Memorandum 9
Submission from the Osmosis Unit
1. EXECUTIVE
SUMMARY
1.1 Ongoing UK space medicine research,
performed by the Osmosis Unit, has identified a mechanism of fluid
balance shifts in astronauts. Confirmation of this mechanism is
predicted to lead to the development of novel pharmacological
agents to overcome these fluid shifts, make space flight more
tolerable, and prevent the orthostatic intolerance presently exhibited
by astronauts on their return to Earth gravity. This research
will have a positive impact on the status of British Scientists
across the world.
1.2 The terrestrial impact of this research
is predicted to be the development of medical devices for the
assisted diagnosis and therapeutic monitoring of hypertension,
oedema and shock. In addition, four new pharmacological agents
for the treatment of these diseases are apparent from this research.
1.3 The estimated annual income from the
four diagnostic devices and drugs is $4.5 billion. However, for
this research and its related intellectual property to remain
within the UK, Britain must be an active member of ESA. Failure
of the UK to join will inevitably result in the loss of this potential
income and its transfer to Europe or the USA.
2. INTRODUCTION
2.1 Exposure to just a few days of weightlessness
results in the inability to stand on return to the Earth's surface.1-2
Weightlessness also results in a shift of plasma volume from the
lower to the upper part of the body3-4 and an overall decrease
in total plasma volume.5 These findings challenge the Starling
Hypothesis of fluid exchange,6 one of the fundamental hypotheses
of cardiology. The implications of this on the diagnosis and therapeutic
treatment of cardiac disease are immense.
2.2 The Osmosis Unit has been investigating
fluid exchange since it was spun out of the Health Service in
2000. Fluid balance and exchange are controlled by the interaction
of the capillary blood pressure and the osmotic pressure across
the capillary membrane (MOP). The MOP of plasma is highly dependent
on the pore size (permeability) of the capillary wall7 which is
highly dynamic. Pulse Reverse Osmosis8-10 (PRO) is a new theory
of fluid exchange which suggests that fluid balance is controlled
by capillary pore size and fluid exchange is controlled by the
capillary pulse.
2.3 The changes in fluid balance and exchange
in astronauts led to the design of a study investigating the effects
of gravity on plasma MOP. Results from this preliminary study
are presented below.
3. PRELIMINARY
RESULTS FROM
THE STUDY
3.1 Change in posture from lying to standing
in six informed healthy volunteers resulted in a 13.7% increase
(Fig 1) in MOP10K (t test p<0.001), a 10.6% change in MOP1K
(p<0.001) and a 0.4% change in plasma osmolality (MOP0K) which
was not significant (p = 0.30).
Fig 1 Effect of change in posture on plasma
MOP10K
3.2 The Starling hypothesis predicts that
changes in plasma osmotic pressure results from the movement of
water between the plasma and the interstitium. If this were the
case, the percentage change in MOP's measured across the three
membranes should be the same as they would all be diluted by the
same amount. However, the measured % change was different for
all three measurements (Fig 2).
Fig 2 Percentage change in MOP between
lying and standing for MOP 0, 1 and 10k Dalton
3.3 These changes are consistent with the
concept of change of capillary pore size with change in hydrostatic
pressure. The finding that the change in MOP10K is greatest suggests
that the tight junctions between epithelial cells in the capillary
are changing in size with posture.
4. TILT TABLE
STUDIES
4.1 As a follow-on from these preliminary
studies we have established links with the department of Sports
Medicine at Glasgow University to further investigate these changes.
This study has been set up to investigate the osmotic, pulse and
blood pressure changes in informed volunteers on a tilt table.
Fig 3 is typical of the changes observed.
Fig 3 Cardiac and osmotic changes observed
in tilt table tests
The results from this one volunteer show a slowly
increasing MOP10K over the 30 minutes following the change in
position, coupled with a transient rise in diastolic blood pressure
and pulse rate. The observed changes are consistent with the predictions
from PRO that fluid balance is related to pore size and the pulse
changes transiently to rebalance fluid exchange.
4.2 We are planning to incorporate 6°
head down tilt into this experiment in order to mimic the effects
of hypogravity. If the results of this study are satisfactory
we would aim to obtain samples from astronauts in the International
Space Station.
5. SIGNIFICANCE
TO SPACE
EXPLORATION
5.1 The short-term aim of the research is
to establish the physiological mechanisms underlying the fluid
balance shifts and orthostatic intolerance during space flight.
It is our hypothesis that the body maintains
postural fluid balance by constricting the pores in the lower
part of the body (below the heart) and opening them in the head.
Exposure to long term weightlessness temporarily suppresses pore
diameter variation on return to Earth gravity and results in orthostatic
intolerance. Identification of the mechanism will enable the development
of pharmacological and physical methods of overcoming these changes.
6. TERRESTRIAL
SIGNIFICANCE OF
THIS RESEARCH
6.1 In addition to their relevance in space
medicine these studies also provide a platform for testing the
principles underlying PRO. This hypothesis suggests that hypertension,
oedema and shock are all imbalances between the capillary pulse
pressure and the plasma membrane osmotic pressure (Fig 4).
Fig 4 Cardiac diseases as predicted by
PRO
6.2 Practical demonstration of the imbalances
shown in Fig 4 will logically lead to the invention of novel medical
devices for the assisted diagnosis and therapeutic monitoring
of these diseases.
6.3 Fig 4 suggests four imbalances between
the capillary blood pressure and the MOP pharmacological treatment
would be designed to change the pore size or blood pressure until
the patient parameters moved from the disease to the homeostatic
area. Four new pharmacological agents would be required to achieve
osmotic and blood pressure equilibrium.
7. ECONOMIC IMPACT
THIS RESEARCH
7.1 PRO provides a basis for the design
of medical devices for the assisted diagnosis and therapeutic
monitoring of hypertension, oedema and shock. Present ECG, blood
pressure and other monitoring devices have a market estimated
to be $1-5 billion annually. If PRO-related medical devices took
10% of this market, this would represent an income to the UK of
$100 to $500 million per year.
7.2 Profits on a standard me-to cardiovascular
drugs are generally in the region of $500 million per year. If
less than that most pharmaceutical companies would consider them
to be uneconomic. Novel blockbuster therapies are expected to
gross at least $1billion annually. PRO suggests four novel pharmacological
entities. These have the potential to be worth $4 billion annually
to the UK.
8. CONCLUSION
8.1 UK Space medicine research has already
suggested a mechanism for fluid shifts in astronauts. Further
research should show if the relevance of this mechanism on the
development of orthostatic hypotension in astronauts returning
to Earth gravity. In addition this research provides a novel method
of testing the principles underlying PRO a new physico chemical
model of blood pressure. Proof of these principles is predicted
to lead to the development of new medical devices and four pharmacological
agents. The potential value of these devices and drugs to the
UK is estimated at $4.5 billion annually.
8.2 All of the above is dependent on the
UK being an active member of ESA space medicine research program.
Failure for the UK to join will inevitably result in the loss
of this potential income and its transfer to Europe or the USA.
October 2006
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