Re: P. JAEP and ERIC: alkalizing agents & Fluconazole synergy

[Guest guest]

Barb, I’m on Fluconazole 200mg

daily, Minocin 100mg BID and Placquenil 200mg daily. Patrice

From: Barb Peck

[mailto:egroups1bp@...]

Sent: Wednesday, March 09, 2005

12:09 PM

infections

Subject:

[infections] P. JAEP and ERIC: alkalizing agents &

Fluconazole synergy

and :

Looks like the dose of fulconazole

can be reduced when the PH is

raised in the cell.

This is the same theory as Sam

Donta's Lyme therapy -using HCQ to

alkalize the cell compartment so one of the

tetracyclines can enter

the cell compartment and kill the intra cellular

pathogen.

Anyone taken HCQ and fluconazole

together?- what about Schardt's

IOWA group-?

Barb

______________________________________________________________

Pharm Res. 2004 Dec;21(12):2207-12. Related

Articles, Links

Prophylactic role of liposomized chloroquine

against murine

cryptococcosis less susceptible to fluconazole.

Khan MA, Jabeen R, Mohammad O.

Aligarh Muslim University, Aligarh

202002, India.

alammasood1@r...

PURPOSE: The prophylactic role of liposomized

chloroquine (lip-CQ)

has been assessed against less susceptible

Cryptococcus neoformans

infection in murine model. METHODS: In the current

study, we

investigated the antifungal activity of lip-CQ

against C. neoformans

in macrophages cell line (J 774) and murine model.

Mice were

pretreated with free as well as liposomized

formulations of CQ at

various doses. The anticryptococcal activity of

fluconazole was

compared in mice with or without CQ pretreatment.

The efficacy of CQ

prophylaxis was assessed by survival as well as

colony forming units

(cfu) in brain and lungs of treated mice. RESULTS:

Fluconazole alone

was not found significantly effective against C.

neoformans in both

in vitro and in vivo studies. However, the

antifungal activity of

fluconazole increases in chloroquine-pretreated

mice. Lip-CQ was

found to be more effective in comparison to the

same dose of free

chloroquine in reducing fungal burden from

macrophages in vitro and

lungs and brain of C. neoformans infected mice.

CONCLUSIONS: The enhanced prophylactic activity of

lip-CQ seems due

to rapid uptake of drug-containing liposomes by

macrophages. The

liposome-mediated accumulation of CQ in

macrophages makes the

environment unfavorable (alkaline) for the

intracellular

multiplication of C. neoformans. Moreover, the

increased incidence of

multi-drug resistance and diversity of pathogenic

microorganisms

inhibited or killed by CQ makes it the drug of

choice for

prophylactic therapy.

_________________________________________________________________

J Antimicrob Chemother. 2005 Feb;55(2):223-8. Epub

2004 Dec 08.

Related Articles, Links

Enhanced anticryptococcal activity of chloroquine

in

phosphatidylserine-containing liposomes in a

murine model.

Khan MA, Jabeen R, Nasti TH, Mohammad O.

Interdisciplinary Biotechnology Unit, Aligarh Muslim University,

Aligarh-202002, India.

OBJECTIVES: The anticryptococcal activity of

chloroquine was assessed

after incorporation in phosphatidylserine

(PS)-containing negatively

charged liposomes in a murine model. METHODS: In

the present study,

we investigated the antifungal activity of

chloroquine entrapped in

PS liposomes against Cryptococcus neoformans in

the macrophage cell

line J 774 and in a murine model. Mice were

treated with free as well

as liposomal formulations of chloroquine before

and after challenging

with C. neoformans infection. The anticryptococcal

activity of

chloroquine was also evaluated in combination with

fluconazole in the

treatment of systemic murine cryptococcosis. The

efficacy of

chloroquine treatment was assessed by continued

survival as well as

by colony forming units (cfu) in liver and brain

of treated mice.

RESULTS: Chloroquine entrapped in PS liposomes

shows increased

activity against C. neoformans infection both in

in vitro and in vivo

studies. Moreover, the antifungal activity of

fluconazole increases

when used in combination with liposomal

chloroquine. Chloroquine in

PS liposomes was found to be more effective in

comparison with the

same dose of free chloroquine or chloroquine

entrapped in neutral

liposomes.

CONCLUSIONS: The enhanced anticryptococcal

activity of chloroquine in

PS liposomes seems to be due to uptake of

drug-containing PS

liposomes by macrophages. It can be assumed that

liposome-mediated

delivery of chloroquine to macrophages results in

an unfavourable

(alkaline) environment for the growth of C.

neoformans inside

macrophages.

PMID: 15590713 [PubMed - in process]

PMID: 15648251 [PubMed - in process]

_____________________________________________________________

And another full paper at:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=14688042

[Guest guest]

Barb,

Citing PMID 2184505, Schardts paper says " in vitro investigations

failed to reveal a direct antibacterial effect of fluconazole on

Borrelia spp. "

The (unknown) action of the drug on Bb is apparantly different from

its action on fungi, so personally I would draw no conclusion

regarding borrelia from experiments involving cryptococcus. As I

understand the HCQ thing, its ability to raise the phagosomal or

phagolysosomal pH restores the activity of drugs that are poorly

active at low pH (???because at low pH they are mostly tied up in

the form of some sort of less-bacterially-bioavailable salts???).

But with borrelia we arent sure how the drug is working (assuming

Schardts ref on the inactivity of fluconazole against borrelia in

vitro is correct). It could be that fluc deprives borrelia of a

human metabolite it needs - or, by inhibiting certain CYPs, causes

the buildup of human metabolites toxic to borrelia.

Alas, the data are all over the place, as so often in these studies,

so they dont give much of a clue. Many of Schardts patients improved

greatly in like 3 days, whereas is now reporting some people

realizing great benefit only at 30 days. And Schardts paper makes no

ref to herxing, whereas during my fluc herx many months ago (for 36h

starting 36h into 17 days of fluc at 100 mg /d) I was in bed all

day, almost too miserable to deal with heating up some canned soup

and eating, and many times crabbier even than usual.

>

> and :

>

> Looks like the dose of fulconazole can be reduced when the PH

is

> raised in the cell.

>

> This is the same theory as Sam Donta's Lyme therapy -using HCQ

to

> alkalize the cell compartment so one of the tetracyclines can

enter

> the cell compartment and kill the intra cellular pathogen.

>

> Anyone taken HCQ and fluconazole together?- what about

Schardt's

> IOWA group-?

>

>

> Barb

>

> [abstracts snipped]