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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Clinical Pharmacology (Dr Frey, Dr Mück, Dr Artmeier-Brandt, Dr Weimann, Dr Wensing) and Global Biostatistics (Ms Unger), Bayer HealthCare AG, Pharma Research Centre, Wuppertal, Germany.
Address for reprints: Dr Reiner Frey, Clinical Pharmacology, Bayer HealthCare AG, Pharma Research Centre, Aprather Weg 18a, 42096 Wuppertal, Germany; e-mail: reiner.frey{at}bayerhealthcare.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Pulmonary hypertension • cyclic GMP • soluble guanylate cyclase • drug therapy • phase I clinical trial
The signaling molecule nitric oxide (NO), which is derived from the endothelial cells, plays a pivotal role in the maintenance of pulmonary vascular tone. In the healthy lung, vascular perfusion is matched with alveolar ventilation. The pulmonary vasculature is kept in a low-pressure state by the balanced activities of vasoconstrictive agents, such as thromboxane A2 and endothelin, and vasodilatory agents, such as NO and prostacyclins.2 Nitric oxide achieves its vasodilatory effects by acting on the enzyme soluble guanylate cyclase (sGC), leading to increased production of the vasodilatory second-messenger cyclic guanosine monophosphate (cGMP).2,3 As well as inhibiting pulmonary arterial constriction directly, NO is also able to reduce pulmonary smooth muscle cell growth and platelet aggregation.4 In individuals with PH, reduced availability of endogenously produced vasodilators such as NO or impaired responsiveness to these vasodilators, together with a concomitant increase in the activity of vasoconstrictive agents, leads to chronic pulmonary vasoconstriction.2
Several supportive treatments are used that attempt to reduce the severity of symptoms and conditions that occur frequently in patients with PH, including diuretics (to reduce swelling of the limbs), anticoagulants (to decrease the risk of blood clots), inhaled oxygen (to improve oxygen levels in the blood), and digoxin (to increase the strength of contraction of the heart). However, none of these supportive treatments has an effect on the elevated pulmonary pressure in patients with PH.
Inhalation of NO in low doses can lead to pronounced, selective vasodilation,5 with the effect continuing for 2 to 5 minutes after administration ceases.6 However, the long-term use of NO donor drugs is hampered by the substantial proportion of patients with PH who do not respond to these agents,7 the development of tolerance,8 the occurrence of rebound pulmonary hypertension when the drugs are withdrawn,9 and the technical problems of administration. Nitric oxide donor drugs are also thought to be ineffective under conditions of oxidative stress, when increased production of ONOO– inactivates the sGC with respect to NO sensing.10
Six drugs have been approved so far by the US Food and Drug Administration (FDA) for the treatment of PH, all of which target components of the endothelial vasodilatory and vasoconstrictive signaling pathways: the prostacyclin analogs epoprostenol, treprostinil, and iloprost; the endothelin receptor antagonists ambrisentan and bosentan; and the phosphodiesterase-5 inhibitor sildenafil.11,12 A further endothelin receptor antagonist, sitaxsentan, has been approved by the European Medicines Agency (EMAE) but is still undergoing review by the FDA. An emerging clinical paradigm is the use of a combination of therapies with different modes of action, which could potentially enhance efficacy by targeting multiple pathways, although the optimal timing of initiation and the sequence of therapies are not yet known.11 However, a significant proportion of patients with PH experience minimal or no improvement despite therapy,13-17 and there is an unmet need for a therapy that extends survival and improves quality of life in patients with PH while also having a favorable safety profile and a convenient mode of administration.
A promising new candidate in clinical development for the treatment of PH is the oral sGC stimulator BAY 63-2521. This drug has a novel mode of action targeting the NO-sGC-cGMP vasodilatory pathway. However, unlike the NO-donor drugs discussed above, BAY 63-2521 stimulates sGC directly to increase cGMP production and vasodilation, without the need for NO. In addition to this NO-independent stimulation of sGC, BAY 63-2521 also acts synergistically to enhance the sensitivity of sGC to low levels of bioavailable NO. This raises the possibility that BAY 63-2521 may induce pulmonary vasodilation in patients with PH, thus reducing the workload of the right heart while maintaining the balance between vascular perfusion and alveolar ventilation.
In animal models of pulmonary hypertension, the sGC stimulator BAY 41-2272—a chemical analog of BAY 63-2521—was shown to produce beneficial effects, including a significant reduction in pulmonary hypertension and a reversal in right ventricular hypertrophy and structural remodeling of the lung vasculature.18
This phase I clinical trial in healthy male volunteers was the first evaluation of BAY 63-2521 in humans. The aim of the study was to investigate the safety and tolerability of a single administration of ascending oral doses of BAY 63-2521 and to assess the pharmacokinetics and pharmacodynamics of the study compound in healthy volunteers.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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95 mm Hg, and had a negative drug screen. Exclusion criteria consisted of a history of organ diseases, a history of medical conditions that could impair the subject's ability to participate in or complete the study, febrile illness in the week before the study, and pathological changes in the electrocardiogram (ECG), such as a second- or third-degree atrioventricular block or prolongation of the QRS complex >120 ms or of the QT/QTc interval >450 ms. Patients could not be enrolled if they had participated in a clinical trial in the previous 3 months, donated more than 100 mL blood in the preceding 4 weeks or 500 mL in the preceding 3 months, or had a regular daily consumption of more than 40 g (5 units) of alcohol, 1 L of xanthine-containing beverages, or 25 cigarettes.
Study Drug
BAY 63-2521 (methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-ylmethylcarbamate) or matching placebo was administered orally in the morning after a fasting period of at least 10 hours with approximately 240 mL of tap water at room temperature. BAY 63-2521 was administered in solution (0.5 mg/mL) or as an immediate-release tablet (2.5 mg).
Study Design and Treatments
The study was designed as a randomized, placebo-controlled, single-blinded, parallel-group trial and was conducted between August 2004 and February 2005. It was carried out in a single center in Germany in accordance with the Declaration of Helsinki and adhered to the International Conference of Harmonization good clinical practice guidelines and the German drug law (AMG). The study protocol was approved by the Ethics Committee of the North-Rhine Medical Council, Düsseldorf. Subjects received a single oral dose of BAY 63-2521 in solution (0.25 mg, n = 6; 0.5 mg, n = 5; 1 mg, n = 12; 2.5 mg, n = 6; or 5 mg, n = 10), as an immediate-release tablet (2.5 mg, n = 6), or a matching placebo solution (n = 11) or placebo tablet (n = 2). Based on experience, a sample size of n = 8 subjects (6 active, 2 placebo) per dose step was considered sufficient to initiate the examination of the safety, tolerability, pharmacokinetics, and pharmacodynamics of BAY 63-2521. To obtain more representative results in the hemodynamically effective dose ranges, we increased the sample size of subjects by repeating the dose steps with the 1-mg and 5-mg solution. The study period consisted of an examination, admission to the ward 25 hours before dosing, a single-dose administration of BAY 63-2521 or placebo, a profile day and an in-house observational period of 72 hours, and a final examination approximately 1 week after drug administration.
Safety and Tolerability
The first cohort received BAY 63-2521 at a dose of 0.25 mg. Enrollment of sequential, dose-escalating cohorts proceeded following evaluation of safety data from the prior cohort. Safety and tolerability were evaluated using standard vital signs and laboratory biochemistry. In addition, adverse events were identified by subject questioning or self-reporting and were classified according to their degree of severity (mild, moderate, severe) and according to whether they were serious.
Pharmacodynamic Evaluation
Pharmacodynamic effects were assessed after administration of BAY 63-2521 using the following parameters: heart rate, heart rate over 1 minute, blood pressure, levels in plasma of vasoactive hormones (renin, angiotensin, aldosterone, noradrenaline), platelet aggregation, cGMP in plasma, and 8-hour urine samples. Blood pressure was measured using the standing blood pressure procedure to estimate the orthostatic effects: subjects spent 20 minutes in the supine position, followed by 3 minutes in the sitting position, 2 minutes in the standing position, and another 5 minutes in the supine position. Blood pressure was measured at the following time points: after 20 minutes in the supine position; after 1, 2, and 3 minutes in the sitting position; after 1 and 2 minutes in the standing position; and then again after 1, 3, and 5 minutes in the supine position. Clinically relevant orthostatic reactions, including dizziness and early termination of the sitting or standing position, were also noted.
Pharmacokinetic Evaluation
Blood plasma samples were obtained at regular intervals for up to 48 hours after BAY 63-2521 administration for analysis of pharmacokinetic parameters and stored at –15°C until analysis. BAY 63-2521 concentrations in plasma and urine were determined by high-performance liquid chromatography/mass spectrometry (HPLC/MS) assay. [2H3]BAY 63-2521 was used as an internal standard (calibration range, 0.1-100 µg/L). The transitions monitored were m/z 423 
109 for BAY 63-2521 and m/z 426 109 for [2H3]BAY 63-2521. Quality control samples in the concentration range from 0.3 to 75.0 µg/L were determined with an accuracy of 92.3% to 101.9% and a precision of 5.3% to 9.0%. The area under the concentration-time curve (AUC), maximum concentration (Cmax), time to maximum concentration (tmax), and half-life associated with the terminal slope (t1/2) for BAY 63-2521 were calculated using noncompartmental methods by KINCALC (Bayer, Wuppertal, Germany). The linear-logarithmic trapezoidal method was used to calculate AUC, and t1/2 was calculated by linear least squares regression after logarithmic transformation of the terminal concentrations. Cmax and AUC values are also reported as dose-normalized values (Cmax/D and AUC/D, where D = dose). Plasma concentration-time courses of BAY 63-2521 (calculated when two thirds or more of the individual values were greater than the lower limit of quantification [LLOQ]) are presented as geometric mean values.
Exploratory analysis of the relationship between hemodynamic effects (heart rate over 1 minute, taken in the supine position up to 4 hours postdosing from the 1-, 2.5-, and 5-mg dosing groups) and BAY 63-2521 plasma concentrations was conducted via graphical inspection and fitting of directly linked Emax models.
Statistical Methods
The statistical evaluation was performed using the SAS software package. The logarithms of AUC/D and Cmax/D were subjected to an analysis of variance (ANOVA), including the factor treatment to explore dose proportionality for the oral solution of BAY 63-2521. A detailed investigation of the profiles of pharmacodynamic data was performed using an exploratory analysis of covariance (ANCOVA) on heart rate, blood pressure, and plasma levels of vasoactive hormones and cGMP. The fixed-factor treatment, time, treatment-by-time interaction, and covariate baseline, as well as the random subject factor, were included. Pairwise comparisons were performed for each dose of active solution against corresponding placebo.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Safety and Tolerability
Twenty-nine of 58 subjects (50%) reported at least 1 treatment-emergent adverse event. All adverse events were mild or moderate. No serious adverse events were reported during this study, and there were no life-threatening events. All adverse events had resolved by study completion, with the exception of a stretched ligament in the left ankle joint of 1 subject (0.25-mg cohort) who was lost to follow-up. All subjects had normal ECGs without clinically significant abnormalities. In no subject was the increase in duration of the corrected QT interval (QTc, Bazett or Fridericia correction) greater than 60 ms. There were no clinically relevant abnormalities in the laboratory values for hematology, clinical chemistry, or urinalysis.
Of the 45 individuals who received BAY 63-2521, 24 (53%) reported at least 1 adverse event. The most commonly reported adverse events considered to be possibly related to BAY 63-2521 were headache (11 subjects), flushing (8 subjects), orthostatic hypotension (7 subjects), nasal congestion (7 subjects), and feeling hot (7 subjects).
The rate of adverse events was dose dependent, being highest in the 5.0-mg cohort (30 adverse events in a cohort of 10 subjects), followed by the 2.5-mg tablet cohort (10 adverse events, n = 6 subjects) and the 2.5-mg solution cohort (8 adverse events, n = 6 subjects). No relevant differences were observed between the rate of adverse events in the placebo solution cohort and the 0.25-, 0.5-, and 1-mg BAY 63-2521 cohorts.
Pharmacodynamics
Heart Rate Over 1 Minute
BAY 63-2521 had significant dose-dependent effects on heart rate at doses of 1.0 to 5.0 mg when compared with placebo (P < .01). Mean heart rate measured over 1 minute increased by 4 beats per minute (bpm) in the 1.0-mg cohort (95% confidence interval [CI]: 1.1-7.1), by 7.8 bpm in the 2.5-mg (solution) cohort (95% CI: 4.2-11.3), and by 11.3 bpm in the 5-mg cohort (95% CI: 8.3-14.4) (Figure 1). The effects on heart rate observed with the 2.5-mg tablet of BAY 63-2521 were similar to those observed with the 2.5-mg solution of the study compound.
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Blood Pressure
Administration of BAY 63-2521 produced a slight but statistically significant reduction in diastolic blood pressure and mean arterial blood pressure at doses of 1 mg and 5 mg (Figure 2). Systolic blood pressure was not significantly affected. Parallel to the reduction in peripheral vascular resistance, there was an increase in the pharmacodynamically driven adverse events. Orthostatic reactions were reported by 1 subject each in the 0.5-, 1.0-, and 2.5-mg BAY 63-2521 solution cohorts and the 2.5-mg tablet cohort, as well as by 3 subjects in the 5.0-mg solution cohort. Orthostatic hypotension was observed in 2 subjects in the 2.5-mg tablet and in 3 subjects in the 5.0-mg solution cohort.
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In doses up to 5.0 mg, BAY 63-2521 did not have significant effects on plasma aldosterone and angiotensin II levels. BAY 63-2521 also had no effect on platelet aggregation.
Pharmacokinetics
BAY 63-2521 was readily absorbed, with plasma concentrations peaking 0.5 to 1.5 hours postdosing and declining thereafter with a terminal half-life in the range of 5 to 10 hours (Figure 4). When escalating the dose of BAY 63-2521, plasma concentrations and AUC showed dose-dependent increases, with no obvious deviation from dose proportionality or linear pharmacokinetics (Table I). The ANOVA performed on the log-transformed values across the 5 doses of BAY 63-2521 oral solution indicated a slight deviation from dose proportionality for Cmax,norm (P = .0226). Pronounced interindividual variability was noted, especially with respect to terminal half-life and area under the concentration-time curve (AUC). The two 2.5-mg formulations of BAY 63-2521 (oral solution and immediate-release tablet) exhibited similar bioavailability (results not shown).
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Heart rate measured over 1 minute, identified as a sensitive hemodynamic parameter reflecting BAY 63-2521 vasodilating activity in these healthy subjects, correlated directly with the plasma concentrations of BAY 63-2521, as described by a sigmoid Emax model: relative change in heart rate = 1 + [(0.47xCp)/(82.3 + Cp)] (Figure 5).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Administration of BAY 63-2521 led to a reduction in peripheral vascular resistance, as indicated by an increase in heart rate over 1 minute. The effect on heart rate is considered a very sensitive noninvasive parameter for indirect estimation of a vasodilating agent on the cardiovascular system in healthy young subjects. In such subjects, the cardiovascular system compensates for changes in blood pressure with changes in heart rate, leading to an increased cardiac output, to keep the blood pressure constant for as long as possible. The observed increase in heart rate was dose dependent at single oral doses of BAY 63-2521 of 1.0 to 5.0 mg. The drug produced a slight decrease in diastolic blood pressure but did not significantly affect systolic blood pressure, probably because there was successful hemodynamic regulation in these healthy young subjects. The effective concentrations of BAY 63-2521, as characterized using the sigmoid Emax model, were in accordance with in vitro and animal data (J. P. Stasch, unpublished data, 2006.
Vasoactive hormones were investigated to assess the effect of BAY 63-2521 on important blood pressure control mechanisms and thereby demonstrate the extent of compensational efforts. BAY 63-2521 did not affect noradrenaline levels at single doses up to 2.5 mg, but a statistically significant increase was observed at the 5-mg dose. This observation is in line with the increased number of hemodynamically driven adverse events and orthostatic reactions observed in the 5-mg dose group. In contrast, no relevant increase in noradrenaline was observed at doses of 1 mg and 2.5 mg, which were well tolerated. An increase in renin activity was observed at doses of 1.0 to 5.0 mg, in parallel with an increase in heart rate. The increased renin activity was not paralleled by an increase in angiotensin II or aldosterone. There was also no effect on platelet aggregation. Plasma cGMP levels showed statistically significant increases at doses of 2.5 mg and 5.0 mg (plasma cGMP is seen as an overspill of intracellular cGMP, and no relevant biological activity is known).
BAY 63-2521 was readily absorbed, and no relevant differences in bioavailability were detected between the oral solution and the immediate-release tablet. A pronounced degree of interindividual variability was observed with regard to the pharmacokinetic properties of BAY 63-2521, and it is likely that this characteristic will need to be taken into account in the clinical setting when titrating the dose. This can be easily addressed with a titration scheme, which is to be developed in phase III clinical trials.
Pulmonary hypertension is a disabling condition with high mortality characterized by sustained elevation in pulmonary artery pressure and pulmonary vascular remodeling. Despite the approval in recent years of 7 drugs for the treatment of PH, there is an unmet need for an efficacious treatment with a favorable safety profile and a convenient mode of administration. The phosphodiesterase-5 inhibitor sildenafil, which inhibits the breakdown of cGMP to GMP, is ineffective in at least some patients with PH.19,20 This fact may be explained, at least in part, by its dependence on an intact NO-sGC-cGMP pathway.21 Of the 3 prostacyclin analogs approved for PH, 2 are administered by injection, either intravenously (epoprostenol)22 or intravenously/subcutaneously (treprostinil),16 which, in addition to causing considerable inconvenience to the patient, also carries the risk of infection. (The third approved prostacyclin analog, iloprost, is administered by inhalation.) Bosentan and sildenafil interact with the cytochrome P450 enzyme system, a factor that needs to be taken into account, especially when considering the use of combination therapy.11 In this respect, the prostacyclin analogs treprostinil, epoprostenol, and iloprost have the advantage of not having appreciable substrate activity for cytochrome P450.11
BAY 63-2521 has the potential to provide a new mode of action for the treatment of PH and has the benefit of convenient oral administration. In the present randomized, placebo-controlled study, BAY 63-2521 was shown to decrease blood pressure in healthy volunteers, based on a reduction in vascular resistance, and to have a pharmacokinetic profile in line with its pharmacological mode of action. BAY 63-2521 had a favorable safety pattern and was well tolerated in a single oral dose of up to 2.5 mg. Its pharmacodynamic and pharmacokinetic properties suggest that BAY 63-2521 may offer a unique treatment for PH, by inducing pulmonary vasodilation and thus reducing the workload of the right heart. In addition to NO-independent vasodilation, BAY 63-2521 may also be able to produce targeted pulmonary vasodilation in synergy with NO, preferentially in well-ventilated areas of the lung, thus directing blood flow to regions of the lung with the greatest supply of oxygen and supporting ventilation/perfusion matching. Additional studies are under way to define the utility of BAY 63-2521 further in patients with PH.23
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: All authors are employees of Bayer HealthCare AG. The authors have full control of all primary data and agree to allow the journal to review their data if requested.
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REFERENCES |
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1. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991;115: 343-349.
2. Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov. 2006;5: 755-768.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3':5'-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci USA. 1977;74: 3203-3207.
4. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333: 214-221.
5. Channick RN, Newhart JW, Johnson FW, et al. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests. Chest. 1996;109: 1545-1549.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Olschewski H, Walmrath D, Schermuly R, Ghofrani A, Grimminger F, Seeger W. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med. 1996;124: 820-824.
7. Klinger JR, Thaker S, Houtchens J, Preston IR, Hill NS, Farber HW. Pulmonary hemodynamic responses to brain natriuretic peptide and sildenafil in patients with pulmonary arterial hypertension. Chest. 2006;129: 417-425.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Munzel T, Daiber A, Mulsch A. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005;97: 618-628.
9. Atz AM, Adatia I, Wessel DL. Rebound pulmonary hypertension after inhalation of nitric oxide. Ann Thorac Surg. 1996;62: 1759-1764.
10. Stasch JP, Schmidt PM, Nedvetsky PI, et al. Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels. J Clin Invest. 2006;116: 2552-2561.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Benza RL, Park MH, Keogh A, Girgis RE. Management of pulmonary arterial hypertension with a focus on combination therapies. J Heart Lung Transplant. 2007;26: 437-446.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov. 2006;5: 689-702.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346: 896-903.
14. Barst RJ, Langleben D, Badesch D, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006;47: 2049-2056.
15. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353: 2148-2157.
16. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165: 800-804.
17. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347: 322-329.
18. Dumitrascu R, Weissmann N, Ghofrani HA, et al. Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation. 2006;113: 286-295.
19. Preston IR, Klinger JR, Houtches J, Nelson D, Farber HW, Hill NS. Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension. Respir Med. 2005;99: 1501-1510.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Bhatia S, Frantz RP, Severson CJ, Durst LA, McGoon MD. Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy. Mayo Clin Proc. 2003;78: 1207-1213.
21. Michelakis ED. The role of the NO axis and its therapeutic implications in pulmonary arterial hypertension. Heart Fail Rev. 2003;8: 5-21.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
22. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334: 296-302.
23. Ghofrani HA, Weimann G, Frey R, et al. BAY 63-2521, an oral soluble guanylate cyclase stimulator, has a favourable safety profile, improves cardiopulmonary haemodynamics and has therapeutic potential in pulmonary hypertension. BMC Pharmacol. 2007;7: S8.[CrossRef]
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