Lactams, glutamate transport and fatigue

[Guest guest]

Penny

So I spent a little time looking over these two articles (bad form

to cite articles before you actually read them, I know) and they are

even more interesting than I thought they might be.

The first paper can be downloaded free of charge and figure 1,

along with its legend, summarizes things well.

http://tinyurl.com/cwkt3

Briefly, many neurons remove from the synapse the very

transmitters that they secrete into the synapse. Neurons that

use glutamate as a neurotransmitter, however, do not appear to

be responsible for clearing the synapse of this transmitter.

Instead several other cells in the brain do this, primarily

astrocytes. The astrocytes have a transporter embedded in their

membranes that pump the glutamate into the astrocytes. It's

been documented that inflammatory cytokines decrease the

ability of astrocytes to carry out this function. This leads to an

increase in extracellular glutamate which causes several

problems. Toxicity, with cell death, is one of them. The above

authors speculate about how the excess glutamate may cause

the fatigue that is associated with a wide spectrum of diseases,

as well as things like sensitivity to sound and light. Or so this is

how my error-prone memory recorded things....

This paper:

http://tinyurl.com/7722e

shows that lactams can increase the expression of the

transporter in astrocytes. This should increase the clearance of

glutamate from the synapse and surrounding extracellular

space, and thereby decrease the harmful consequences. They

demonstrated this in a number of ways, including an in vivo

mouse model of glutamate transport deficiency. The mice that

received the lactam benefitted as measured by several

parameters. But the benefits were seen early on. After that, the

treated mice seemed to decline at roughly the same rate as the

untreated, though for a while at least the initial benefits were

maintained. That is, the mice seemed to benefit X amount over

the initial time period but then declined at about the same rate

as the untreated mice while keeping the X amount benefit. The

authors state, however, that the strength gains were eventually

lost, implying to me that eventually the treated mice performed

no better on this test than the untreated mice (they didn't actually

graph the data out far enough to see this loss; it was just stated

in the text).

This would be consistent with the loss of efficacy that you've

experienced with Ceftin. (Abx resistance is also consistent).

How long did you use ceftin before it started to lose its efficacy?

How much were you taking?

If ceftin makes you feel better due to increased glutamate

transport, this in no way diminishes the role that bacteria may

be playing. After all, it seems to be inflammatory cytokines that

cause the transport problem. And Cipro, a completely unrelated

antibiotic, worked wonders for you.

If ceftin lost its efficacy for you due to Abx resistance, then I would

expect that the bacterial population would've retained a certain

fraction of resistant members (more than were present prior to

your first use of ceftin) and that ceftin will lose its efficacy more

quickly this time. Alternatively, I'd tend to think that if the effect is

due to glutamate transport, that ceftin will work for you about as

long as it did before.

I'm not encouraged by this approach (as a glutamate transport

modifier) as a long term therapy, due to its apparently transient

benefits. I've used a wide variety of abx now, though only for 2 to

3 weeks at a time. My first encounter with Cipro gave me

meningitis-like symptoms vastly out of proportion to my normal

experience (presumably a herxheimer reaction). But since then,

no antibiotic has had any noticeable effect on me, good or bad.

So I plan on testing ceftin (or some other lactam that crosses the

BBB) short-term. If it helps in, say, one week's time, I'd be

hard-pressed to think this was due to its antibiotic properties. If

it works, I might use it to get me through my flares (provoked

mainly by dark, cloudy weather).

What were all the benefits for you? Just relief of fatigue? Did it

relieve pain at all? I think Sue posted on

CFSExperimental that excess glutamate could cause pain. The

first article above also cites an article suggesting this. Was your

pain being controlled to such an extent by Benicar that you would

not have noticed an improvement in pain, or do you have enough

untreated pain that you could comment on any influence ceftin

might have had?

Matt

>

> Matt, this seems really important to me, and I think there's

> something to it. Unfortunately, I don't know where to go with it

> since I can see myself fitting both scenarios.

>

> All I can say for sure is that it's not that I relapse badly after

> going OFF the lactams. I go off the lactams because I start

> relapsing. The fatigue starts coming back and they no longer

seem to

> work, so I stop and start something else, or take a break. I'd

> always thought it was because my bugs had built resistance to

the

> abx, but perhaps it's just my body adapting, getting around it as

> you describe. Sometimes, I notice that if I wait 6 months or so,

the

> abx do seem to regain some effectiveness.

>

> But there are two important points to consider, supporting the

> resistance scenario in my case.

>

> 1) There is some research that shows that resistant bacteria

can

> once again become susceptible to certain abx.

>

> 2) Testing shows that my bugs develop resistance easily. First

time

> my organisms were tested, they showed resistance to 12 of

the 14 abx

> they tested.

>

> Gotta go now, but this is very interesting.

>

> penny

>

>

[Guest guest]

Matt, I've followed these posts about Lactams and glutamate

transport, and they amaze me. This is such fascinating stuff!

At the end you mention a comment by Sue B. about glutamate and pain.

My pain specialist informs me that in addition to the mu-opiod

receptor there is another type of pain receptor that is triggered by

glutamate, and that this corresponds to sharp, sudden pain.

Regrettably, he was telling me this to explain his enthusiasm for

methadone, which I really hope not ever to have to take. It blocks

glutamate receptors in the brain as well as the peripheral nervous

system, and in the brain this can increase pain, rather than relieve

it. It also has a far uglier rap among chronic pain patients than

it's enthusiastic backing by pain doctors would lead one to guess.

I am going to try and get a better handle on the glutamate issues

myself, both in relation to pain and the long list of neurological

disorders where failure of glutamate transport appears to be a key

factor.

That antibiotics can have these effects is very striking to reflect

on. You introduced me to a different set of effects related to

mitochondria, which wound up helping me to grasp what people were

talking about with mitochondrial disorders, just because your

explanations were so darn lucid.

I'm very grateful you make time to post here when you can.

> >

> > Matt, this seems really important to me, and I think there's

> > something to it. Unfortunately, I don't know where to go with it

> > since I can see myself fitting both scenarios.

> >

> > All I can say for sure is that it's not that I relapse badly

after

> > going OFF the lactams. I go off the lactams because I start

> > relapsing. The fatigue starts coming back and they no longer

> seem to

> > work, so I stop and start something else, or take a break. I'd

> > always thought it was because my bugs had built resistance to

> the

> > abx, but perhaps it's just my body adapting, getting around it

as

> > you describe. Sometimes, I notice that if I wait 6 months or so,

> the

> > abx do seem to regain some effectiveness.

> >

> > But there are two important points to consider, supporting the

> > resistance scenario in my case.

> >

> > 1) There is some research that shows that resistant bacteria

> can

> > once again become susceptible to certain abx.

> >

> > 2) Testing shows that my bugs develop resistance easily. First

> time

> > my organisms were tested, they showed resistance to 12 of

> the 14 abx

> > they tested.

> >

> > Gotta go now, but this is very interesting.

> >

> > penny

> >

> >

[Guest guest]

" phagelod " <mpalmer@u...> wrote:

>> How long did you use ceftin before it started to lose its

efficacy?

I'd say it worked really well for a couple of months? I can't recall

exactly. I think I refilled the prescription at least twice.

>>How much were you taking?

1,000 mg per day. I started feeling better (like the others that have

worked) within 2 to 3 days.

> What were all the benefits for you? Just relief of fatigue? Did

it relieve pain at all? > Matt

Well, hard to say as I was taking Benicar which was relieving the pain

for me. But I think, based on past similar experiences, it's primarily

the fatigue that lifts. Perhaps just a little of the pain, but mainly

the fatigue.

I've always said I could live with the pain if I could just have some

energy. None of the abx I've taken have helped with the pain or worked

on inflammation the way the Benicar has. For example, I continued to

have migraines, neck & shoulder pain, anxiety, etc. until I started

the Benicar. Unfortunately, the Benicar does nothing for the fatigue

at all. And it's hard to say what the abx are doing when they don't

lift the fatigue. I've usually stopped taking them once the fatigue

comes back, because that's been my sign they're no longer working, but

now I'm not so sure. I've continued taking zithromax, even though I

have no idea if it's helping, as the fatigue has not lifted much at

all with it. Since I added Ceftin around a week ago, the chest

congestion started to go, and my energy has lifted slightly, but I'm

still feeling pretty exhausted.

This is one area where Tony's remarkable experience doesn't help me.

He didn't have the kind of debilitating fatigue I do. He mainly had

severe pain, the kind that sends you to the hospital and almost out of

your head. Whenever an abx was working for him, it was relieving some

of his pain. And of course, as we all know, Tony's entirely well now,

thanks to his many varied approaches and determination to kill the

bugs with whatever worked.

penny

[Guest guest]

" Schaafsma " <compucruz@y...> wrote:

>

>> My pain specialist informs me that in addition to the mu-opiod

> receptor there is another type of pain receptor that is triggered by

> glutamate, and that this corresponds to sharp, sudden pain.

> Regrettably, he was telling me this to explain his enthusiasm for

> methadone, which I really hope not ever to have to take. It blocks

glutamate receptors in the brain as well as the peripheral nervous

system, and in the brain this can increase pain, rather than relieve

it. It also has a far uglier rap among chronic pain patients than it's

enthusiastic backing by pain doctors would lead one to guess.

>

>

Hi ,

I wonder if there's some similar mechanism to explain why narcotics

will, 7 times out of 10, wire me up, rather than put me to sleep.

Actually, they'll often knock me out for an hour or two, then I wake

up and can't go back sleep. Usually I feel relaxed but can't sleep,

but sometimes I actually feel wired and very antsy. These are from

drugs that put other " normal " people right out. Of course, it's

probably no surprise that we PWC, who, even though we are exhausted

can't seem to sleep normally, would get wired on sleeping pills. :-)

And of course, I still get to enjoy the next day sleeping pill

hangover.

I suppose this is why Benicar has been so miraculous for me. No drug

hangover. Just pain and anxiety relief and better sleep.

penny

[Guest guest]

Matt, I take that back about pain. It's true for body pain, but one

way I gauge whether an antibiotic seems to be working or not, is the

reduction in jaw pain, where my infection is most active. If the pain

is gone, I know something's working. When I'm off abx, or when the

effects wear off, the pain starts coming back. This is often my signal

that it's time for my next dose.

penny

> > What were all the benefits for you? Just relief of fatigue?

Did

> it relieve pain at all? > Matt

[Guest guest]

I prefer to apply Occam's razor (the simplest explanation is

usually best) but with the tetracyclines (and perhaps the

macrolides) there does seem to be this bizarre coincidence: they

can reduce (somewhat) the inflammation that's being caused by

bacteria, while also killing off the bacteria themselves. In so far

as mitochondria are viewed as remnants of bacteria and that the

rRNA of mitoribosomes (the protein synthesis inhibitors bind to

rRNA, not ribosomal proteins) is more similar to bacterial rRNA

than to cytoribosomal rRNA, I can accept this dual effect. Heck, I

might even insist upon it.

But my tolerance for bizarre coincidences is finite. So these folks

show this non-antibiotic effect of lactam antibiotics--the lactams

may blunt the harmful effects of inflammation-mediated increase

in extracellular glutamate, while also killing off the bacteria that

we know can cause the inflammation. Their data look good to

me, and furthermore they were not one of these groups that

sought ahead of time to explain the " anti-inflammatory " effects of

antibiotics by sidestepping the causal role bacteria play in the

inflammation. Instead they randomly screened 1,400

compounds and came up with the lactams.

OK, so maybe this universe has offered up yet another bizarre

coincidence that PWCs have to incorporate into to their

increasingly complex models.

But none of these alternative mechanisms of certain antibiotics

excludes bacteria from playing a causal role. Indeed, the burden

for explaining the inflammation remains unmet by these folks.

I qouted from this article before:

http://content.nejm.org/cgi/content/full/352/13/1376

Again, they said, " ...there are anecdotal claims that chronic

fatigue syndromes respond to ceftriaxone (or other antibiotics)

because the underlying problem is chronic Lyme disease.

However, the study by Rothstein and colleagues1 indicates that

ceftriaxone may exert important effects on the central nervous

system that are independent of its role as an antibiotic. "

" or other antibiotics " ?

Notice, they didn't say " or other lactam antibiotics " .

Are they suggesting that all classes of antibiotics can be

expected to have " feel good " properties independent of the

bacteriostatic/cidal ones? Can they, for example, offer a " feel

good " mechanism for the fluoroquinolones that have produced

such strong benefits for select PWCs?

This newly discovered property of the lactams has the potential

to shed some insights. It also has the potential to be used to

suppress insights. There are a lot of lymies with a lot of

experience with the lactam antibiotics. Hopefully they, and the

LLMDs, will aggressively, and rapidly, investigate this issue and

come to some conclusions about the extent to which lactams

may, or may not, be helping by way of glutamate transport. I'd

like to see the LLMDs get out in front on this and define the issue

early on as an and/both one, before others can define it as an

either/or one.

>

> > > What were all the benefits for you? Just relief of fatigue?

> Did

> > it relieve pain at all? > Matt

[Guest guest]

Hi

I don't have any experience with lactams yet so I won't be able to

contribute any reports for awhile. And, mercifully, pain is rarely

one of my problems, so hopefully I'll never be in a position to

comment from experience on that issue.

Interesting about the " sharp, sudden " description of glutamate

pain. That's the kind of nuance that can help us discover what's

what. If some people report " lactams don't help my pain " and

other say " lactams help my pain " , we might save a lot of time by

asking up front about the nature of the pain being discussed.

I'm also interested in your comment that the influence of

glutamate depends on whether it is in the periphery or in the

CNS. As I read it, it is the failure of astrocytes in the CNS to

remove excess glutamate that is the source of the problem. I'm

thinking there aren't any astrocytes in the PNS. So if some

people report that lactams aggravate their pain, then this might

be an explanation. Could also be another type of pseudo-herx. I

think you are probably much more familiar with lyme patient

testimony than I am. Are you aware of any bias of the lactams to

produce herxheimer pain. Just a thought.

The issues may turn out to be quite complex.

Matt

>

> At the end you mention a comment by Sue B. about glutamate

and pain.

> My pain specialist informs me that in addition to the mu-opiod

> receptor there is another type of pain receptor that is triggered

by

> glutamate, and that this corresponds to sharp, sudden pain.

>

> Regrettably, he was telling me this to explain his enthusiasm

for

> methadone, which I really hope not ever to have to take. It

blocks

> glutamate receptors in the brain as well as the peripheral

nervous

> system, and in the brain this can increase pain, rather than

relieve

>

>

[Guest guest]

Can you give the name of the NEJM article that is the source of this

quote. I couldn't reach it from the link, but have access to hard

copies from the med school library, and would like to see the article.

Again, they said, " ...there are anecdotal claims that chronic

fatigue syndromes respond to ceftriaxone (or other antibiotics)

because the underlying problem is chronic Lyme disease.

However, the study by Rothstein and colleagues1 indicates that

ceftriaxone may exert important effects on the central nervous

system that are independent of its role as an antibiotic. "

Thank you.

> I qouted from this article before:

>

> http://content.nejm.org/cgi/content/full/352/13/1376

>

> Again, they said, " ...there are anecdotal claims that chronic

> fatigue syndromes respond to ceftriaxone (or other antibiotics)

> because the underlying problem is chronic Lyme disease.

> However, the study by Rothstein and colleagues1 indicates that

> ceftriaxone may exert important effects on the central nervous

> system that are independent of its role as an antibiotic. "

>

> " or other antibiotics " ?

>

> Notice, they didn't say " or other lactam antibiotics " .

>

> Are they suggesting that all classes of antibiotics can be

> expected to have " feel good " properties independent of the

> bacteriostatic/cidal ones? Can they, for example, offer a " feel

> good " mechanism for the fluoroquinolones that have produced

> such strong benefits for select PWCs?

>

> This newly discovered property of the lactams has the potential

> to shed some insights. It also has the potential to be used to

> suppress insights. There are a lot of lymies with a lot of

> experience with the lactam antibiotics. Hopefully they, and the

> LLMDs, will aggressively, and rapidly, investigate this issue and

> come to some conclusions about the extent to which lactams

> may, or may not, be helping by way of glutamate transport. I'd

> like to see the LLMDs get out in front on this and define the issue

> early on as an and/both one, before others can define it as an

> either/or one.

[Guest guest]

I actually wondered if that wasn't a freely available article, and if I

should provide the PubMed citation.

Brown RH Jr.

Amyotrophic lateral sclerosis--a new role for old drugs.

N Engl J Med. 2005 Mar 31;352(13):1376-8.

PMID: 15800236

http://tinyurl.com/cr6lu

Matt

>

> Can you give the name of the NEJM article that is the source of

this

> quote. I couldn't reach it from the link, but have access to hard

> copies from the med school library, and would like to see the

article.

>

> Again, they said, " ...there are anecdotal claims that chronic

> fatigue syndromes respond to ceftriaxone (or other antibiotics)

> because the underlying problem is chronic Lyme disease.

> However, the study by Rothstein and colleagues1 indicates

that

> ceftriaxone may exert important effects on the central nervous

> system that are independent of its role as an antibiotic. "

>

> Thank you.

>

[Guest guest]

I have a question related to the discussion a couple of weeks ago about

certain antibiotics functioning to transport glutamate out of the CNS,

relieving neurotoxicity.

Does anyone know of supplements or foods that stimulate glutamate

receptors and re-uptake?

Tempe