Viagra fights heart and
lung diseases and saves lives
German researchers reported today in
Melbourne on their latest findings on the impact of Viagra on pulmonary
hypertension, and announced a new collaboration with Monash University to turn
their results into clinical applications.
High blood pressure in the vessels of
the lung results in a dramatic reduction of quality of life and often to heart
failure. There are limited treatments for pulmonary hypertension which causes 10
per cent of all cases of heart failure worldwide.
In
2004 Professors Friedrich Grimminger and Werner Seeger from the German
University of Gießen Lung Centre showed
Viagra protected mountain
climbers’ lungs from problems associated with high altitude.
This,
and other discoveries by the German team led to the US Food and Drug
Administration approving Viagra's active ingredient ‑ sildenafil citrate ‑ in
June this year for the treatment of pulmonary hypertension.
Their
latest trial, in rabbits, has shown Viagra not only lowers blood pressure but
also regenerates diseased blood vessels.
The
researchers now plan to enter into collaboration with Monash to bring their
research to Australia.
Professor
Harald Schmidt, one of the leaders of the German research, has been recruited to
lead a new Australian attack on cardiovascular disease, as head of Monash
University’s Department of Pharmacology.
“Blood
vessel diseases such as stroke, pulmonary hypertension, angina pectoris,
myocardial infarction and coronary heart disease represent the number one cause
of death worldwide,” Professor Schmidt said.
“How
these diseases develop is insufficiently understood. Consequently, only symptoms
such as elevated blood pressure rather than causes of diseases can be treated.
We need to do better.”
There
are plans to create a Centre of Excellence for Vascular Health at Monash, said
Professor Warwick Anderson, head of the School of Biomedical Sciences.
The
Frontiers of Vascular Medicine conference brings together researchers from
German and US centres of excellence, the Baker Institute, RMIT, the University
of Melbourne, the Australian Synchrotron, and many other Australian universities
and institutes.
For information contact Diane
Squires in the Media Communications Office on 0417 603 400.
Media Communications: Phone +61 3 9905
5828, Mobile 0417 125 700
Email:
media@adm.monash.edu.au, Website:
www.monash.edu.au
TOP
Background
The Frontiers of Vascular Medicine
conference brings together leaders in research on blood vessel diseases. In this
group belongs angina pectoris, myocardial infarction, coronary heart disease,
and stroke. Collectively they represent the number one cause of death world-wide
including third world countries with an increasing socio-economic financial
burden.
How these diseases develop is
insufficiently understood; consequently, only symptoms, such as elevated blood
pressure, rather than causes of diseases can be treated. Moreover, patients at
risk are identified with poor precision and the individual treatment success
cannot be monitored at present.
World-wide, researchers therefore aim
at identifying the genes and molecules responsible for these vascular diseases
in order to identify patients at risk – ideally before any symptoms become
apparent – and subsequently to treat those patients to prevent disease outbreak
or progression with unprecedented precision.
Other breakthroughs include the role
of free radicals in the blood vessel wall and new drugs that may replace
nitroglycerin as an emergency medication. Researchers in Germany, the USA and
Australia are leaders in this research field.
In order to become more efficient and
successful, teamwork is the key. “No single researcher is more successful than
highly supportive and networked collaborative groups and Centres”, says
Professor Harald Schmidt, recently recruited from Germany, heading the
Department of Pharmacology at Monash University and currently setting up a
Centre for Vascular Health.
It’s an exciting development for
Monash’s biomedical research which has recently received, ranking as the number
one in Australia and amongst the top 30ies in the world”, says Professor Warwick
Anderson, co-organizer and Head of the School of Biomedical Sciences at Monash.
Schmidt anticipates also a boost for
Victorian biotechnology which is chronically lacking in the presence of major
pharmaceutical activities. We have to become so good at an international level
that companies want to come here because they are afraid of missing exciting
opportunities.
And he plans a Centre of Excellence
for Vascular health (Prevention and Regenerative Medicine) funded by major
research council and charities; bi- and international links to exchange and
train the best young scientists and to install major program grants and centres
of excellence between the countries.
TOP
Publications
1: Respir Res.
2005 Jul 20;6(1):76.
Lung vasodilatory response to
inhaled iloprost in experimental pulmonary hypertension: amplification by
different type phosphodiesterase inhibitors.
Schermuly RT, Inholte C, Ghofrani HA, Gall H, Weissmann N, Weidenbach A,
Seeger W, Grimminger F.
Medical Clinic II/V, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
ralph.schermuly@innere.med.uni-giessen.de
Inhaled prostanoids and
phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe
pulmonary hypertension. In catheterized rabbits with acute pulmonary
hypertension induced by continuous infusion of the stable thromboxane analogue
U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3
inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled
iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure
decline, levelling off within <20 min, without significant changes in blood
gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and
sildenafil caused each a dose-dependent decrease in pulmonary artery pressure,
with sildenafil possessing the highest efficacy and at the same time selectivity
for the pulmonary circulation. When combining a per se ineffective dose of each
PDE inhibitor (200 microg/kg x min 8-Methoxymethyl-IBMX, 1 microg/kg x min
sildenafil, 5 microg/kg x min motapizone) with subsequent iloprost nebulization,
marked amplification of the prostanoid induced pulmonary vasodilatory response
was noted and the area under the curve of PPA reduction was nearly threefold
increased with all approaches, as compared to sole iloprost administration.
Further amplification was achieved with the combination of inhaled iloprost with
sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic
hemodynamics and gas exchange were not altered for all combinations. We conclude
that co-administration of minute systemic doses of selective PDE inhibitors with
inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory
response to inhaled iloprost, with maintenance of pulmonary selectivity and
ventilation perfusion matching. The prominent effect of sildenafil may be
operative via both PDE1 and PDE5, and is further enhanced by co-application of a
PDE3 inhibitor.
2: Herz. 2005 Jun;30(4):296-302.
Emerging Therapies for the Treatment of Pulmonary
Arterial Hypertension. [Article in German]
Ghofrani HA, Voswinckel R,
Reichenberger F, Grimminger F, Seeger W.
Medizinische Klinik II, Klinikstrasse 36, 35392, Giessen,
ardeschir.ghofrani@innere.med.uni-giessen.de.
Besides all progress in the therapy of
pulmonary arterial hypertension over the past years, there is still no cure for
this devastating disease. By introducing effective and nonparenteral medications
(e. g., oral endothelin receptor antagonists [ERAs], inhaled prostanoids),
quality of life, exercise tolerance and prognosis of patients have substantially
improved. However, applicability of these therapies can be hampered by serious
side effects and/or the necessity for elaborate application techniques. Whether
selective ERAs-due to their specificity for the A-type receptor-have potential
benefits over the nonselective ERA bosentan remains to be answered by the
analysis of pivotal trials recently carried out with ambrisentan and sitaxsentan.
Inhaled treprostinil can potentially have benefits over the already approved
inhaled iloprost, related to its higher pulmonary selectivity as well as to the
longer biological half-life. However, this has yet to be proven in long-term
randomized controlled trials. In comparison to the previously mentioned
substances, the selective phosphodiesterase-5 (PDE5) inhibitor sildenafil
approached approval closest as new therapy for pulmonary arterial hypertension.
Oral sildenafil has proven its efficacy as a selective pulmonary vasodilator in
various forms of pulmonary hypertension. The results of the pivotal phase III
trial have confirmed the strong efficacy and excellent tolerability of this
substance. Combination therapies, despite all progress seen for single agents,
can be regarded as the most promising therapeutic approach for the future.
However, controlled randomized trials that are currently under consideration
have to confirm this notion.
3: Internist (Berl). 2005 Mar;46(3):341-9.
Therapy of pulmonary arterial hypertension
Olschewski H, Ghofrani A, Enke B,
Reichenberger F, Voswinckel R, Kreckel A, Ghofrani S, Wiedemann R, Schulz R,
Grimminger F, Seeger W.
Medizinische Klinik, Klinikum der Justus-Liebig-Universitat Giessen.
New drugs for pulmonary arterial
hypertension have shown efficacy in randomized controlled trials. Endothelin
receptor antagonists (ERA) and prostanoids are most important for clinical
practice. Bosentan represents the first approved orally active therapy for PAH.
Besides its hepatotoxicity it is mostly well tolerated. The first approved
prostanoid, epoprostenol, is currently first choice only for decompensated right
heart failure in PAH. It has to be delivered continuously intravenously and is
prone to complications, side effects and very high costs. Alternatively,
subcutaneous treprostinil can be applied. It is less risky and expensive but may
cause local pain at the infusion site. Inhaled iloprost combines the features of
a prostanoid with pulmonary and intrapulmonary selectivity. Alternatively,
iloprost is being used as continuous intravenous infusion. The
phosphodiesterase-5 inhibitor sildenafil was effective in two randomized
controlled trials but has not been approved for PAH therapy.
4: J Am Coll Cardiol. 2004 Oct
6;44(7):1488-96.
Differences in hemodynamic and oxygenation
responses to three different phosphodiesterase-5 inhibitors in patients with
pulmonary arterial hypertension: a randomized prospective study
Ghofrani HA, Voswinckel R,
Reichenberger F, Olschewski H, Haredza P, Karadas B, Schermuly RT, Weissmann N,
Seeger W, Grimminger F.
Department of Internal Medicine, University Hospital Giessen, Giessen, Germany.
OBJECTIVES: We sought to compare the
short-term impact of three different phosphodiesterase-5 (PDE5) inhibitors on
pulmonary and systemic hemodynamics and gas exchange parameters in patients with
pulmonary arterial hypertension (PAH). BACKGROUND: The PDE5 inhibitor sildenafil
has been reported to cause pulmonary vasodilation in patients with PAH.
Vardenafil and tadalafil are new PDE5 inhibitors, recently being approved for
the treatment of erectile dysfunction. METHODS: Sixty consecutive PAH patients
(New York Heart Association functional class II to IV) who underwent right heart
catheterization received short-term nitric oxide (NO) inhalation and were
subsequently assigned to oral intake of 50 mg sildenafil (n = 19), 10 mg (n = 7)
or 20 mg (n = 9) vardenafil, or 20 mg (n = 9), 40 mg (n = 8), or 60 mg (n = 8)
tadalafil. Hemodynamics and changes in oxygenation were assessed over a
subsequent 120-min observation period. RESULTS: All three PDE5 inhibitors caused
significant pulmonary vasorelaxation, with maximum effects being obtained after
40 to 45 min (vardenafil), 60 min (sildenafil), and 75 to 90 min (tadalafil).
Sildenafil and tadalafil, but not vardenafil, caused a significant reduction in
the pulmonary to systemic vascular resistance ratio. Significant improvement in
arterial oxygenation (equally to NO inhalation) was only noted with sildenafil.
CONCLUSIONS: In PAH patients, the three PDE5 inhibitors differ markedly in their
kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil), their
selectivity for the pulmonary circulation (sildenafil and tadalafil, but not
vardenafil), and their impact on arterial oxygenation (improvement with
sildenafil only).
Careful evaluation of each new PDE5
inhibitor, when being considered for PAH treatment, has to be undertaken,
despite common classification as PDE5 inhibitors.
Publication Types: Clinical Trial
Randomized Controlled Trial
5: Ann Intern Med. 2004 Aug
3;141(3):169-77.
Comment in: Ann Intern Med. 2004 Aug
3;141(3):233-5. Ann Intern Med. 2004 Aug 3;141(3):I12.
Sildenafil increased exercise capacity during
hypoxia at low altitudes and at Mount Everest base camp: a randomized,
double-blind, placebo-controlled crossover trial.
Ghofrani HA, Reichenberger F, Kohstall
MG, Mrosek EH, Seeger T, Olschewski H, Seeger W, Grimminger F.
University Hospital Giessen and Justus-Liebig University, Giessen, Germany.
BACKGROUND: Alveolar hypoxia causes
pulmonary hypertension and enhanced right ventricular afterload, which may
impair exercise tolerance. The phosphodiesterase-5 inhibitor sildenafil has been
reported to cause pulmonary vasodilatation. OBJECTIVE: To investigate the
effects of sildenafil on exercise capacity under conditions of hypoxic pulmonary
hypertension. DESIGN: Randomized, double-blind, placebo-controlled crossover
study. SETTING: University Hospital Giessen, Giessen, Germany, and the base camp
on Mount Everest. PARTICIPANTS: 14 healthy mountaineers and trekkers.
MEASUREMENTS: Systolic pulmonary
artery pressure, cardiac output, and peripheral arterial oxygen saturation at
rest and during assessment of maximum exercise capacity on cycle ergometry 1)
while breathing a hypoxic gas mixture with 10% fraction of inspired oxygen at
low altitude (Giessen) and 2) at high altitude (the Mount Everest base camp).
INTERVENTION: Oral sildenafil, 50 mg, or placebo. RESULTS: At low altitude,
acute hypoxia reduced arterial oxygen saturation to 72.0% (95% CI, 66.5% to
77.5%) at rest and 60.8% (CI, 56.0% to 64.5%) at maximum exercise capacity.
Systolic pulmonary artery pressure increased from 30.5 mm Hg (CI, 26.0 to 35.0
mm Hg) at rest to 42.9 mm Hg (CI, 35.6 to 53.5 mm Hg) during exercise in
participants taking placebo. Sildenafil, 50 mg, significantly increased arterial
oxygen saturation during exercise (P = 0.005) and reduced systolic pulmonary
artery pressure at rest (P < 0.001) and during exercise (P = 0.031). Of note,
sildenafil increased maximum workload (172.5 W [CI, 147.5 to 200.0 W]) vs. 130.6
W [CI, 108.8 to 150.0 W]); P < 0.001) and maximum cardiac output (P < 0.001)
compared with placebo. At high altitude, sildenafil had no effect on arterial
oxygen saturation at rest and during exercise compared with placebo. However,
sildenafil reduced systolic pulmonary artery pressure at rest (P = 0.003) and
during exercise (P =0.021) and increased maximum workload (P = 0.002) and
cardiac output (P = 0.015). At high altitude, sildenafil exacerbated existing
headache in 2 participants. LIMITATIONS: The study did not examine the effects
of sildenafil on normoxic exercise tolerance. CONCLUSIONS: Sildenafil reduces
hypoxic pulmonary hypertension at rest and during exercise while maintaining gas
exchange and systemic blood pressure. To the authors' knowledge, sildenafil is
the first drug shown to increase exercise capacity during severe hypoxia both at
sea level and at high altitude.
Publication Types: Clinical Trial
Randomized Controlled Trial
TOP
