Patrice : HCQ/Mino/fluconazole -

[Guest guest]

Patrice:

Correct me if I'm wrong- but I think you're on 200 mg HCQ/200mg

Fluconazole/ and 200 mg Mino daily (from your reply to me message

#221)

My previous post references possible synergy between HCQ and Mino,

and here's 2 references that indicate they can be antagonistic.

So there's definitely drug-drug interavtions going on between the two.

And,

I have listed the references previously for the synergy between HCQ

and fluconazole.

So, there is alot of drug drug interactions between these three drugs.

QUESTIONS:

1) I'm interested as to how long you've been doing these dosages and

if you've experienced any adverse reactions (which would be vertigo,

tinnitus or nausea).

2) Were you Candida baselined (IgA, IgG, IgM titers) before you

started.

3) ARe you having a blood chemistry panel done periodically?

4) Is this triple combo releiving your symptoms.

I'm WONDERING........................

In light of the synergy between HCQ and fluconazle - why has you

DOc kept the dose of fluconazole so high?

I seriously think this trple combo is a fantastic one - I just dont

understand why your doses are so high - I can't tolerate 200mg

Mino/200mg HCQ without haveing vestibular dysfunction-

I'd be greatfull for your thoughts or experience.

Barb

REFERENCES:

REFERENCES:

Oncogene. 2003 Jun 19;22(25):3927-36.

Mitochondrial membrane permeabilization is a critical step of

lysosome-initiated apoptosis induced by hydroxychloroquine.

Boya P, -Polo RA, Poncet D, u K, Vieira HL, Roumier T,

Perfettini JL, Kroemer G.

Centre National de la Recherche Scientifique, UMR 8125, Institut

Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-

94805 Villejuif, France.

Hydroxychloroquine (HCQ) is a lysosomotropic amine with cytotoxic

properties. Here, we show that HCQ induces signs of lysosomal

membrane permeabilization (LMP), such as the decrease in the

lysosomal pH gradient and the release of cathepsin B from the

lysosomal lumen, followed by signs of apoptosis including caspase

activation, phosphatidylserine exposure, and chromatin condensation

with DNA loss. HCQ also induces mitochondrial membrane

permeabilization (MMP), as indicated by the insertion of Bax into

mitochondrial membranes, the conformational activation of Bax within

mitochondria, the release of cytochrome c from mitochondria, and the

loss of the mitochondrial transmembrane potential. To determine the

molecular order among these events, we introduced inhibitors of LMP

(bafilomycin A(1)), MMP (Bcl-X(L), wild-type Bcl-2, mitochondrion-

targeted Bcl-2, or viral mitochondrial inhibitor of apoptosis from

cytomegalovirus), and caspases (Z-VAD.fmk) into the system. Our data

indicate that caspase-independent MMP is rate-limiting for LMP-

mediated caspase activation. Mouse embryonic fibroblasts lacking the

expression of both Bax and Bak are resistant against

hydroxychloroquine-induced apoptosis. Such Bax(-/-) Bak(-/-) cells

manifest normal LMP, yet fail to undergo MMP and subsequent cell

death. The data reported herein indicate that LMP does not suffice to

trigger caspase activation and that Bax/Bak-dependent MMP is a

critical step of LMP-induced cell death.

PMID: 12813466 [PubMed - indexed for MEDLINE]

__________________________________________________________________

J Am Coll Cardiol. 2004 Mar 3;43(5):865-74. Related Articles, Links

Minocycline inhibits caspase activation and reactivation, increases

the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial

leakage of cytochrome C and smac/DIABLO.

Scarabelli TM, Stephanou A, Pasini E, Gitti G, Townsend P, Lawrence

K, Chen-Scarabelli C, Saravolatz L, Latchman D, Knight R, Gardin J.

Division of Cardiology, Detroit, St Hospital and Medical Center,

Detroit, Michigan 48236, USA. tiziano.scarab

OBJECTIVES: This study is aimed at investigating the novel use of

minocycline for cardiac protection during ischemia/reperfusion (I/R)

injury, as well as its mechanism of action. BACKGROUND: Minocycline

is a tetracycline with anti-inflammatory properties, which is used

clinically for the treatment of diseases such as urethritis and

rheumatoid arthritis. Experimentally, minocycline has also been shown

to be neuroprotective in animal models of cerebral ischemia and to

delay progression and improve survival in mouse models of

neurodegenerative diseases. METHODS: We studied 62 rat intact hearts

exposed to I/R and cell cultures of neonatal and adult rat

ventricular myocytes. RESULTS: Minocycline significantly reduced

necrotic and apoptotic cell death, both in neonatal and adult

myocytes, not only when given prior to hypoxia (p < 0.001), but also

at reoxygenation (p < 0.05). Moreover, in the intact heart exposed to

I/R, in vivo treatment with minocycline promoted hemodynamic recovery

(p < 0.001) and cell survival, with reduction of infarct size (p <

0.001), cardiac release of creatine phosphokinase (p < 0.001), and

apoptotic cell death (p < 0.001). In regard to its antiapoptotic

mechanism of action, minocycline significantly reduced the expression

level of initiator caspases, increased the ratio of XIAP to

Smac/DIABLO at both the messenger RNA and protein level, and

prevented mitochondrial release of cytochrome c and Smac/DIABLO (all,

p < 0.05). These synergistic actions dramatically prevent the post-

ischemic induction of caspase activity associated with cardiac I/R

injury. CONCLUSIONS: Because of its safety record and multiple novel

mechanisms of action, minocycline may be a valuable cardioprotective

agent to ameliorate cardiac dysfunction and cell loss associated with

I/R injury.

PMID: 14998631 [PubMed - indexed for MEDLINE]