What new drugs are coming down the pipeline that may help pulmonary
hypertension in children. My 13 year old son suffers from what's
called secondary pulmonary hypertension. This was caused by dual VSD
which was detected last november. We've consulted doctors here in New
Zealand and they've said that it's a terminal illness and he's
currently being treated on Viagra as this apparently relaxes the lung
muscles, because lungs are damaged and heart is having to work harder,
etc. My goal is to try to find drugs that will stabalize the problem,
not make it worse, let him live normal life as possible, and
hopefully, perhaps, get a lung transplant in future. What research is
happening now? What research is coming down the track in 2-3 years.
Any help would be appreciated.

Hello adbuy,

  I am sorry to hear of your son?s diagnosis, and I?m hoping his VSD
been successfully repaired, or will be soon. I have found information
on the latest therapies for pulmonary hypertension, and have listed
only those that are used for treating secondary pulmonary
hypertension. Please keep in mind that this answer is not intended to
be used for diagnostic purposes, nor are any of the therapies endorsed
or recommended, being presented for informational purposes only.

  The Pulmonary  Hypertension Association UK is optimistic about
treating PAH, ?The future for patients with Pulmonary Hypertension is
getting increasingly brighter. However, there is still some way to go
before we fully understand the causes of Pulmonary Hypertension and
formulate drugs to combat or even prevent the disease developing.
History has shown us though that lung diseases that were once thought
to be incurable (TB) can be overcome. The role of the clinical trial
proved vitally important in that struggle, and continues to play a
fundamental role today.? (Near bottom of the page)
http://www.pha-uk.com/research/nov2001.htm

   I?m also sorry and surprised to read this: ?Access in Australia to
effective PAH therapies has lagged behind that in other affluent
countries.?
And
   ?Historically, Australia has been unable to offer patients with PAH
adequate treatment, largely because of the high cost of therapy. The
performance of pulmonary thromboendarterectomy in Australia was
recently shown to achieve success rates similar to international
practice. Transplantation continues to be limited by donor
availability.
Now, with the availability of new and effective oral agents, we can
abandon the therapeutic nihilism of past decades, and offer patients
effective therapies. Some of these agents allow reverse remodelling of
the right ventricle within very short periods. Reverse remodelling of
the pulmonary artery and the potential to reverse the entire disease
process are realistic targets.?
http://www.mja.com.au/public/issues/178_11_020603/keo10709_fm.html



Therapies

++++++++++++
Ventavis (iloprost) 
+++++++++++++
  Ventavis is one of the newest prostacyclin pulmonary artery
dilators, made by CoTherix. Patients seem to show an increased
tolerance to exercise and an overall improvement of symptoms.
?Ventavis is an inhaled formulation of iloprost, a prostacyclin analog.
CoTherix is developing Ventavis for the treatment of pulmonary arterial
Hypertension?
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/09-08-2004/0002246331&EDATE=

   ?The clinical trial results showed an end point of improvement in
NYHA functional class and at least 10 percent increase in the distance
walked in six minutes was met by more by patients receiving Ventavis
than by patients receiving the placebo.
In September 2003, Ventavis was approved in Europe by the European
Commission in a Centralized Procedure for the treatment of primary
pulmonary hypertension. US approval is pending.?
http://www.pulmonary-hypertension-treatments.com/ventavis.html

   The European Respiratory Society met in Berlin, and concluded that
inhaled Iloprost has proved it?s value:    ??what has been proved in a
large-scale clinical trial is that when patients with pulmonary
hypertension who fall into class 3 and 4 of the New York Heart
Association classification of disability, benefit from inhaling
Iloprost 6 to 9 times per day using a specialised nebuliser. In this
study 203 patients were included. 101 received active Iloprost whilst
102 received placebo (a non active dummy drug) Patients were treated
for a period of 12 weeks during which their exercise capacity was
measured along with their pulmonary pressures. This study showed that
for those who were on active treatment their exercise capacity was
improved significantly, as were their pulmonary pressures, quality of
life and their levels of breathlessness.?
http://www.pha-uk.com/research/oct2001.htm


++++++++++++++++++++
Flolan (epoprostenol)
++++++++++++++++++++
  ?Flolan is a high-priced drug that costs between $70,000 and
$100,000 per year per patient, and there are about 2,500 to 3,000
patients on the drug now. This drug, which is delivered with a central
line catheter, needs to be delivered on a continuous basis. Flolan has
a very short half-life ' on the order of about five minutes ' and it
is not stable at room temperature, so it must be continuously kept
cold with an ice pack. The patient must carry around a backpack with
an ice pack to keep the drug as well as the pump cold on a continuous
basis?
http://archive.twst.com/notes/articles/xag802.html?netscape

   ?In clinical trials, Flolan has been shown to improve survival
rate, exercise capacity, and hemodynamics (blood circulation) and to
date is one of only two FDA approved drugs treatments for PPH.
Now intravenous Flolan infusions are used to treat patients who fail
to respond to oral calcium antagonists such as Nifedipine, and may be
used either as long-term therapy or as a precursor to transplantation.
It has been shown to both improve blood circulation and increase
exercise tolerance in PPH patients who have been unresponsive to
conventional therapy.?
http://www.pulmonary-hypertension-treatments.com/flolan_epoprostenol.html

  ?Chronic intravenous epoprostenol therapy has had a substantial
impact on the clinical management of patients with severe PAH. It
improves exercise capacity, hemodynamics, and survival in patients
with idiopathic pulmonary arterial hypertension (IPAH). It also
improves exercise capacity and hemodynamics in patients with PAH
occurring in association with scleroderma.?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15194179

  ?Flolan is helping many severely ill patients who do not respond to
treatment with calcium channel blockers such as Nifedipine. Flolan
imitates the natural prostacyclin produced by the body to keep blood
vessels healthy by removing the build up of lipids, lowering blood
pressure. People respond to increased doses of prostaglandin which
dilate, or open up, blood vessels in the lungs and throughout the
body. This Flolan-Prostacyclin also appears to prevent blood clots
from forming. Flolan has been studied in clinical trials, and is the
only FDA approved drug treatment for PPH.?
http://www.flolan-center.com/pages/flolan_effective.html


+++++++++++++++++++++++++++
Ambrisentan, made by Myogen
+++++++++++++++++++++++++++
  Ambrisentan is a  type-A selective endothelin receptor antagonist: 
?many scientists believe that agents that block the detrimental
effects of endothelin will provide significant benefits in the
treatment of these conditions. Ambrisentan is selective for the ET(A)
receptor versus the ET(B) receptor and demonstrates a half-life that
may be suitable for once a day dosing.?
http://www.pslgroup.com/dg/244a76.htm

  ?Ambrisentan is an ETA selective receptor antagonist being developed
as an oral therapy for patients with pulmonary arterial hypertension.
Ambrisentan is a member of a class of therapeutic agents known as
endothelin receptor antagonists, or ETRAs, that can be orally
administered. Endothelin is a small peptide hormone that is believed
to play a critical role in the control of blood flow and cell growth.
Elevated endothelin blood levels are associated with several
cardiovascular disease conditions, including pulmonary arterial
hypertension, chronic kidney disease, hypertension, chronic heart
failure, stroke and restenosis of arteries after balloon angioplasty
or stent implantation. Therefore, many scientists believe that agents
that block the detrimental effects of endothelin will provide
significant benefits in the treatment of these conditions. Recently,
it has been discovered that there are two classes of endothelin
receptors, ETA and ETB, which play significantly different roles in
regulating blood vessel diameter. The binding of endothelin to ETA
receptors located on smooth muscle cells causes vasoconstriction, or
narrowing of the blood vessels. However, the binding of endothelin to
ETB receptors located on the vascular endothelium causes vasodilation
through the production of nitric oxide. The activity of the ETB
receptor is thought to be counter-regulatory, protecting against
excessive vasoconstriction.?
http://www.myogen.com/pipeline/ambrisentan.php

   ?Ambrisentan is an orally administered type-A selective endothelin
receptor antagonist designed to reduce elevated pressure in the
pulmonary artery. The condition limits the outflow of blood from the
heart and through the lung, thus preventing the flow of oxygenated
blood to the body.?
http://www.pharmacist.com/articles/h_ts_0601.cfm

   ?Ambrisentan is a type-A selective endothelin receptor antagonist
and potent inhibitor of endothelin-induced vasoconstriction.
Endothelin is a small peptide hormone that is believed to play a
critical role in the control of blood flow and cell growth. Elevated
endothelin blood levels are associated with several cardiovascular
disease conditions, including pulmonary arterial hypertension, chronic
kidney disease, hypertension, chronic heart failure, stroke and
reclosure of coronary arteries after balloon angioplasty or stent
implantation. Therefore, many scientists believe that agents that
block the detrimental effects of endothelin will provide significant
benefits in the treatment of these conditions. Ambrisentan is
selective for the ET(A) receptor versus the ET(B) receptor and
demonstrates a half-life that may be suitable for once a day dosing.?
http://www.merckmedicus.com/pp/us/hcp/hcp_newsarticle.jsp?newsid=300379&newsgroup=3


++++++++++++++++++++++++++
Remodulin (UT-15)
++++++++++++++++++++++++++
?The other competitive drug on the market is Remodulin, delivered
subcutaneously. This is a much safer drug based on the fact that it
has a longer half- life, on the order of hours versus minutes, and it
doesn't need to be continuously kept cold, because it's stable at room
temperature. Remodulin is delivered using a pump the size of a pager;
essentially it's the same pump that's used to deliver insulin. The
pager sized pump is made by MiniMed. Currently, as of the last
quarter, there are about 625 patients on the drug who are paying
customers, and the drug costs about $90,000-$100,000 per year per
patient?
http://archive.twst.com/notes/articles/xag802.html?netscape

?UT-15 is a synthetic, stable form of prostacyclin. It has been
developed by United Therapeudics as an important new treatment for
advanced pulmonary hypertension (PH) as well as late-stage peripheral
vascular disease (PVD).
According to the company that makes UT-15 (Remodulin), United
Therapeutics, the drug is currently in important Phase III clinical
trials for advanced PH. Phase III trials are usually used for FDA
approval to market the drug. UT-15 is apparently significantly longer
lived in the human body than Flolan reducing the need for constant
infusion, additionally Remodulin is stable at room temperature for up
to five years, unlike Flolan. The drug's dilation action lasts from
4-6 hours versus the the short 2-3 minute action of Flolan. Because of
its long life in the body it can be administered under the skin rather
than into the bloodstream. The biggest benefit of UT-15 (Remodulin) is
this under the skin deliver called subcutaneous infusion which works
with a pager-sized MiniMed microinfusion device. UT-15 lowers the risk
of sepsis infection and related hospitalization associated with the
Flolan catheter which is a central I.V. line.

The side effects of UT-15 include jaw pain, headaches, nausea,
diarrhea, flushing and localized pain at the delivery site under the
skin. This pain has been reported as slight irritation to severe.?
http://www.flolan-center.com/pages/UT-15_other.html


+++++++++++++++++++++++++++++++++++++++++++++++++++++++
Tracleer (Bosentan), An endothelin receptor antqagonist
+++++++++++++++++++++++++++++++++++++++++++++++++++++++

?The product is sold by Actelion, a Swiss company. This product is the
first endothelin receptor antagonist that's come to the market. On a
per-patient-per-year basis, it costs about $35,000 for this therapy.?
http://archive.twst.com/notes/articles/xag802.html?netscape

?Bostenan (Tracleer) blocks the action of a hormone called endothelin.
PH patients have too-high levels of endothelin, which is hard on the
lungs. Bostenan use may lower endothelin levels and lower artery
pressure.?
http://www.chfpatients.com/ph.htm#treatments


?Tracleer blocks the action of endothelin, a substance made by the
body. Endothelin narrows blood vessels and elevates blood pressure.
Although endothelin is present in healthy people, high concentrations
of the hormone have been found in the plasma and lungs of patients
with PAH suggesting it is capable of causing the disease.?
http://www.flolan-center.com/pages/tracleer.html

Read a package insert here:
http://www.chfpatients.com/text/tracleer_prescribing_info.pdf


++++++++++++++++++++++++++
Thelin (sitaxsentan)
++++++++++++++++++++++++++
??is currently in a comprehensive pivotal development program. They're
working on their second pivotal trial, a 240-patient trial which they
call Stride-2, an 18-week-long treatment study. The company is nearing
completion of enrollment for the study, and we expect them to complete
the enrollment phase during the third quarter of 2004.?
?Thelin was shown to result in a statistically significant improvement
in walking distance. It's undergoing a second trial right now, and
they are looking to confirm the results they saw in the first trial. A
class-specific issue associated with endothelin antagonists is
liver-toxicity, hepatotoxicity. Tracleer has a rate of about 10%-12%
liver toxicity an elevation of greater-than-three-times- normal of
liver enzymes, and that's the hallmark for liver toxicity associated
with these drugs.?
http://archive.twst.com/notes/articles/xag802.html?netscape

?Sitaxsentan is an experimental treatment being tested to treat
pulmonary hypertension. It is in a class of drugs called endothelin
antagonists. Endothelin is a hormone which attaches to endothelin
receptors in blood vessels causing them to narrow. Endothelin becomes
more abundant in pulmonary hypertension and is believed to be the
cause of the disease. By blocking the endothelin receptors,
Sitaxsentan reverses the narrowing effect of pulmonary hypertension
and assists blood flow.?
http://www.pulmonary-hypertension-treatments.com/sitaxsentan.html

?Sitaxsentan is still in clinical trials at this time. It is hoped
that the drug may have fewer problems with liver toxicity compared to
drugs developed earlier from the same class.
Sitaxsentan is being developed by ICOS-Texas Biotechnology L.P.:  A
50/50-owned limited partnership of ICOS and Texas Biotechnology
Corporation to develop and commercialize endothelin receptor
antagonists such as sitaxsentan and TBC3711.?
http://www.phcentral.org/medical/treatments/sitaxsentan.html
?Sitaxsentan is a small molecule that antagonizes the action of
endothelin, a potent mediator of blood vessel constriction and growth
of smooth muscle in vascular walls. Endothelin receptor antagonists
may prove to be effective in the treatment of a variety of diseases
where the regulation of vascular constriction is important.
Sitaxsentan is a highly selective endothelin A receptor antagonist and
is 6000 times more selective for endothelin A than endothelin B
receptors.
Sitaxsentan being developed to treat pulmonary arterial hypertension,
a condition that involves high blood pressure and structural changes
in the walls of the pulmonary arteries, which are the blood vessels
that connect the right side of the heart to the lungs. PAH causes
shortness of breath, limits activity, and shortens life-expectancy.
Primary and secondary pulmonary arterial hypertension are estimated to
afflict over 100,000 people worldwide, many of whom are young adults.?
http://www.tbc.com/products.html


?Thelin(TM) May Offer Alternative for PAH Patients Who Have Failed on
Bosentan, According to Data Presented at European Respiratory Society
Congress?
http://biz.yahoo.com/prnews/040908/nyw078a_1.html




For the Future:
++++++++++++++++++++++++++
Excerpted from an interview in the Official Journal of Pulmonary
Hypertenison Association, four doctors discussed current and future
therapies for pulmonary hypertension:
?Dr Wessel: As we move forward I think it?s important that we have a
more aggressive attitude toward intervening with these patients. We
are now seeing treatments for patients referred to us as ?Do Not
Rescuscitate? status because there is thought to be no therapy. Yet
they?ve had sometimes spectacular results from existing lines of
therapy for treatment of their pulmonary hypertension. It is our
obligation to really exhaust all those forms of medical treatment and
then consider more heroic efforts like transplantations. It is also
important to inform the medical and patient communities that trials
and treatments do exist for them.

Dr Bridges: I agree with everything that?s been said and I would add
that it?s important both for those of us who are more spe-cialized in
seeing patients with PH and the general pediatric cardiologist to view
each patient with an open mind. As I?ve had more patients with PH
referred to me, I?ve found that there are more variations of the
disease than I originally recognized and it?s easy to be too quick to
categorize the patient. That?s a mis-take. We need to start out with
the view that we do not know the disease and make sure the evaluation
is complete and the approach to therapy is flexible. Given how much
ignorance we still have about the patients we are treating, we need to
remain humble when faced with this disease.

Dr Barst: I think it is also important for us to collaborate with our
colleagues in adult cardiology as more and more children with
congenital heart disease are surviving into adulthood. Each patient
with pulmonary vascular disease deserves an individualized evaluation
and treatment approach.?
http://www.phassociation.org/Medical/Advances_in_PH/Summer_2003/PH_Roundtable-page3.asp


++++++++++++++
Aviptadil (Senetek)
++++++++++++++
Aviptadil is made by  mondoBIOTECH of Italy, and is undergoing
clinical trials. The treatment shows promise, but may not be available
until 2007.

?Collina d'Oro and Bubendorf, Switzerland, July 28, 2004. mondoBIOTECH
Holding SA and Bachem AG (SWX: BANB) today announced a collaboration
agreement for production and supply of mondoBIOTECH īs lead compound
Aviptadil. mondoBIOTECH is entering phase II clinical trial to treat
pulmonary arterial hypertension and plans to bring Aviptadil to the
market in 2007.?

And

?Aviptadil (Vasoactive Intestinal Peptide) is one of the most
abundant, biologically active peptides found in the human lungs. It
belongs to the glucagon-growth-hormone releasing factor secretin
superfamily and influences many aspects of pulmonary biology.
Aviptadil consists of 28 amino acids and is synthetically produced. At
present, Aviptadil as an inhalation treatment is in phase II clinical
trials in patients with primary pulmonary hypertension. Available
clinical results are highly promising.

mondoBIOTECH has been granted orphan drug designation for Aviptadil
for the treatment of pulmonary arterial hypertension and chronic
thromboembolic pulmonary hypertension by the European Agency for the
Evaluation of Medicinal Products (EMEA). Orphan drug designation gives
the designated drug several years of market exclusivity after market
authorisation.?
http://194.209.137.235/default.aspx?sId=33&newId=35

+++++++
TBC3711
+++++++
?A more potent endothelin compound, TBC3711, entered Phase I testing
in December 2001. This drug holds potential for treating chronic heart
failure and essential hypertension.  It is not indicated yet whether
this drug will be tested for use in pulmonary hypertension. Like
Sitaxsentan, this drug is also being developed by ICOS-Texas
Biotechnology L.P.?
http://www.phcentral.org/medical/treatments/sitaxsentan.html

?Waiting in the wings for sitaxsentan to complete its Phase 3 trial,
is TBC3711, an endothelin A antagonist that showed excellent kinetics
in Phase 1 studies. Based on the positive data we?ve received for
sitaxsentan, our first endothelin A antagonist, we believe TBC3711
holds promise as a next generation compound.?
http://www.tbc.com/products.html




I realize your son is 13, but this therapy may be of interest to you.
?Inhaled nitrite, a salt commonly used to counteract the effects of
cyanide poisoning, can be used to treat the narrowing of blood vessels
in the lungs of newborn babies.
Neonatal pulmonary hypertension is a life-threatening condition
characterised by the constriction of lung blood vessels, resulting in
poor blood oxygenation throughout the body. The researchers tested the
effect of inhaled nitrite in newborn lambs with pulmonary
hypertension, and found that it reduced pulmonary hypertension for
long periods with no apparent side effects. The action of nitrite
seemed to depend on the production of the gas nitric oxide, which has
well-known relaxing effects on blood vessels and is absent in cases of
pulmonary hypertension.?
http://www.rds-online.org.uk/pages/headlines.asp?i_ToolbarID=6&i_PageID=54


Additional Information and Resources:
Pulmonary Hypertension Association
http://www.phassociation.org/Chat/

About lung transplantation
http://www.pha-uk.com/research/feb2002.htm
?There are two issues when you?re looking at thoracic organ
replacement in people with coexisting congenital heart disease and
pulmonary vascular disease. First is the technical set of issues. It?s
obviously much more straightforward when you?re considering lung
transplantation for a person with PPH; these patients rarely need
heart replacement. You need to be sure that you have a good
understanding of the technical risks associated with transplantation
for this particular patient and make a very careful decision about
what sort of thoracic organ replacement will be done, heart and two
lungs, heart and one lung, or heart repair plus one or two lungs. It?s
a very individu-alized decision.?
http://www.phassociation.org/Medical/Advances_in_PH/Summer_2003/PH_Roundtable-page3.asp

?A new evidence-based guideline for pulmonary arterial hypertension
(PAH) cautions the use of calcium channel blockers, a commonly used
treatment for high blood pressure, in unstable patients due to the
potentially fatal side effects associated with the medication. PAH is
a life-threatening condition that occurs when the arteries that supply
blood to the lungs become constricted, limiting the blood flow to the
lungs and, ultimately, causing high blood pressure to develop within
the lung arteries.?
http://www.rheumatology.org/press/2004/accp0704.asp?aud=prs
From the National Heart, Lung and Blood  Institute: Future Directions
in Pulmonary Hypertension
http://www.nhlbi.nih.gov/meetings/workshops/pah-wksp.htm

Pulmonary Hypertension Treatments
http://www.pulmonary-hypertension-treatments.com/

http://circ.ahajournals.org/cgi/reprint/106/24/e192.pdf

People may look askance at you if you mention Viagra is being used for
treatment of pulmonary hypertension, but Viagra was originally being
tested for heart problems, and not ED!
http://www.standards.org.au/NEWSROOM/NEWS%20RELEASE/2001-05-31/2001-05-31.HTM

VSD + Pulmonary Hypertension
http://www.redtail.net/owc/10.html
and
http://www.phassociation.org/Medical/Advances_in_PH/Summer_2003/PH_Roundtable.asp

PHA Message Boards may provide tips and support for you
http://www.phassociation.org/Message_Boards/


I hope this answer provides you with the information you were seeking.
If not, or if I have repeated information you already had, please
request an Answer Clarification. By requesting an Answer
Clarification, before rating, I may assist you further, if possible.

I wish you and your son all the best.
Sincerely,
crabcakes

Search Terms

pulmonary hypertension +  clinical trials + Australia
pulmonary hypertension research 2004
secondary pulmonary hypertension therapy
drugs + pulmonary hypertension

I truly appreciate your efforts in answering my question. There were important 
leads here. I'll explore the sites you have referred and get back if I
need further help. Thank you.