IOWA group (HCQ/Fluconazole/Mino/Schardt)

[Guest guest]

I've been reviewing the papers which indicate that of raising the PH

in the cell may allow for synergistic killing at lower doses of some

abx in combo.

From my own experience, I know this is true for HCQ

(Hydroxychloroquine) and Mino.

The papers below indicate it's true for HCQ/fluconazole (at least in

the petrie dish).

**** What is the opinion from the IOWA group..???????? ***

Are you guys finding this to be true? Have you adjusted the doses

downward?? DID you baseline prior to treatment for Candida?

Thanks,

Barb

Referring to message #217:

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-?

I did hear from someone in the Iowa group - they're on HCQ/Mino?

fluconazole

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

>

> 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 MORE ON HCQ and immune modulation:

more on HCQ- PH and immune modulation

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Mol Cell Biol. 2005 Feb;25(3):1025-40. Inhibition of macroautophagy

triggers apoptosis.

Boya P, -Polo RA, Casares N, Perfettini JL, Dessen P,

Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T, Pierron

G, Codogno P, Kroemer G.

CNRS-UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39

rue Camille-Desmoulins, F-94805 Villejuif, France. kroemer@i....

Mammalian cells were observed to die under conditions in which

nutrients were depleted and, simultaneously, macroautophagy was

inhibited either genetically (by a small interfering RNA targeting

Atg5, Atg6/Beclin 1-1, Atg10, or Atg12) or pharmacologically (by 3-

methyladenine, hydroxychloroquine, bafilomycin A1, or monensin). Cell

death occurred through apoptosis (type 1 cell death), since it was

reduced by stabilization of mitochondrial membranes (with Bcl-2 or

vMIA, a cytomegalovirus-derived gene) or by caspase inhibition. Under

conditions in which the fusion between lysosomes and autophagosomes

was inhibited, the formation of autophagic vacuoles was enhanced at a

preapoptotic stage, as indicated by accumulation of LC3-II protein,

ultrastructural studies, and an increase in the acidic vacuolar

compartment. Cells exhibiting a morphology reminiscent of

(autophagic) type 2 cell death, however, recovered, and only cells

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the point of no return and inexorably died even under optimal culture

conditions. All together, these data indicate that autophagy may be

cytoprotective, at least under conditions of nutrient depletion, and

point to an important cross talk between type 1 and type 2 cell death

pathways.

PMID: 15657430 [PubMed - in process]

________________________________________________________________

Gut. 1982 Mar;23(3):181-7. Related Articles, Links

Inhibition of leucocyte motility and prevention of immune-complex

experimental colitis by hydroxychloroquine.

JM, McLaughlin JE, Brown DJ, Nuttall LA, Jewell DP.

The inhibitory effects of hydroxychloroquine on leucocyte motility

have been compared with those of prednisolone. It has been shown to

have similar potency to prednisolone as an inhibitor of human

neutrophil and monocyte motility. Hydroxychloroquine has then been

compared with placebo in the prevention of an immune-complex

experimental colitis in rabbits. Rectal biopsies were taken from

rabbits 24 hours after initiation of colitis, coded, and graded

histologically. The summated gradings for acute inflammation and

goblet cell depletion had worsened more in the control rabbits (mean

grade +6.7) than in the treated rabbits (mean grade +1.8) P less than

0.05. There was no difference in the mononuclear cell infiltrate

between the two groups. Hydroxychloroquine, which is a potent

inhibitor of leucocyte motility, effectively prevents the acute

inflammatory infiltrate in this experimental colitis model and

therefore merits trial in human ulcerative colitis.

PMID: 7068043 [PubMed - indexed for MEDLINE]

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