From: firstname.lastname@example.org (Steve Harris sbharris@ROMAN9.netcom.com)
Subject: Re: Anti-Asthma Medications: Too Much of a Good Thing?
Date: 15 Nov 2003 19:13:27 -0800
email@example.com wrote in message
> On Sat, 08 Nov 2003 02:28:40 GMT, "CBI" <firstname.lastname@example.org> wrote:
> >At normal doses it shouldn't be a problem. At high doses the beta agonists
> >can stimulate the heart and cause rapid heart rates but, presumably, in this
> >situation you need them to keep you breathing.
> I use 1 puff of the Serevent Diskus two times daily (50mcg per puff),
> and my lisino-hctz dose is 1 pill (20mg lisino and 25mg hctz) daily.
A major side effect of lisinopril-class drugs (called ACE inhibitors)
is cough, which can be difficult to distinguish from symptomatic
asthma. And which can add to asthmatic cough already present. It's
probably caused by proinflammatory substances called bradykinins
produced by the drug in the lungs. Some people get this side effect
(up to 20% of normals), and some don't. The problem is that's it's
very difficult to tell. The effect can also take weeks to come on, and
weeks to clear up after you stop the drug, so it's very sneaky. I can
testify to this.
There are lots of other classes of effective antihypertensives. If you
cough, go to your doc and demand a change. Even if you don't, you
might think about a long course on another drug, just to see what
happens. These days lisinopril is claimed to be safe for asthma, but
the truth is that the objective airway obstruction data on ACE
inhibitors and asthma are conflicting-- some studies find no effect,
but others do. In the early days, a lot of wheezing as well as cough
was reported as ACE inhibitor side effect. I hardly think that this
has somehow magically gone away as the drugs became more widely used.
All in all, risking something that *may* make your symptoms worse
seems a silly thing to do, especially if you have alternatives.
From: Steve Harris <email@example.com>
Newsgroups: sci.med, sci.med.nutrition, sci.life-extension
Subject: ACE is the place for the youthful hardware, man? Re: ACE Inhibition Is
Partial "Fountain Of Youth"
Date: 14 Dec 2004 17:42:50 -0800
> University of California, Irvine Researcher Confirms GenoMed, Inc.'s
> Patent-Pending Discovery: ACE Is Major Aging Gene, ACE Inhibition Is Partial
> "Fountain Of Youth"
An interesting story. This company is convinced that
Angiotensin Converting Enzyme (ACE) gene alleles of various
kinds are associated with rapid aging syndromes, which could
be modulated by ACE inhibitors. Of course, what the article
doesn't tell you is that ACE inhibitor compounds have been
part of medicine for more than 20 years. These compounds
general end with the suffix "-pril", as for example
Captopril (capoten) which was the first one commercially
This is all starting to get interesting, however, because
there have been suggestions for some time that ACE
inhibitors do more beneficially for people than just lower
blood pressure (their ostensible use). In fact, they are
vaguely reminiscent of the statins in being overall "tonics"
for diabetics, interfering in all kinds of diabetic angio
and arteriolar complications by mechanisms uncertain.
Recently, angiotensin II ("AII", a major regulatory peptide
which results, after two steps, from ACE action) has been
implicated in the formation of fibrous changes in the heart.
These cause the ventricular stiffness which is seen not only
in chronic hypertension, but also to some extent in normal
aging, even if people are never hypertensive. Everybody's
left ventricle and arteries lose elasticity with age.
And so do their lungs, all of which is replaced by fibrous
tissue. These changes in the lungs result in the well-known
decrease in Forced Expiratory Volume (1 sec) which is one of
the aging changes which is most robust and least susceptible
to positive modification, in longitudinal aging studies.
That is, you can always make your FEV(1) drop faster by
smoking or mistreating your lungs, but there's nothing you
can do, exercise included, to stop its normal
non-pathological age-related decline. If ACE or AII have
anything to do with any of these changes, in normal aging
heart OR lungs, it would be a very, very exciting result.
Previously, we've had absolutely nothing to use to modify
these processes which replace youthful elastic fibers with
elderly stiff fibrous collagen.
ACE action is part of the body's regulatory action, and ACE
inhibition, even partial inhibition, does sometimes have
unacceptable side effects. Interestingly, ACE does more than
make AII. It also helps to break down bradykinin, a major
inflammatory mediator. So if you inhibit ACE, bradykinin
goes up, and so does inflammation in some places (whether
inflammation from bradykinin or anti-inflammation from less
AII wins out, depends on the tissue). Inflammation in some
cases might be a good thing, for it increases blood flow
(for example, perhaps in heart arterioles). In some cases,
ACE inhibition causes enough new bradykinin release to cause
angioedema or at least a chronic irritative cough.
More recently, however, a number of angiotensin II blocking
drugs (ATB drugs), which directly act at the AII receptor,
have become available in medicine, and these may also end up
doing more than simply lowering blood pressure. So we have a
very, very specific way of blocking AII effects in humans,
and these drugs are already well tested, quite benign, and
long-approved pharmaceuticals (they typically end in the
suffix "-sartan" as in olmesartan = Benicar). Will either
ACE inhibitors or ATBs turn out to have anti-aging
properties? This whole area is one to watch.
From: Steve Harris <firstname.lastname@example.org>
Subject: Yikes, sartan / ATBs may INCREASE MIs. Re: Aging, ACE, and Angiotensin
Date: 17 Oct 2005 16:39:29 -0700
> Hi Kofi,
> While there are exceptions AT2R activation is generally
> beneficial in lab and animal studies. AT1R is not, nor in humans. It
> provokes the bad effects of angiotensin II. ARB's block only AT1R, so
> there is a large literature suggesting their benefits. Gold standard
> human trials however are in general showing little or no benefit, or
> even some harm except in certain conditions.
Right you are, and that will teach me to post without checking the
lastest meta analyses of clinical stuff. Sometimes things become clear
there, which are missed in single trials. We've had 3 big sartan drug
(ATB) trials, and 2 out of 3 prevented stroke (what you worry about
most, in hypertension). Alas, when you put them all together, MI risk
goes up 10%, and this is now statistically signicant. Risk of new
diabetes goes down 20%, which is impressive and also significant. All
this adds up to no gain, however, in overall mortality. Not what you'd
expect, or demand, from an antihypertensive. Yikes!
Although prevention of DM II is nothing to sneeze at, and means ATBs
must be doing something good to glucose sensitivity. It's going to take
some time to figure out where they fit, clinically. Perhaps in treating
the obese hypertensive with borderline glucoses, but also good lipid
profiles (if you can find any :).
Meanwhile, ATBs don't look too good as stuff to give people who've had
one MI already, and there must be zillions of *those* people taking
them. One wonders if the sartans are the next Vioxx.....
This is not a complete joke. If we had to blue-sky an explanation for
increase MI on sartan / ATBs, there's been some suggestion that the
bradykinin increases invoked by the ACE inhibitors might even be
vasodilitory, and thus good for the heart. Hmmmm. Obviously that
doesn't happen with ATB drugs, so perhaps your inflammation level goes
(relatively) down with ATBs, and thus production of COX-2 prostacyclin,
and all this does EXACTLY the same thing to hearts that Vioxx did. So
it's all sort of the same thing. Maybe. A little inflammation where
your coronary lesions are, might be good for you, go figure.
Thanks for making me go back to the literature.
J Hum Hypertens. 2005 Aug 25; [Epub ahead of print]
Meta-analysis of large outcome trials of angiotensin receptor blockers in
Cheung BM, Cheung GT, Lauder IJ, Lau CP, Kumana CR.
1Department of Medicine, The University of Hong Kong, Hong Kong, China.
Angiotensin receptor blockers (ARBs), also known as sartans, block the
activation of angiotensin type 1 receptors and have a recognised role
in the treatment of heart failure and nephropathy. Since 2002, there
have been three major outcome trials of ARBs in hypertension. We
performed a meta-analysis to evaluate the impact of ARB on major
outcomes. Randomised controlled trials of ARBs in hypertensive subjects
with an average follow-up of at least 2 years and at least 100 major
cardiovascular events were included. For each trial, the ARB used,
number and characteristics of subjects, baseline and change in blood
pressure, cardiovascular and noncardiovascular outcomes were recorded.
Three trials involving 29 375 subjects were included in the
meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study
on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan
Antihypertensive Long-term Use Evaluation
trial (VALUE), an ARB reduced the occurrence of the primary end point
and stroke compared to control. Compared to other antihypertensive
drugs, ARB treatment was associated with no significant change in
all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06,
P=0.45). There was an increase in myocardial infarction (RRR, 1.12, 95%
CI: 1.01-1.26, P=0.041), but a decrease in new-onset diabetes mellitus
(RRR, 0.80, 95% CI: 0.74-0.86, P<0.0000001). In conclusion, the
reduction in new-onset diabetes partly offsets any increase in the risk
of myocardial infarction. Most hypertensive patients require more than
one class of drugs. Small differences in treatment outcome should not
over-ride the importance of good blood pressure control.
Journal of Human Hypertension advance online publication, 25 August
PMID: 16121197 [PubMed - as supplied by publisher]