phenothiazines -

[Guest guest]

,

What really got my attention is that the phenothiazines MBCs for

starved M tuberculosis are only a few fold higher than their MBCs for

log phase Mtb. For most drugs and most bugs the ratio is much higher.

http://aac.asm.org/cgi/reprint/49/11/4778.pdf

The target is addressed in this paper and seems to be the respiratory

chain. Two new anti-Mtb drugs in clinical trials this year are

rumored to be highly active on Mtb in some hypometabolic situation or

other, and both of these also appear to target respiration (in this

case the F0F1 ATP synthase. Both of the new drugs are inactive on

most bacteria, otherwise I'd be in my apartment right now trying to

sythesize them.

http://www.pubmedcentral.gov/picrender.fcgi?artid=555520 & blobtype=pdf

Several phenothiazine experiments have been done on mycobacteria in

the Amaral lab and others. This one particularly caught may attention:

s M, Bleiss W, Marko A, Ordway D, Viveiros M, Leandro C,

Pacheco T, Molnar J, Kristiansen JE, Amaral L.

Clinical concentrations of thioridazine enhance the killing of

intracellular methicillin-resistant Staphylococcus aureus: an in

vivo, ex vivo and electron microscopy study.

In Vivo. 2004 Nov-Dec;18(6):787-94.

PMID: 15646821

Now, its key to let the bacteria adjust to the host cell they are in

for maybe 24 hours before introducing the abx. Theres a paper with

data that really drives this point home, but I have lost it. I would

expect growth slows rapidly after a bacterium is phagocytosed by an

unaccommodating cell - such as a macrophage for Cpn or virtually any

cell (to my knowledge) for SA - but other phyisological changes may

take longer to complete. Amaral may not have waited; he may have

added the abx immediately after infecting the cells. I forget.

However, *if* the general abx resistance state enjoyed by

instracellular SA is like the general resistance state enjoyed by

starved Mtb, then for phenothiazines, unlike most abx, it may not

matter nearly as much whether you wait 24 hours for the general abx

resistance state to mature. Because phenothiazines might

be " resistant to the resistance. " Just as they are only 2.5x less

active on Mtb when Mtb is in a starvation-induced general abx-

resistance state, they might also be pretty good at killing SA in its

host-cell-induced general resistance state. These different

resistance states evoked by different stresses definitely have strong

physiological differences, and its unclear what are the final pathway

(s) of the resistance states they induce, and also unclear whether

various different states would behave the same with respect to a

given abx or all abx.

Finally, if this is something that might somehow be effective, where

are the adventitious remissions and/or herxes in patients going on

pheothiazines, who also have one of the proven immune diseases? I

havent been able to find any. Nitroimidazoles are sometimes taken by

people for various reasons, but not for very long, so adventitious

improvement is unlikely to occur. Phenothiazines on the other hand, I

think, are a chronic therapy taken by plenty of people for years on

end. You have to think that if they had some stellar effect on the

immune diseases, that this would have been noticed by now. So I

really find the whole matter very disappointing.

I think quetiapine has been used by many ILADS patients (including

myself for a few days). But it has an extra carbon in the central

ring, compared to the phenothiazines... so I dont think it would

necessarily have the same antimicrobic activity, tho it might.

>

> Dear

> You have piqued my interest . Back in the bad old days (Early 70's)

when Iwas still actively suffering with what I now know was Lyme, I

was prescribed this. It was the only thing that offered some relief

though I was prescribed it at far too high a dose rate . I would be

very interested in any refs you may have pertaining to its

antimicrobial qualities and especially ,its effect in relation to

macrophages.

> Regards

> Windsor

> (in Australia)

>