphoblasts via a naloxone-reversible mechanism1997In: MOLECULAR AND CELLULAR ENDOCRINOLOGY, ISSN 0303-7207, Vol. 135, no 2, p. 147-152Article in journal (Other scientific)
    Abstract [en]

    The immune system and the neuroendocrine system are functionally interactive. Lymphocytes possess opioid receptors as well as growth hormone receptors (GHR) by which opioids and growth hormone (GH) may modulate immune functions. In this study, we have inv

  • 6.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Pulmonary Hypertension and the Nitric Oxide System2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pulmonary hypertension (PH) is a pathophysiological state associated with several medical conditions, leading to progressive rise in pulmonary vascular resistance (PVR) and right ventricular failure. The clinical PH classification encompasses five main World Health Organization (WHO) groups; pulmonary arterial hypertension (PAH), PH due to left heart disease, PH due to lung diseases and/or hypoxia, chronic thromboembolic PH, and PH with unclear multifactorial mechanisms. Nitric oxide (NO) is a potent vasodilator. Impaired NO production via the classical L-arginine-NO synthase (NOS) pathway has been implicated in PH. Phosphodiesterase-5 (PDE5) inhibitors augment NO signalling, and are considered as one of the cornerstone treatments in PAH. The studies in this thesis aim at to explore and expand the understanding of the NO system in patients with PH.

    In paper I, we found that PAH patients (WHO group 1) have lower bronchial NO flux compared to healthy controls and patients with PH (WHO group 2–4). This implies reduced bronchial NO formation in PAH. Compared to healthy controls, increased alveolar NO levels were found in patients with PH (WHO group 1-4) and patients with PAH. This may reflect NO diffusion disturbances in the alveoli. PAH patients had higher plasma and salivary levels of nitrite than healthy controls, which may reflect a compensatory upregulation of NOS-independent NO generating pathways.

    In paper II, we observed that a single oral dose of vardenafil (a PDE5 inhibitor) causes rapid changes in cardiopulmonary haemodynamics in PH patients with PH (WHO group 1-4). We found a correlation between plasma vardenafil concentrations and the changes in mean pulmonary arterial pressure as well as PVR.

    In paper III, we show that a single oral dose of vardenafil to patients with PH (WHO group 1-4) alter the plasma levels of arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the arginine/ADMA ratio in a favourable manner. The increase in arginine and the arginine/ADMA ratio were associated with improved cardiac index, and the increase in the arginine/ADMA ratio at 540 min correlated with the exposure to vardenafil. Higher baseline plasma levels of ADMA and SDMA and a low arginine/ADMA ratio was associated with a more severe pulmonary haemodynamic disease state in patients with PH.

    In paper IV, we found that ingestion of beetroot juice, containing inorganic nitrate, increased plasma and salivary levels of nitrate and nitrite, increased exhaled NO, decreased plasma ornithine levels and increased relative arginine availability in patients with PAH compared to placebo. Higher plasma levels of nitrite after the placebo period, reflecting basal conditions, were associated with a more severe PAH phenotype. Our findings indicate that the nitrate-nitrite-NO pathway is active and upregulated in PAH patients.

    List of papers
    1. Increased plasma and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial hypertension
    Open this publication in new window or tab >>Increased plasma and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial hypertension
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    2011 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 41, no 8, p. 889-897Article in journal (Refereed) Published
    Abstract [en]

    Background Conflicting results on exhaled NO in pulmonary hypertension (PH) exist. Therefore, we analysedexhaled NO, as well as systemic and local nitrite, a possible alternative source of NO, in PH with regard to PHaetiology.Methods Exhaled NO at multiple flow-rates, as well as plasma and salivary nitrite and nitrate, was measured in22 patients with PH and 21 healthy controls. Alveolar NO (CalvNO) and bronchial flux (J’awNO) were calculatedusing the slope–intercept model. Patients with PH were subdivided into pulmonary arterial hypertension (PAH)and PH WHO Groups II–IV, according to the WHO clinical classification of PH.Results Exhaled NO was reduced at flow-rates in the range of 20)200 mL s)1 in patients with PAH (n = 13) vs.PH WHO Group II–IV (n = 9) (P < 0Æ05 all). Patients with PAH had higher CalvNO than healthy controls [2Æ61(2Æ23, 3Æ36) vs. 1.97 ppb (1Æ22, 2Æ49), P = 0Æ03] and similar to PH WHO Group II–IV (P = 0Æ51). Patients with PAHhad lower J’awNO than patients with PH WHO Group II–IV or healthy controls [430 (371, 702) vs. 807 (557, 993)or 731 pL s)1 (580, 818), P < 0Æ05 both]. Subjects with PAH were characterized by higher levels of salivary andplasma nitrite than healthy controls (P < 0Æ05 both).Conclusions Patients with PAH have lower bronchial NO flux compared to healthy controls and patients withPH WHO Group II–IV along with elevated salivary and plasma nitrite compared to controls. This implies reducedbronchial NO synthase-derived NO formation in PAH. Increased alveolar NO levels were found in subjects withPH compared to controls, especially in subjects with PAH. This may reflect NO diffusion disturbances in thealveoli.

    Keywords
    Exhaled nitric oxide, nitrate, nitrite, NO flow-independent exchange parameters, pulmonary hypertension
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97887 (URN)10.1111/j.1365-2362.2011.02488.x (DOI)000292465600010 ()
    Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2018-04-06Bibliographically approved
    2. 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
    Show others...
    2012 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 74, no 6, p. 990-998Article 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.

    National Category
    Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-188138 (URN)10.1111/j.1365-2125.2012.04303.x (DOI)000311108800011 ()
    Available from: 2012-12-12 Created: 2012-12-12 Last updated: 2018-04-06Bibliographically approved
    3. Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension
    Open this publication in new window or tab >>Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension
    Show others...
    2015 (English)In: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 73, p. 71-77Article in journal (Refereed) Published
    Abstract [en]

    Objective: We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine. Patients and methods: ADMA, SDMA, and arginine were measured (0-540 min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60 min. Results: A reduction in ADMA was observed at 30 and 45 min with a median change of -11.1% (P = 0.021) and -12.5% (P = 0.002). SDMA decreased with a median -5.3% change (P = 0.032) at 45 min. An increase in arginine, median 40.3% (P = 0.002), 45.0% (P = 0.010), and 77.1% (P = 0.008) was observed at 120,300, and 540 min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P = 0.012), 32.5% (P = 0.003), 26.5% (P = 0.021),33% (P = 0.007), 48.5% (P = 0.007), and 63.1% (P = 0.008) was observed at 15, 45, 60, 120, 300, and 540 min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540 min (r = 0.80; P = 0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r = 0.65; P = 0.023), and baseline SDMA (r = 0.61; P = 0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r = 0.59; P = 0.045) and baseline cardiac index (CI) (r = 0.61; P = 0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r = -0.79; P = 0.002). A correlation between change (0-60 min) in CI and change in arginine (r = 0.77; P = 0.003) as well as change in the arginine/ADMA ratio (r = 0.61; P = 0.037) was observed. Conclusions: Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in Cl.

    Keywords
    Pulmonary hypertension, Vardenafil, Hemodynamics, Dimethylarginines, Arginine
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-265699 (URN)10.1016/j.vph.2015.04.010 (DOI)000362056600011 ()25934511 (PubMedID)
    Available from: 2015-11-03 Created: 2015-11-02 Last updated: 2018-04-06Bibliographically approved
    4. Effects of oral supplementation with nitrate-rich beetroot juice in patients with pulmonary arterial hypertension – results from BEET-PAH a randomised, double-blind, placebo-controlled crossover study
    Open this publication in new window or tab >>Effects of oral supplementation with nitrate-rich beetroot juice in patients with pulmonary arterial hypertension – results from BEET-PAH a randomised, double-blind, placebo-controlled crossover study
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-346671 (URN)
    Available from: 2018-03-20 Created: 2018-03-20 Last updated: 2018-04-06
  • 7.
    Henrohn, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Sandqvist, Anna
    Umeå universitet.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Egeröd, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Acute haemodynamic response in relation to plasma vardenafil concentrations in patients with pulmonary hypertension2012In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 74, no 6, p. 990-998Article in journal (Refereed)
    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.

  • 8. Khan, N. A.
    et al.
    Spencer, H. J.
    Abda, E. A.
    Alten, R.
    Pohl, C.
    Ancuta, C.
    Cazzato, M.
    Gher, P. I.
    Gossec, L.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hetland, M. L.
    Inanc, N.
    Jacobs, J. W. G.
    Kerzberg, E.
    Majdan, M.
    Oyoo, O.
    Peredo-Wende, R. A.
    Selim, Z. I.
    Skopouli, F. N.
    Sulli, A.
    Hrslev-Petersen, K.
    Taylor, P. C.
    Sokka, T.
    Patient's global assessment of disease activity and patient's assessment of general health for rheumatoid arthritis activity assessment: Are they equivalent?2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 12, p. 1942-1949Article in journal (Refereed)
    Abstract [en]

    Objectives: To assess (A) determinants of patient's global assessment of disease activity (PTGL) and patient's assessment of general health (GH) scores of rheumatoid arthritis (RA) patients; (B) whether they are equivalent as individual variables; and (C) whether they may be used interchangeably in calculating common RA activity assessment composite indices. Methods: Data of 7023 patients from 30 countries in the Quantitative Standard Monitoring of Patients with RA (QUEST-RA) was analysed. PTGL and GH determinants were assessed by mixed-effects analyses of covariance models. PTGL and GH equivalence was determined by Bland-Altman 95% limits of agreement (BALOA) and Lin's coefficient of concordance (LCC). Concordance between PTGL and GH based Disease Activity Score 28(DAS28), Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) indices were calculated using LCC, and the level of agreement in classifying RA activity in four states (remission, low, moderate, high) using κ statistics. Results: Significant differences in relative and absolute contribution of RA and non-RA related variables in PTGL and GH ratings were noted. LCC of 0.64 and BALOA of -4.41 to 4.54 showed that PTGL and GH are not equivalent. There was excellent concordance (LCC 0.95-0.99) for PTGL and GH based DAS28, CDAI and RAPID3 indices, and >80% absolute agreement (κ statistics 0.75-0.84) in RA activity state classification for all three indices. Conclusions: PTGL and GH ratings differ in their determinants. Although they are individually not equivalent, they may be used interchangeably for calculating composite indices for RA activity assessment.

  • 9.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eriksson, André
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lundberg, Jon O
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Increased plasma and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial hypertension2011In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 41, no 8, p. 889-897Article in journal (Refereed)
    Abstract [en]

    Background Conflicting results on exhaled NO in pulmonary hypertension (PH) exist. Therefore, we analysedexhaled NO, as well as systemic and local nitrite, a possible alternative source of NO, in PH with regard to PHaetiology.Methods Exhaled NO at multiple flow-rates, as well as plasma and salivary nitrite and nitrate, was measured in22 patients with PH and 21 healthy controls. Alveolar NO (CalvNO) and bronchial flux (J’awNO) were calculatedusing the slope–intercept model. Patients with PH were subdivided into pulmonary arterial hypertension (PAH)and PH WHO Groups II–IV, according to the WHO clinical classification of PH.Results Exhaled NO was reduced at flow-rates in the range of 20)200 mL s)1 in patients with PAH (n = 13) vs.PH WHO Group II–IV (n = 9) (P < 0Æ05 all). Patients with PAH had higher CalvNO than healthy controls [2Æ61(2Æ23, 3Æ36) vs. 1.97 ppb (1Æ22, 2Æ49), P = 0Æ03] and similar to PH WHO Group II–IV (P = 0Æ51). Patients with PAHhad lower J’awNO than patients with PH WHO Group II–IV or healthy controls [430 (371, 702) vs. 807 (557, 993)or 731 pL s)1 (580, 818), P < 0Æ05 both]. Subjects with PAH were characterized by higher levels of salivary andplasma nitrite than healthy controls (P < 0Æ05 both).Conclusions Patients with PAH have lower bronchial NO flux compared to healthy controls and patients withPH WHO Group II–IV along with elevated salivary and plasma nitrite compared to controls. This implies reducedbronchial NO synthase-derived NO formation in PAH. Increased alveolar NO levels were found in subjects withPH compared to controls, especially in subjects with PAH. This may reflect NO diffusion disturbances in thealveoli.

  • 10. Sandqvist, A. M.
    et al.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schneede, J.
    Egerod, H. C.
    Hedeland, M.
    Bondesson, U. G.
    Wikstrom, Björn G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Comparison of vardenafil and adenosine for vasoreactivity testing in patients with pulmonary hypertension2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no Suppl 1, p. 1013-1013Article in journal (Other academic)
  • 11. Sandqvist, A. M.
    et al.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schneede, J.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Egerod, H. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bondesson, Ulf G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Wikström, Björn G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension2013In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 2, p. 197-207Article in journal (Refereed)
    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.

  • 12.
    Sandqvist, Anna
    et al.
    Umea Univ, Clin Pharmacol, Dept Pharmacol & Clin Neurosci, S-90187 Umea, Sweden..
    Schneede, Jörn
    Umea Univ, Clin Pharmacol, Dept Pharmacol & Clin Neurosci, S-90187 Umea, Sweden..
    Kylhammar, David
    Lund Univ, Dept Clin Sci Lund, Cardiol, Lund, Sweden.;Skane Univ Hosp, Sect Heart Failure & Valvular Dis, Lund, Sweden..
    Henrohn, D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lundgren, Jakob
    Lund Univ, Dept Clin Sci Lund, Cardiol, Lund, Sweden.;Skane Univ Hosp, Sect Heart Failure & Valvular Dis, Lund, Sweden..
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Science. Natl Vet Inst SVA, Dept Chem, Uppsala, Sweden..
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Science. Natl Vet Inst SVA, Dept Chem, Uppsala, Sweden..
    Rådegran, Göran
    Lund Univ, Dept Clin Sci Lund, Cardiol, Lund, Sweden.;Skane Univ Hosp, Sect Heart Failure & Valvular Dis, Lund, Sweden..
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden..
    Plasma l-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction2018In: Heart and Vessels, ISSN 0910-8327, E-ISSN 1615-2573, Vol. 33, no 3, p. 255-263Article in journal (Refereed)
    Abstract [en]

    Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from l-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, l-arginine, l-ornithine, and l-citrulline were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma levels of ADMA and SDMA were higher, whereas l-arginine and l-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of l-arginine than patients with LVSD (p < 0.05). l-Arginine correlated to 6 min walking distance (6MWD) (r (s) = 0.58, p = 0.006) and l-arginine/ADMA correlated to WHO functional class (r (s) = -0.46, p = 0.043) in PAH. In conclusion, l-arginine levels were significantly lower in treatment na < ve PAH patients compared to patients with LVSD. Furthermore, l-arginine correlated with 6MWD in PAH. l-arginine may provide useful information in differentiating PAH from LVSD.

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