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!"

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

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!"

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!"

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

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 intracellularⁱ 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!"

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!"

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 50 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 400 miles, and the surface area of the brain capillary endothelium in the human brain is 20 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 200 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. 

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.

Scusi! I see that the tildes in my quotation came out as "not, vert, similar." Such is life.

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 metronidazole / tinidadazole.) It has been effective so far; there has been no return of symptoms in three years.

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