Antibiotics useful against CPn which cross the blood brain barrier well?

I recently recovered some information from the former web site of Dr. Sririam pertaining to the usefullness of antibioticsi against Cpni and which ones will cross the blood brain barrier.  What I don't know is how accurate this information is or why some antibiotics that appear to be less effective at crossing the blood  brain barrier were chosen.  Why the latter question?  Because at least one of the doctors who have devised protocolsi did so with the specific objective of treating Multiple Sclerosis, a neurological disease.  Crossing the blood brain barrier is critical in the success of such a treatment.

In an case, I'm going to copy and paste some of the relavant information here.  This information comes from the former website of Dr. Sririam and was recovered using the WayBackMachine at www.archive.org<.

Partial list of antibiotics which have been used against C. pneumoniae-in blood or CSF.
updated 09-24-01

OFLOXACIN (racemic mixture) a fluoroquinolone***@MW=361
RIFAMPIN  lipophilic       -----------------in plans for VU tests***@-need liver monitoring
METRONIDAZOLEi (Flagyl)- lipophilic@
COTRIMOXAZOLE (Bactrim)  a sulfa drug@-some folks report severe allergy to this one
SPARFLOXACIN (Zagam) a fluoroquinolone
LEVOFLOXACIN Levaquin, a fluoroquinolone****@MW=740
DOXYCYCLINE (vibramycin)  a tetracycline type-lipophilic.****
MINOCYCLINE-a Tetracycline
GREPAFLOXACIN-
AMOXICILLINi-  a penicillin type, passes BBBi only weakly
BIAXIN-a macrolide-passes BBB weakly
ZITHROMAX- a macrlide-passes BBB weakly @
ERYTHROMYCIN  a macrolide---passes BBB, but not as well as other antibiotics.
@-Known to have been used by VU, or planned for use.
****=prime medicines of choice.
********************************************************
In order to kill pathogens, there must be at least a certain minimum concentration of antibiotic--
MIC=minimum inhibitory concentration.
MBC=minimum bactericidal concentration-the killing concentration.
**********************

     Table of Antibiotic properties in CSF-For Those That Cross BBB Easily
                                         (units: micrograms/milliliter)
                                        Pathogen is C. pneumoniae
The way to read this table is to look for MBC values that are less than the CSF concentration. Those antibiotics will be effective against C.pneumoniae. Those MBC values are underlined. More data are needed to complete the table, and will be added as found.
 

Ofloxacin       CSF level=.9-4; at dose of 200 mg, b.i.d.; 50% active  isomer      MBC=.5,
Rifampin        CSF level=.4-1; 600 mg/day;                                                           MBC=.005-.1
Moxifloxacin   CSF level= >.125; with dose -----                                                   MBC=.01-.125
Doxycycline   CSF level =.5-2.6;   with dose of 200 mg/day;                                MBC= .06-.5;
Isoniazid         CSF level= 2.4-4; at dose of 300 mg/day; MBC=?
Metronidazole(flagyl) CSF level= >10xMIC;  at dose of 2.4 mg/kg/day
Cotrimoxazole (Bactrim)CSF level=---, with dose=---; MBC=---
Sparfloxacin    CSF level=---, with dose=---;                                                         MBC=.063
Grepafloxacin CSF level=---,with dose=---; MIC=                                               MBC=.06-.12
Levofloxacin-  at least as effective as Ofloxacin;100% levo (active) isomer      MBC= < .5
Minocycline    CSF level=.65-.83;at dose of 400 mg/day;                                    MBC= .25
***************************************************************************
 Properties of Antibiotics which cross the BBB less well.
Erythromycin   CSF level=?;  MBC=.25-1.0 or .05-.1
Amoxicillin      CSF level=.35;  at dose of 33mg/kg, or 1600 mg/day for 110 pound person
***********************************************************************
***********************************************************************
Antibiotics  effective against C pneumoniae but which do NOT cross the BBB
-except possibly, minutely. Thus they cannot effectively act on C pneumoniae in CSF, but may be effective for CP in the rest of the body. thus they can be of use in multiple antibiotic treatment regimen.

Roxythromycin-Macrolide-used in multicenter trials in Germany, to start in 2000. Data not available.
Biaxin (clarithromycin)-MacrolideCSF level=.02, at single dose of 500 mg; MBC=.125or .03
Azithromycin-(Zithromax)-Macrolide MBC= .25-1;or .05; CSF level low.--in VU study
Vancomycin, a glycopeptide with M.W. of 1485.7, a very large molecule.
For those interested, here are the facts:
*************************************************************************
Clin Pharmacokinet 1989 Apr;16(4):193-214 Related Articles, Books

 Clinical pharmacokinetic properties of the macrolide antibiotics.
 Effects of age and various pathophysiological states (Part I).

 Periti P, Mazzei T, Mini E, Novelli A

 Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.

John there is more information about why these antibioticsi were chosen in the patent pages. You can access them here http://www.cpnhelp.org/mitchell_stratton_patent_< marie On CAPi since Sept '05 for MSi, RA, Asthmai, sciatica. EDSSi at start 5.5. Currently on: Doxyi 200, Azith 3x week, Tinii cont. since April '07, all supplementsi. "Color out side the lines!"

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

And a thread here on the topic as well http://www.cpnhelp.org/a_request_for_info_sarah< marie On CAPi since Sept '05 for MSi, RA, Asthmai, sciatica. EDS at start 5.5. Currently on: Doxyi 200, Azith 3x week, Tinii cont. since April '07, all supplementsi. "Color out side the lines!"

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

John, Thank you, thank you! I know we talked about this last week and I haven't had five minutes to hunt for the answers since then. I'm glad YOU did.  You just made the hunt unnecessary and now I can read the info and get the answers.

Fascinating stuff, and in a bizarre way I owe my cpni infection a small (VERY small) debt of gratitude.  I would never have seen the need nor found the desire to learn about this had I not found myself, shall we say, medically challenged.   WinkDouble-edged sword, hmmm?

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems.  Mohandas Gandhi

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

I was bumped up because of editting. I fit between Mackintosh and Eric. John, one of the reasons that roxithromycin is used in the Wheldon protocol is its ability to achieve very high concentration in a brain. 

Here are few articles about roxithromycin and its extreme BBBi permeability.
 http://www.aegis.com/pubs/atn/1989/ATN07501.html http://www.davidwheldon.co.uk/msi-cpni-qa.html 

Barbara Multiple sclerosis, on Wheldon protocol since February 2004, EDSSi 0 for over 4 years

Cured of multiple sclerosisi, stopped the Wheldon's protocol in Nov,2008. Use only LDNi.

Thanks Barbara, this issue with the macrolides has always been of concern to me. Perhaps I can get the ICAAC abstract mentioned in your first link (probably published in Infection and Immunity?) - that one seems particularly satisfying because the human subjects didn't have a brain infection. I have to wonder, though, whether they didn't have brain tumors or something, as it seems unlikely one would take a brain biopsy from a human without some kind of medical (rather than scientific) justification. I am not informed on how toxoplasmosis or tumors might alter BBBi integrity.

At any rate, I did a little googling to find out that it does seem like 7-50x the serum concentration (the range your first link says was found in brains 12h post-dose in the ICAAC-presented study) would be a fairly decent concentration. This serum concentration curve for a single 150 mg dose shows 1.5 mg/L at 12 hours:

http://jac.oxfordjournals.org/cgi/content/full/55/5/796/F2<

In case anyone was confused by this, I notice your second URL (to David's page) has been altered by cpnhelp's automatic glossary hyperlinks, so it didn't click through properly. Excising the added "i" from the URL in my browser fixed that.

Marie

Thanks for posting these links, they provided a lot of good information that we talk about here and now I can read the source of much of it.  The second patent link seems to have the bulk of the information pertaining to the capi in general.  However, what I didn't find in any of the links, nor elsewhere, is why particular abxi were chosen when they may not penetrate the BBBi well.

I know that Eric and Barbara have replied regarding Roxithromycin, which is fine; however, it's not really available in the U.S. which is where I'm undergoing treatment.  Add to that, I didn't see mention of the use of Azithromycin in Stratton's patent documentation, it didn't seem to be the choice he would make for MS patients and rather oflaxin or some such was used, or bactrim, or rifampicin, or some combination thereof, generally speaking. 

I guess this is coming across as critical of the Wheldon protocol, which on some levels it is; however, it's more about finding out what the best options for someone with MS are with respect to abxi that will not only address the Cpni in the body (as doxyi and azi most assuredly do) but also are well suited for addressing the nervous system infection.  Azithromycin doesn't appear to be well suited for that, though I still don't have any hard evidence beyond the little bit of documenation I found on Dr. Sriram's old site that I posted above.

I did see mention in the link you posted in your second reply to me about something pertaining to this subject having been posted here in the past, but despite a good 30 minutes searching for it, could not get the search feature here to uncover it.  Perhaps you know where to find it?  Thanks for all your help.

all my best

John

RRMSi/EDSSi was 4.5, now 4.??? on Wheldon Protocol (naci, doxycycline, azithromycin, metronidazolei) since 04/12/2006

best, John

RRMSi/EDSSi was 4.5, 5, 6, 6.5, 6.9999, 6.5 on Wheldon/Stratton Protocol beginning 04/12/2006
naci 4x600 mg/day
doxycycline 2x100mg/day
azithromycin 3x250mg/day MWF
metronidazolei 3x400mg/day then 3x500mg/day

Hi Mac, you're welcome.  It's something that has been nagging me for some time and I finally had to check on it.  Based on the Stratton patents and what Dr. Sriram had posted in his old site, it doesn't look convincing that azithromycin is going to help someone with MS much, though I'm still trying to find more concrete information about it one way or the next. 

all my best

John

RRMSi/EDSSi was 4.5, now 4.??? on Wheldon Protocol (naci, doxycycline, azithromycin, metronidazolei) since 04/12/2006

best, John

RRMSi/EDSSi was 4.5, 5, 6, 6.5, 6.9999, 6.5 on Wheldon/Stratton Protocol beginning 04/12/2006
naci 4x600 mg/day
doxycycline 2x100mg/day
azithromycin 3x250mg/day MWF
metronidazolei 3x400mg/day then 3x500mg/day

You are very welcome the patent materials are thick reading but really good for anyone doing this protocol. I wonder how difficult it is to search the research archives considering the effort to find it has resulted in nada, because the article is there!.....go to "research articles" then click "antibiotic research on CPni" then the azith study.... marie On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5. Currently on: Doxyi 200, Azith 3x week, Tinii cont. since April '07, all supplementsi. "Color out side the lines!"

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

John, I think this is what you are looking for:

Distribution of azithromycin into brain tissue, cerebrospinal fluid,

and aqueous humor of the eye

S Jaruratanasirikul, R Hortiwakul, T Tantisarasart, N Phuenpathom and S Tussanasunthornwong
Department of Medicine, Prince of Songkla University, Hat Yai, Songkla, Thailand.

To measure the concentrations of azithromycin in the central nervous system, 20 patients with brain tumors (group I) received a single 500- mg oral dose of azithromycin either 24, 48, 72, or 96 h prior to the tumor removal operation and 10 patients with cataracts undergoing surgery (group II) and 7 patients scheduled to undergo lumbar puncture (group III) received the same dose of azithromycin 24 h prior to the operation or procedure. Serum from all patients, brain tissue from group I, aqueous humor from group II, and cerebrospinal fluid from group III were assayed for azithromycin concentration. The mean concentrations of azithromycin in brain tissue 24, 48, 72, and 96 h after administration were 2.63 +/- 2.58, 3.64 +/- 3.81, 0.74 +/- 0.37, and 0.41 micrograms/g, respectively. In contrast, the concentrations of azithromycin in cerebrospinal fluid and aqueous humor of the eye were very low or undetectable. Therefore, these data show that azithromycin appears to be widely distributed into brain tissue but not into cerebrospinal fluid or aqueous humor of the eye.

http://aac.asm.org/cgi/reprint/40/3/825<  

SarahCool: An Itinerary in Light and Shadow  
Stratton/Wheldon regime since August 2003, for aggressive secondary progressive MS.  Intermittent therapy after one year. 2007 still take this two weeks every three months. Still slowly improving with no exacerbation since starting. EDSSi was 7, now 2
Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.
Yes he is, and it is in our archives also.....I added it that last time we had this question and believe it or not I did not even look there yesterday but added links to the patent and pertinent thread only.. Doh!! marie On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5. Currently on: Doxyi 200, Azith 3x week, Tinii cont. since April '07, all supplementsi. "Color out side the lines!"

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

Hmm, "Doh!!" from me as well.   I didn't know it was already in the archives and spent ages looking for it.  Let that be a lesson to me. Frown...........Sarah
Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.

Marie, Sarah, that is exactly the article I saw listed elsewhere in the posts that Marie replied with yesterday but was unable to find using the search feature here.  Too many pages of results to go through, I think I went back through January 07 before I gave up.  In any case, thank you both very much for finding this and posting the link here again.

I went and read the full text of the report.  I pulled out what I think is the relevant information and I'm going to include it in my reply here.  My reason for doing this is that as a layperson, it's difficult for me to  understand and interpret the results of the report.  The results sound substantial, but are they really?  The Sriram information gave you the secret decoder ring on how to interpret the results.  This report assumes you're a medical professional and already know how to interpret them.  So, what is it saying?

Quoted from the aforementioned research paper:

The mean concentrations of azithromycin in brain tissue 24,

48, 72, and 96 h after the dose were 2.63 6 2.58, 3.64 6 3.81,

0.74 6 0.37, and 0.41 mg/g, respectively, while the mean concentrationsin serum at the same time were 0.031

6 0.044,0.016 6 0.011, 0.012 6 0.005, and 0.008 mg/ml, respectively.

The mean ratios of the concentration of drug in brain tissue to

that in serum 24, 48, 72, and 96 h after the dose were 255.76 6

429.39, 199.06 6 188.90, 62.71 6 5.60, and 51.25, respectively.

The concentrations of azithromycin in aqueous humor ranged

from undetectable to 0.008 mg/ml, and those in CSF ranged from undetectable to 0.015 mg/ml. No toxicity was observed in

any patient.

Okay,  so for the moment, let's assume that these results are conclusive and provide irrefutable proof that azithromycin is effective in the CNSi.  What other information do we have beyond 1 small study that reaffirms this?  I guess I'll be doing some more searching.  Thanks again for your help, I'm just wanting to make sure I'm on the right track.

all my best

John

RRMSi/EDSSi was 4.5, now 4.??? on Wheldon Protocol (naci, doxycycline, azithromycin, metronidazolei) since 04/12/2006

best, John

RRMSi/EDSSi was 4.5, 5, 6, 6.5, 6.9999, 6.5 on Wheldon/Stratton Protocol beginning 04/12/2006
naci 4x600 mg/day
doxycycline 2x100mg/day
azithromycin 3x250mg/day MWF
metronidazolei 3x400mg/day then 3x500mg/day

But John, I thought you were taking roxithromycin.  That gets into the brain tissue best of all.  Unfortunately, it needs an autopsy to show this.........Sarah
  
An Itinerary in Light and Shadow  
Stratton/Wheldon regime since August 2003, for aggressive secondary progressive MSi.  Intermittent therapy after one year. 2007 still take this two weeks every three months. Still slowly improving with no exacerbation since starting. EDSSi was 7, now 2
Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.
And now MY question: If azith doesn't show in spinal fluid, is it penetrating where spinal lesions exist? I'm thinking particularly of Yguner here...

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems.  Mohandas Gandhi

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

Sarah        

Not sure what gave you that idea.  I've been on azi since May 2006.  As you may notice, my sig has included azithromycin since July 2006 or roughly thereabouts. 

all my best

John

RRMSi/EDSSi was 4.5, now 4.??? on Wheldon Protocol (naci, doxycycline, azithromycin, metronidazolei) since 04/12/2006

best, John

RRMSi/EDSSi was 4.5, 5, 6, 6.5, 6.9999, 6.5 on Wheldon/Stratton Protocol beginning 04/12/2006
naci 4x600 mg/day
doxycycline 2x100mg/day
azithromycin 3x250mg/day MWF
metronidazolei 3x400mg/day then 3x500mg/day

Ditto the question.  I'm thinking that part of the reason there is some concentration in brain tissue is due to blood flow.  I'm guessing the spine has blood flow as well otherwise it wouldn't be there, lol!  Hey, maybe a test could be devised to check for the existance of the spine or lack thereof.  Oh, wait, that exists already, we use that at work all the time.  My boss tested negative.

all my best

John

RRMSi/EDSSi was 4.5, now 4.??? on Wheldon Protocol (naci, doxycycline, azithromycin, metronidazolei) since 04/12/2006

best, John

RRMSi/EDSSi was 4.5, 5, 6, 6.5, 6.9999, 6.5 on Wheldon/Stratton Protocol beginning 04/12/2006
naci 4x600 mg/day
doxycycline 2x100mg/day
azithromycin 3x250mg/day MWF
metronidazolei 3x400mg/day then 3x500mg/day

Hah! My boss and my counterpart. So sad. But abxi wouldn't help either of them.

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems.  Mohandas Gandhi

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

Ok here is a paper on MIC in azith: Am J Med. 1991 Sep 12;91(3A):12S-18S. Clinical microbiology of azithromycin. Neu HC. Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032. Azithromycin contains an aza-methyl substitution in the 15-membered aglycone ring and as such it is the prototype antibiotic of the azalide class, similar in mechanism of activity to the macrolides. It demonstrates a broad spectrum of activity against many aerobic and anaerobic Gram-positive species, and also inhibits a number of important aerobic and anaerobic Gram-negative bacteria. Significantly, azithromycin shows good activity against Haemophilus influenzae, an organism against which older macrolide antibioticsi have proved disappointing. It is highly effective in inhibiting clinically significant intracellulari pathogens such as Chlamydia trachomatis and Legionella. Bactericidal activity is seen for certain streptococci and for H. influenzae. Closely linked with azithromycin's microbiologic activity are its novel pharmacokinetics. Azithromycin moves rapidly from blood to tissue compartments where it remains for prolonged periods. Although serum concentrations remain low, the levels attained in the tissues (often greater than 2 mg/kg) are higher than the minimum inhibitory concentration for many common pathogens, and delivery of drug to infection sites by phagocytic cells contributes to these concentrations. This penetration into eukaryotic and prokaryotic cells may be responsible for azithromycin's expanded spectrum of activity, particularly against intracellular organisms. The use of antibiotic blood levels as breakpoints for susceptibility would appear to be inappropriate in the case of azalides. Rather, levels of drug at the tissue site of infection should be considered as guides to predicting efficacy. The in vitro activity of azithromycin, together with its unique tissue pharmacodynamics, define an agent that should demonstrate utility in infectionsi of the respiratory tract, skin and skin structures, and certain sexually transmitted diseasesi. Look at the part that John copied from the other paper a few posts above. Then referenceing these both, since this paper discusses the MIC as being adequate for most bugs (it varies a little germ to germ) when over 2 we have sufficient MIC all the way out to 96 hours by looking at the reference above in Johns post. Notice that the serum is a poor way to judge the concentrations on Azith. Clearly the CSF is too. It all goes into tissues and leaves serum alone. The CSF usually test negative for CPni anyway and as DW has pointed out it is a fast moving stream being replaced 3 times a day, so I am glad it goes into tissues and leaves the CSF free! That is not where they are! marie On CAPi since Sept '05 for MS, RA, Asthmai, sciatica. EDSSi at start 5.5. Currently on: Doxyi 200, Azith 3x week, Tinii cont. since April '07, all supplementsi. "Color out side the lines!"

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

 Yikes! My laptop went belly up, so have to borrow a computer to post.

John, one correction: the website was not, repeat not Srirams. It belonged to a Bill something or other who was part of the original studies. It is also years old, so I would see if there is more current research than that of the figures presented there.

CAPi for Chlamydia pneumonia since 11/04. 25yrs CFSi & FMSi- Currently: 300mg INHi, 200 Doxycycline, 500mg MWF Azithromycin, 1000mg Tinii daily (Taking a break from continuous protocol)

 

CAPi for Cpni 11/04. Dxi: 25+yrs CFSi & FMSi. Currently: 250 aithromycin mwf, doxycycline 100mg BIDi, restarted Tinii pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

Jim, Oh NO! Not the dread belly up computer. I hate that when it happens..... marie On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5. Currently on: Doxyi 200, Azith 3x week, Tinii cont. since April '07, all supplementsi. "Color out side the lines!"

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

My interest does not lie in researching drugs and the science behind Cpni and effective antibioticsi, but I do appreciate the fact that other people here are busy constantly researching and questioning the protocol. It is also reassuring to know that the standard Stratton/Wheldon protocol continues to prove itself most effective. And after all why should it not... the people who have put it together have long experience and much knowledge, additionally they have questioning minds. This combination is what made this protocol possible in the first place and I'm sure that eventually it will gain the recognition it deserves and save many more people from a fate worse than death...

Michele (UK) GFAi: Wheldon CAP1st May 2006 . Daily Doxyi, Azi MWF, Flagyli at 400mg for 7 days prior to 5 day pulses at 1200mg three weeks cycle. Spokesperson for Ella, RRMSi Wheldon CAP 16th March 2006

Michèle (UK) GFAi: Wheldon CAPi 1st May 2006. Daily Doxyi, Azi MWF, metroi pulse.

John and Mac, the macrolides are highly concentrated inside cells, relative to the concentrations found outside cells. The CSF is an extracellular fluid, hence the low concentrations seen there. However, John's suspicions about the relevant anatomy are correct. It's not the CSF that really matters for the exposure of neurons to circulating molecules. As mama always used to say,

"In the human brain, there are over 100 billion capillaries. The distance between capillaries is not, vert, similar50 μm. Therefore, the maximum diffusion distance in brain parenchyma following transvascular delivery is only 25 μm. Even a molecule as large as albumin, 68,000 Da molecular mass, will diffuse 25 μm in less than 1 s.< Because the intercapillary distance in brain is so small, every neuron is virtually perfused by its own blood vessel. The length of capillaries in human brain is not, vert, similar400 miles, and the surface area of the brain capillary endothelium in the human brain is not, vert, similar20 m2. However, the volume of the intraendothelial space is only 1 μl for adult rat brain and is only 5 ml for the human brain. Therefore, the brain capillary endothelial surface, which forms the BBBi in vivo, forms a very broad but thin barrier system. The thickness of the endothelial cell is only not, vert, similar200 nm, which is less than 5% of the thickness of most cells."

There's some amazin' science facts in there fit for the back of a cereal box. But the problem that remains to me - since I don't know of any information that proves my personal BBB is intact or non-intact - is whether these macrolide studies on brain tumor patients properly represent what happens with the intact BBB. Are these people's BBBs intact, or are they compromised by the presence of the tumor? I'm just beginning to pry into the question. Here's the first paper I found:

http://clincancerres.aacrjournals.org/cgi/content/full/13/6/1663<

"Thus, the BBB is less intact in primary and metastatic brain tumors compared with the normal brain vasculature. Although there is a spectrum of barrier integrity and permeability, in general, the BBB at sites of tumor seems to have an increased level of permeability. This has led some to describe the tumor capillary bed as a "blood-tumor barrier" rather than a BBB."

However, no functional studies were cited in the text upstream of this conclusion. Studies were cited re the expression of transporter pumps, and the appearance of the endothelial cells, near the tumor. Functional studies on the amounts of sugars or other agents able to pass into the CSF in the tumor patients would be more informative IMOi.

This further discussion was revealing: 

"So how do we explain the apparent contradiction that radiographically evident brain metastases respond to therapy, while at the same time brain metastases is a known poor and independent prognostic factor for survival in diseasesi such as lung and breast cancer, and that the incidence of brain metastases is going up as our chemotherapy agents and combinations are improving in their efficacy? The answer lies in what is known about how the BBB is disrupted at the site of significant brain disease. At these sites, the ‘tumor-blood barrier’ is greatly impaired in terms of transporter expression and function, as well as in terms of the permeability of the endothelium. This allows sufficient systemically delivered chemotherapy to reach the tumor and effect a response. However, this is only at larger brain lesions. In smaller aggregates of metastatic tumor cells, the disruption of the BBB is less significant. Therefore, less drug reaches these so-called micrometastases, and they are allowed to continue to grow, develop neovasculature structures, and ultimately reach a clinically significant size. This theory is partially confirmed by the fact that as our technical ability to radiographically detect brain metastases has improved from the use of first CT scans and now magnetic resonance imaging, more patients are now found at the time of evaluation to have brain involvement with small lesions in addition to larger and symptomatic lesions."

Thus, it sounds like the compromise of the BBB near tumors may be localized enough that the rest of the intra-BBB compartment is not fully suffused with drug (assuming of course that we are discussing a drug unable to pass the intact BBB), even though the tumor is suffused. Therefore, when we look at zithi concentrations in brain tissue, it matters whether the biopsy is taken near the tumor or far from it. (Just how far would be far enough? I have no idea.)

CONCLUSIONS: none for now. 

John and Mac, the macrolides are highly concentrated
inside cells, relative to the concentrations found
outside cells. The CSF is an extracellular fluid,
hence the low concentrations seen there. However,
John's suspicions about the relevant anatomy are
correct. It's not the CSF that really matters for the
exposure of neurons to circulating molecules. As mama
always used to say,

"In the human brain, there are over 100 billion
capillaries. The distance between capillaries is not,
vert, similar50 μm. Therefore, the maximum
diffusion distance in brain parenchyma following
transvascular delivery is only 25 μm. Even a
molecule as large as albumin, 68,000 Da molecular
mass, will diffuse 25 μm in less than 1 s.
Because the intercapillary distance in brain is so
small, every neuron is virtually perfused by its own
blood vessel. The length of capillaries in human brain
is not, vert, similar400 miles, and the surface area
of the brain capillary endothelium in the human brain
is not, vert, similar20 m2. However, the volume of the
intraendothelial space is only 1 μl for adult rat
brain and is only 5 ml for the human brain. Therefore,
the brain capillary endothelial surface, which forms
the BBBi in vivo, forms a very broad but thin barrier
system. The thickness of the endothelial cell is only
not, vert, similar200 nm, which is less than 5% of the
thickness of most cells."

There's some amazin' science facts in there fit for
the back of a cereal box. But the problem that remains
to me - since I don't know of any information that
proves my personal BBB is intact or non-intact - is
whether these macrolide studies on brain tumor
patients properly represent what happens with the
intact BBB. Are these people's BBBs intact, or are
they compromised by the presence of the tumor? I'm
just beginning to pry into the question. Here's the
first paper I found:
[continued in next post] 


http://clincancerres.aacrjournals.org/cgi/content/full/13/6/1663<

"Thus, the BBBi is less intact in primary and
metastatic brain tumors compared with the normal brain
vasculature. Although there is a spectrum of barrier
integrity and permeability, in general, the BBB at
sites of tumor seems to have an increased level of
permeability. This has led some to describe the tumor
capillary bed as a "blood-tumor barrier" rather than a
BBB."

However, no functional studies were cited in the text
upstream of this conclusion. Studies were cited re the
expression of transporter pumps, and the appearance of
the endothelial cells, near the tumor. Functional
studies on the amounts of sugars or other agents able
to pass into the CSF in the tumor patients would be
more informative IMOi.

This further discussion was revealing:

"So how do we explain the apparent contradiction that
radiographically evident brain metastases respond to
therapy, while at the same time brain metastases is a
known poor and independent prognostic factor for
survival in diseasesi such as lung and breast cancer,
and that the incidence of brain metastases is going up
as our chemotherapy agents and combinations are
improving in their efficacy? The answer lies in what
is known about how the BBB is disrupted at the site of
significant brain disease. At these sites, the
‘tumor-blood barrier’ is greatly impaired in terms of
transporter expression and function, as well as in
terms of the permeability of the endothelium. This
allows sufficient systemically delivered chemotherapy
to reach the tumor and effect a response. However,
this is only at larger brain lesions. In smaller
aggregates of metastatic tumor cells, the disruption
of the BBB is less significant. Therefore, less drug
reaches these so-called micrometastases, and they are
allowed to continue to grow, develop neovasculature
structures, and ultimately reach a clinically
significant size. This theory is partially confirmed
by the fact that as our technical ability to
radiographically detect brain metastases has improved
from the use of first CT scans and now magnetic
resonance imaging, more patients are now found at the
time of evaluation to have brain involvement with
small lesions in addition to larger and symptomatic
lesions."

Thus, it sounds like the compromise of the BBB near
tumors may be localized enough that the rest of the
intra-BBB compartment is not fully suffused with drug
(assuming of course that we are discussing a drug
unable to pass the intact BBB), even though the tumor
is suffused. Therefore, when we look at zithi<
concentrations in brain tissue, it matters whether the
biopsy is taken near the tumor or far from it. (Just
how far would be far enough? I have no idea.)

CONCLUSIONS: none for now.

Good work peeps!

I am truly amazed at the information being amassed here on this site.

The times they are a changing & I suspect, in time so will our treatment methods. 

This is allll good.

Grace & Peace

Ruth

CFIDSi/ME, FMSi, IBSi, EBVi, Cpni, Babesia, insomnia (sleep- melatonin">i, GABA, tarazadone, temazepam, novocyclopine, allergy formula, 2 gm tryptophan), Natural HRT peri-M, NACi 2.5 gm, Doxyi 200 mg day pm, Azith 250 mg M/W/Fday

CFIDSi/ME, FMSi, MCS, IBSi, EBVi, CMV, Cpni, H1, chronic insomnia, Chronic Lyme, HME, Babesia, Natural HRT-menopause, NAC 2.4 gm,Full CAP 6-2-07, all supplementsi+Iodorol, Inositol-depression, ultra Chitosan, L lysine Pulse#27 04-19-10 1gm Flagyli/day-5 days<

Scusi! I see that the tildes in my quotation came out as "not, vert, similar." Such is life.
Eric, It just made it a bit of a challenge to read, once it was clear what was happening.

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems.  Mohandas Gandhi

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

Though this thread is about the passage of antibioticsi into the brain, the entry of antimicrobials into cells is just as important.

One of the appeals of roxithromycin is its ability to be concentrated within monocytes; it is the best of its class in this [Hand WL, King-Thompson NL. The entry of antibiotics into human monocytes. J Antimicrob Chemother. 1989 23(5): 681-9.] These key immunei cells are readily parasitized by C. pneumoniae; such infected cells are refractory to treatment [Gieffers J et al., Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment. Circulation 2001 Jan 23;103(3):351-6.] Roxithromycin has been found to hasten the killing of intraphagosomal pathogens [Cuffini AM, Carlone NA, Tullio V, Borsotto M.] Comparative effects of roxithromycin and erythromycin on cellular immune functions in vitro. 3. Killing of intracellulari Staphylococcus aureus by human macrophages. Microbios. 1989;58(234):27-33.] Sarah took 6 months roxithromycin plus doxycycline followed by 7 months roxithromycin plus rifampicin (with pulses of metronidazolei / tinidadazole.) It has been effective so far; there has been no return of symptoms in three years.

D W - [Myalgia and hypertension">i (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazole. Off all medication. BP this am (28th July) 105/70.]

D W - [Myalgia and hypertension">i (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazolei. No medication now. Morning BP typically 110/75]

Wow D W

Look at you with the great BP & NO meds, now that's what we are talking about!

Grace & Peace

Ruth

CFIDSi/ME, FMSi, IBSi, EBVi, Cpni, Babesia, insomnia (sleep- melatonin">i, GABA, tarazadone, temazepam, novocyclopine, allergy formula, 2 gm tryptophan), Natural HRT peri-M, NACi 2.5 gm, Doxyi 200 mg day pm, Azith 250 mg M/W/Fday

CFIDSi/ME, FMSi, MCS, IBSi, EBVi, CMV, Cpni, H1, chronic insomnia, Chronic Lyme, HME, Babesia, Natural HRT-menopause, NAC 2.4 gm,Full CAP 6-2-07, all supplementsi+Iodorol, Inositol-depression, ultra Chitosan, L lysine Pulse#27 04-19-10 1gm Flagyli/day-5 days<

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