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The following message was posted to: PharmPK
Dear all,
does anybody know the minimum effective concentration of Naproxen,
Ranitidine or verapamil or the reference where i can find it.
than you very much
Sanjay Patel
Creighton university,
omaha, NE
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[Three replies - db]
From: Nick HolfordDate: Thu, 24 Jan 2002
19:54:57 +1300
To: david.at.boomer.org
Subject: Re: PharmPK MEC of Naproxen, Ranitidine, Verapamil
The following message was posted to: PharmPK
"Sanjay Patel (by way of David_Bourne)" wrote:
>
>PharmPK - Discussions about Pharmacokinetics
>Pharmacodynamics and related topics
>
>The following message was posted to: PharmPK
>
>Dear all,
>does anybody know the minimum effective concentration of Naproxen,
Ranitidine or verapamil or the reference where i can find it.
I wonder if anybody knows the MEC of any drug? IMHO this is a fictional
parameter that only exists in theoretical textbooks but has never been
rigorously defined for a real drug. Can anybody provide a definition and
an actual drug example?
Nick
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology University of
Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.aaa.auckland.ac.nz
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
---
From: Dimiter TerziivanovDate: Thu, 24 Jan 2002
04:43:05 -0800 (PST) To: david.-at-.boomer.org
Subject: Re: PharmPK MEC of Naproxen, Ranitidine, Verapamil
The following message was posted to: PharmPK
Dear Dr. Patel,
Regarding MEC of Naproxen, Ranitidine and Verapamil:
Ranitidine plasma levels necessary to inhibit 50% of stimulated gastric
acid secretion are estimated to be 36 to 94 ng/ml.
For drugs like Naproxen, Ranitidine and Verapamil blood levels bear no
consistent relationships to dose or degree of biological response
because of complex nonlinear dependency between variables and occurence
of hysteresis.
Kind regards,
Dimiter Terziivanov, MD
Clinic for Therapeutics and Clinical
Pharmacology, Univ Hosp "St. I.Rilsky",
15 D. Nestorov st, 1431 Sofia, Bulgaria
---
From: "Gobburu, Jogarao V"Date: Thu, 24 Jan
2002 09:35:46 -0500
To: david.at.boomer.org
Subject: RE: PharmPK MEC of Naproxen, Ranitidine, Verapamil
The following message was posted to: PharmPK
Dear Sanjay,
The following article presents the minimum effective concentrations of
naproxen:
Davies NM, Anderson, KE. Clinical pharmacokinetics of naproxen.
Clin.Pharmacokinet. 1997, Apr;32(4), 268-293.
Hope it helps.
Regards,
Joga Gobburu,
Pharmacometrics,
CDER, FDA
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The following message was posted to: PharmPK
Hi
In response to Nicks comment...
>I wonder if anybody knows the MEC of any drug? IMHO this is a fictional
parameter that only exists in theoretical textbooks but has never been
rigorously defined for a real drug. Can anybody provide a definition and
an actual drug example?
I agree with Nick that the minimum effective concentration is more
theoretical than a reality. However sometimes the maximum no-effect
dose/concentration is known. It also gets around the tricky problem of
determining 'effective'.
Steve
Stephen Duffull
School of Pharmacy
University of Queensland
Brisbane 4072
Australia
http://www.uq.edu.au/pharmacy/duffull.htm
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The following message was posted to: PharmPK
>In response to Nicks comment...
>
>>I wonder if anybody knows the MEC of any drug? IMHO this is a
fictional parameter that only exists in theoretical textbooks but has
never been rigorously defined for a real drug. Can anybody provide a
definition and an actual drug example?
>
>I agree with Nick that the minimum effective concentration is more
theoretical than a reality. However sometimes the maximum no-effect
dose/concentration is known. It also gets around the tricky problem of
determining 'effective'.
The maximum no-effect dose/concentration is presumably 0 for a drug that
has no effect (at any dose) -- but is this of any interest?
The idea of a minimum effective concentration implies the biological
fiction that there is some magical threshold below which nothing happens
and above which an acceptable level of effect is achieved. The graded
relationship between concentration and response has been around for over
a hundred years (and between dose and response for much longer). We must
also recognize, in the real world, that there are often big differences
between individual responses to drugs and this needs to be an integral
part of this discussion. A more rational approach would be to define the
target effect and then ask "What is the typical concentration in the
target population that achieves the target effect? i.e. the target
concentration" followed by "What is the distribution of target
concentrations in the target population and what dosing strategy will
benefit the individual and population?"
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology University of
Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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[Three replies - db]
From: Nick HolfordDate: Fri, 25 Jan 2002
15:44:46 +1300
To: david.-a-.boomer.org
Subject: Re: PharmPK Re: MEC of Naproxen, Ranitidine, Verapamil Status:
RO
The following message was posted to: PharmPK
>In response to Nicks comment...
>
>>I wonder if anybody knows the MEC of any drug? IMHO this is a
fictional parameter that only exists in theoretical textbooks but has
never been rigorously defined for a real drug. Can anybody provide a
definition and an actual drug example?
>
>I agree with Nick that the minimum effective concentration is more
theoretical than a reality. However sometimes the maximum no-effect
dose/concentration is known. It also gets around the tricky problem of
determining 'effective'.
The maximum no-effect dose/concentration is presumably 0 for a drug that
has no effect (at any dose) -- but is this of any interest?
The idea of a minimum effective concentration implies the biological
fiction that there is some magical threshold below which nothing happens
and above which an acceptable level of effect is achieved. The graded
relationship between concentration and response has been around for over
a hundred years (and between dose and response for much longer). We must
also recognize, in the real world, that there are often big differences
between individual responses to drugs and this needs to be an integral
part of this discussion. A more rational approach would be to define the
target effect and then ask "What is the typical concentration in the
target population that achieves the target effect? i.e. the target
concentration" followed by "What is the distribution of target
concentrations in the target population and what dosing strategy will
benefit the individual and population?"
Nick Holford, Divn Pharmacology & Clinical Pharmacology University of
Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.at.auckland.ac.nz
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
---
From: "Aucoin, Robert"Date: Fri, 25 Jan 2002
08:10:48 -0600
To: david.at.boomer.org
Subject: RE: PharmPK Re: MEC of Naproxen, Ranitidine, Verapamil
This message is in MIME format. Since your mail reader does not
understand this format, some or all of this message may not be legible.
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Nick,
Very well. said. You have encapsulated my problem with "high-end"
pharmacokinetics and pharmacodynamics. The studies are needed in the
labs and they give us guide post however, they are almost never
applicable to the real world.
I much prefer you approach of targeting the effect then working to get
the concentration to achieve that effect.
thanks again,
robert
Robert Aucoin, RPh
Senior Clinical
Pharmacist
The Children's Center
at Our Lady of the Lake RMC
Baton Rouge, LA 70808
e-mail: RAucoin.-a-.ololrmc.com
---
From: jbyczkowski.-at-.netscape.net
Date: Fri, 25 Jan 2002 11:22:14 -0500
To: david.aaa.boomer.org
Subject: RE: PharmPK Re: MEC of Naproxen, Ranitidine, Verapamil
The following message was posted to: PharmPK
Nick Holford wrote:
>"...The maximum no-effect dose/concentration is presumably 0 for a drug
that has no effect (at any dose) -- but is this of any interest?...">>
Nick:
Yes, this may be of interest for toxicologists, who like to know NOAEL
(No observed adverse effect level) and/or LOAEL (Lowest observed adverse
effect level) for any drug. In addition to giving an idea about the
margin of safety (when compared to the therapeutic dose), this
"threshold" has very important legal implications.
However, in your example - for a drug that has "no effect at any dose"
the maximum no-effect dose would be "any dose," but not "0".
Best wishes.
Janusz Z. Byczkowski, Ph.D.,D.Sc.,D.A.B.T.
Consultant
212 N. Central Ave.
Fairborn, OH 45324
e-mail januszb.-at-.AOL.com
homepage: http://members.aol.com/JanuszB/index.html JZB Consulting web
site: http://members.aol.com/JanuszB/consult.htm
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The following message was posted to: PharmPK
Regarding MEC,
The minimum effective concentration is an important parameter in
warfarin pharmacodynamics, where the value of "Cmin" determines at which
point warfarin dosing begins to inhibit the synthesis of prothrombin
complex activity. Between Cmin and Cmax, the synthesis of prothrombin
complex activity obeys the modified Nagashima equation according to the
textbooks. At "Cmax", the inhibition of synthesis of prothrombin complex
activity is maximal, and PCA activity declines in an exponential manner
P= Poe-kdt.
The population average for Cmin is derived from the averages for Cmax,
Kd and M using the modified Nagashima equation:
Cmin= Cmax[e-(Kd100/M)]= 0.533ug/ml
At this concentration in the average patient, warfarin is believed to
begin to exert its therapeutic anticoagulant/ antithrombotic effect.
Mike Leibold, PharmD, RPh
m_leibold.-a-.hotmail.com
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The following message was posted to: PharmPK
Re: MECs for analgesics.
To identify the MEC for an analgesic like naproxen implies detecting the
minimal clinical effect, which is very difficult to achieve in clinical
situations. One way round this might be to use a volunteer model of pain
such as a Laser induced heat threshold with simultaneous assays of
plasma concentrations. One of the few groups to have done this was
Nielsen JC et al (1991, Br J Clin Pharmacol: 31, 267-270) who compared
pain thresholds and plasma levels after 2g of acetaminophen given either
as 2 x Ig tablets 6 hours apart or a single 2g slow release formulation.
In the event the SR form was not superior to placebo in terms of pain
threshold changes while both 500mg and 1000mg tabs of the immediate
release form were effective. This was despite the Cmax for the 2g form
exceeding the Cmax for the 500mg form. Nielsen et al suggested that rate
of change of analgesic concentrations might be an important factor. We
too think that faster absorption does lead to greater efficacy due to
finding changes in pain thresholds after liquid forms but not solid
(though we have never taken assay samples for fear that the procedures
would themselves alter the pain thresholds). The trouble is that the
effects were fleeting so the change disappeared during the descent after
Cmax, when significant plasma levels must have remained in plasma.
Perhaps the concept of MEC for an analgesic has no meaning in terms of
predictable pharmacodynamics at least. Andrew Sutton.
Guildford Clinical Pharmacology
Guildford Clinical Pharmacology
asutton.-at-.gcpl.co.uk
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The following message was posted to: PharmPK
"Mike Leibold (by way of David Bourne)" wrote:
>
>PharmPK - Discussions about Pharmacokinetics
>Pharmacodynamics and related topics
>
>The following message was posted to: PharmPK
>
>Regarding MEC,
>
>The minimum effective concentration is an important parameter in
warfarin pharmacodynamics, where the value of "Cmin" determines at which
point warfarin dosing begins to inhibit the synthesis of prothrombin
complex activity. Between Cmin and Cmax, the synthesis of prothrombin
complex activity obeys the modified Nagashima equation according to the
textbooks.
"All models are wrong -- some models are more wrong than others" The
Nagashima & Levy model is a simple empirical model that fails seriously
at the extremes because it is based on the log-linear pharmacodynamic
relationship ie. it cannot predict the effect when conc=0 and also does
not recognize an upper limit on the effect. The Cmin and Cmax parameters
of this model are ad hoc attempts to patch up the choice of an
inadequate model. An Emax model is more biologically plausible for the
description of enzyme inhibition (the mechanism of warfarin action) and
does not require the concept of a MEC. For further details see Holford
NHG. Clinical pharmacokinetics and pharmacodynamics of warfarin.
Understanding the dose-effect relationship. Clinical Pharmacokinetics
1986; 11:483-504
Nick Holford, Divn Pharmacology & Clinical Pharmacology University of
Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.-at-.auckland.ac.nz
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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[Two replies - db]
From:
Date: Tue, 29 Jan 2002 14:27:41 -0800 (PST) To: david.-at-.boomer.org
Subject: Re: PharmPK Re: MEC of Naproxen, Ranitidine, Verapamil
The following message was posted to: PharmPK
On Tue, 29 Jan 2002, A.Sutton wrote:
>PharmPK - Discussions about Pharmacokinetics
>Pharmacodynamics and related topics
>
>The following message was posted to: PharmPK
>
>Re: MECs for analgesics.
>To identify the MEC for an analgesic like naproxen implies detecting
the minimal clinical effect, which is very difficult to achieve in
clinical
>situations. One way round this might be to use a volunteer model of
[snip]
Hello,
Defining an MEC for "pain" implies that "pain" itself is adequately
defined (and not in a Bill Clinton-esque sort of way). There are many
different types of pain (post-surgical, chronic, phantom, somatic,
neurogenic, etc.) and their treatments can be quite different. Using a
drug like naproxen for neurologic pain would probably generate a huge
"MEC" because it's just not that effective as a drug such as lamotrigine
or gabapentin. However, its MEC for somatic pain, where it's more
effective, would be quite a bit lower and maybe below the level of
detection.
Just a thought,
Richard Molitor, R.Ph.
http://www.angelfire.com/wa/pharmacist
---
From: "Hans Proost"Date: Wed, 30 Jan 2002
08:38:52 MET
To: david.-a-.boomer.org
Subject: Re: PharmPK Re: MEC of Naproxen, Ranitidine, Verapamil
The following message was posted to: PharmPK
Dear colleagues,
Why bothering about a minimum effective concentration (MEC), i.e. the
concentration at which a minimal effect is detectible? Nick Holford
clearly explained that a MEC usually does not exist, i.e. it equals 0. I
fully agree. Who is interested in a minimal effect? Are we treating
patients to obtain a minimal effect? Of course, there may be situation
where it may be used, but, as pointed out by Nick Holford, better
alternatives are available. Instead of using the concept of MEC as the
concentration resulting in a minimal detectible effect, it makes much
more sense to define the concentration leading to the lowest clinical
relevant effect; in other words, the lower bound of the therapeutic
window. Of course, there are many arguments that such a concentration is
diffucult to define, and may vary greatly between patients (the same
applies to the MEC), but it is, at least, more meaningful than the
definition used in the present discussion.
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery University Centre for
Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
Email: j.h.proost.aaa.farm.rug.nl
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The following message was posted to: PharmPK
This has been one of the most interesting fora I have followed. MEC
(IMHO) cannot be defined in the individual patient/subject. Is this pain
relief "effective/not-effective" is pretty undefinable as the subject's
decision is likely to be inconsistent. The problem can be turned around,
however, by using many subjects/patients and incresing the
dose/concentration gradually while asking the question: is your pain
relieved? That way we end usually end up with a sigmoid of dose/conc. or
log doseor log concentration v percent responders. If you care to define
a model such as probit, logit, Hill or integrated Gaussian distribution,
you can fit a curve to extrapolate if you consider this justified.
This population approach is a lot of work and still leaves MEC to be
defined but at least you can now define it as dose/concentration evoking
response in 1%, 5% or whatever you please.
Tom Torda
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)