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Dear all,
I have a query regarding the consumption of water in a BA/BE study.
Is there any impact in the result of a BA/BE study, when the
consumption of water by a subject during dosing was more than the
specified volume
Awaiting for your reply,
Thanks in advance
Sujatha
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Hi Sujatha.
You asked the following
Is there any impact in the result of a BA/BE study, when the
consumption of water by a subject during dosing was more than the
specified volume.
I can give you an example of a calculation that should put it into
perspective:
The usual half emptying time of water in healthy volunteers sitting up
at a 45 degree angle is in the range: 5 to 7.5 minutes. So taking the
example of the stomach contents at 15 minutes when you might take a
plasma sample for assay, and assuming that your subject drank 300ml
instead of 150 ml and his half emptying time was 6 minutes, you would
find that the difference in gastric emptying would be about 28 ml.
Assuming uniform mixing there would be half the concentration within
the erroneous larger volume so it would be equivalent to 14 ml of your
original 150 ml sample, or approximately 10% of it still remaining in
the stomach at that 15-minute time point.
At 24 minutes, or 4 half-lives, the difference reduces to about 9ml,
the equivalent of 4.5ml of your intended 150 ml dose, which is about 3%.
Completely uniform mixing is highly unlikely from any solid oral
dosage form. More likely that they will be eroded by gastric action
and acid near the antrum so their contents tend to leave the stomach
earlier than this simple calclation would predict, which would reduce
these differences. Tablets in particular (no pun intended) would
probably pass through the antrum before they were fully disintegrated,
and then this effect of increased volume of drink would be lost in all
the other sources of variation. However, if you changed the volume for
the whole group I would expect to detect it.
I hope that helps
Andrew Sutton
Consultant in Clinical Pharmacology
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Dears:
Talking about gastric emptying times. Somebody knows if there is
any published reference where I can find the relationship between
"volume of water consumption" and gastric emptying times??
Thanking in advance
Nelida Mondelo
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Hello Nelida,
I think you ask a good question and that you are unlikely to find any
such references because to my knowledge none of the academic
departments of gastroenterology are interested in water as a test
meal, yet they are the only ones with the resources to measure gastric
emptying by the two commonly accepted methods: scintigraphy or the
indirect C-13 Octanoic acid breath test method.(Clements and Nimmo's
method by absorption of paracetamol is very rarely used). They always
want to use so-called physiological meals that contain food whereas I
was interested in water as a standard probe that anyone could
reproduce so as to diagnose delayed gastric emptying even in primary
care clinics using the simple epigastric impedance method.
Unfortunately that method has never been developed because I and my
colleagues at the university of Surrey had no resources. That was a
great pity because it was validated against all the other direct
methods and achieved encouraging results in several clinical
situations including diabetic autonomic neuropathy, opiate use,
migraine and posture in volunteers. We also used it to screen new
benzamides when I was at Beecham Research in the mid-1980s and we did
show that metoclopramide accelerates gastric emptying of water
flavoured with an orange cordial, so not even we were using pure water
at that time
During my development of the epigastric impedance method I actually
did the experiment that gave the answer you seek in my MD thesis
because I needed to know if volume itself affected the outcome and I
found that half emptying times of water were approximately constant
across the range of 150 to 750 ml of de-ionised water. That is why I
assumed it in my reply to Sujatha.
All the best
Andrew
The Reference is: McClelland GR and Sutton JA, 1986. A comparison of
the gastric emptying and central nervous system effects of two
substitued benzamides in normal volunteers. Br J Clin Pharmacology Vol
21, 503-9.
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Andrew,
I think the emptying times of water are an interesting issue. Did you
try other models of emptying apart from the first order model implied
by the emptying half-time? For example did you try a zero-order
emptying model?
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.-at-.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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Andrew,
Would it be possible to measure the emptying of water using MRI? If
so, may
one of our MRI experts here could fit it into their schedule.
I suppose there would be the complication of measuring the phenomenon
when
the subject is supine, but perhaps something of value could be learned
with
such a noninvasive method.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.-at-.simulations-plus.com
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Hello Nick,
Many thanks for your observation and question on models of gastric
emptying of water. I agree that it is an interesting topic and I have
been trying to develop it as a diagnostic method over many years.
We found during dozens if not hundreds of recordings that the classic,
first-order shape was not typical and concluded that they varied so
much that there was no point in trying to find a model to fit them
all. The most interesting was a sinusoidal curve with a rapid fall in
the first 2-3 minutes followed by a plateau or tendency to level out
before another steeper decline. I thought that this shape looked as
though during the plateau the stomach was "thinking" about what had
just left it before mustering its final emptying response. (With my
apologies for the teleology.)
This fitted well with an observation that Bob Heading showed me once
in a video he made with ultrasound. He used tapwater that he had
boiled to get rid of the air bubbles and seeded it with a few biscuit
crumbs because they showed up in scans like stars in a black
background. Initially a few left the field of interest to pass into
the ileum but very soon a reverse motion began so they were moving
repeatedly in out of the pyloric sphincter, back into the stomach and
out again, proving that emptying is not unidirectional as most people
assume. It looked as though the duodenum was sampling the gastric
contents and the plateau occured while the system was "thinking" out
what its responses should be.
Group or even within-individual mean emptying patterns have tended to
revert to a mean more like a first order curve but the variation could
be large. We felt that it was more logical just to use the simple time
taken for the declining impedance line to re-cross the 50% level of
the initial deflection. We called it the 50% emptying time or t50%.
This was a useful statistic with suitable variation. For example, the
Murphy et al paper had a placebo mean t50% of 7.7 +/- 1.2 minutes and
morphine 21.+/- 2.9 minutes in only 10 volunteers. Tramadol produced a
mean of 9.5 minutes with an SD of +/- 1.6 minutes so the study clearly
showed that morphine delayed the emptying of water while tramadol did
not. (Ref: Anaesthesia, 1997, 52, 1212-1229.)
These short emptying times make the test using water a practical one
in contrast to the academic unit's complex food meal which takes hours
to leave the stomach, especially when emptying is impaired of course.
Then the variation is enormous so it is near impossible to interpret
one result.
With water a result that is more than a couple of SD away from the
mean(like the morphine mean itself) looks highly suspicious, making
the test a good diagnostic. Migraine attacks have produced t50%s of
over 30 minutes during an attack and they revert to the normal range
outside attacks in the same patient (Boyle et al, 1990, Br J Clin
Pharmacol, 30, 405-9). During my thesis work I had one female
volunteer whose mean of about 8 recordings was 19 minutes and I
suspected that she was not a normal emptyer but still had to include
her data. I was gratified to learn that 2 years later it was found
that her mother had an inherited condition that involved
autoantibodies to the thyroid and the GI tract mucosa... I don't
believe the accepted scintigraphy method could have achieved even my
level of suspicion. [I wish I could remember the name of that
syndrome. Does anyone out there know it?]
The other interesting aspect of epigastric impedance is that is is so
sensitive that it detects gastric contractions via the indentations
they cause so it can assess emptying rate and motility simultaneously.
The waveform can be analysed in a similar manner to EEG brain waves
so motility can be quantified. Metoclopramide for example increases
both and diabetic autonomic neuropathy decreases both.
Cheers
Andrew
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Hi Walter,
Yes several years ago we did attempt MRI simultaneously with
epigastric impedance but it had problems in that you need a very large
magnet to make the images quickly enough for such rapid changes and a
large region of interest. Impedance requires skin electrodes that
carry an electrical current that can distort the image. I'm not sure
what the metal in the skin electrodes and wires does to the image. I
don't know if simple water would produce acceptable outlines in MRI.
Would the dissolved air tend to cause a fuzzy image? We used
de-ionised water partly because that has a higher specific impedance
than tapwater (Amazingly they are actually 3 orders of magnitude apart)
On using MRI scanners alone for diagnostic purposes, perhaps the
larger scanners more commonly available now would make it possible to
measure water emptying rates. Some lack of accuracy would be involved
in converting 2D images in several planes to a 3D volume, but I guess
that consistent technique would cancel out errors in before-and-after
tests at least.
One thing surprised me when we first tried ultrasound. There is only
the paper-thin diaphragm between the heart and the stomach so every
time the heart beat it sort-of bounced on top of the diaphragm and
caused a shiver to pass all the way down the gastric contents. I
thought that the body was a very clever design as it used a side
effect of the cardiac contractions to help mix the gastric contents!
I presume that this would not affect an MRI scan unduly.
A supine posture would retard emptying somewhat, possibly doubling
emptying t50s compared with a 45 degree upright posture but it is not
a significant problem. We have used it when comparing epigastric
impedance with scintigraphy without problems.
However, MRI scanners defeat the object of my approach, which was to
produce the gastric equivalent of an ECG (EKG is the US)in that it
would be inexpensive, totally non-invasive and could be run almost
anywhere by staff with only a few days' training. That's partly
because so many gastric problems present in primary care...non-ulcer
dyspepsia being the commonest. NUD concerns me because it is very
common and it presents a clinical conundrum precisely because we have
no objective measurement to aid diagnosis and to detect which
treatments and doses are actually working. Currently we have to rely
on vague and fluctuant symptoms of nausea, bloating and appetite loss
and that is very unsatisfactory in my view.
Cheers,
Andrew
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