Re: Patrice : HCQ/Mino/fluconazole -

[Guest guest]

Barb,

I am quite sure you have read this already and it is not using mino + HCQ but doxy +HCQ

"CONCLUSION: Prescription of the doxycycline and hydroxychloroquine combination for at least 18 months allows shortening of the duration of therapy and reduction in the number of relapses."

Nelly

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=9927100

Arch Intern Med. 1999 Jan 25;159(2):167-73.

Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine.Raoult D, Houpikian P, Tissot Dupont H, Riss JM, Arditi-Djiane J, Brouqui P.Unite des Rickettsies, Faculte de Medecine, Universite de la Mediterranee CNRS, Marseille, France. Didier.Raoult@...BACKGROUND: Q fever endocarditis, caused by iella burnetii, is fatal in 25% to 60% of patients. Currently, treatment with a long-term tetracycline and quinolone regimen for at least 4 years is recommended, although relapses are frequent. METHODS: Between January 1987 and December 1997, the reference treatment of Q fever endocarditis was compared with one of doxycycline and hydroxychloroquine sulfate. Patients were treated by conventional therapy until May 1991 and then by the new regimen. Microimmunofluorescence was used for antibody-level determination for diagnosis and follow-up. RESULTS: Thirty-five patients were included in the study, 26 males and 9 females. Of 14 patients treated with a doxycycline and quinolone combination, 1 died, 7 relapsed (3 were re-treated and 4 switched to the new regimen), 1 is still being treated, and 5 were considered cured using this regimen only. The mean duration of therapy for cure in this group was 55 months (median, 60 months). Twenty-one patients received the doxycycline and hydroxychloroquine regimen: 1 patient died of a surgical complication, 2 are still being treated, 17 were cured, and 1 is currently being evaluated. Two patients treated for 12 months but none of the patients treated for longer than 18 months relapsed. The mean duration of treatment in this group was 31 months (median, 26 months). No significant differences were observed between the 2 regimens in terms of death, valve surgery, or tolerance. The mortality rate for both regimens in this study was 5%. CONCLUSION: Prescription of the doxycycline and hydroxychloroquine combination for at least 18 months allows shortening of the duration of therapy and reduction in the number of relapses.PMID: 9927100 [PubMed - indexed for MEDLINE]

[Guest guest]

I have used:

mino 100 mg and 200 mg and had massive eye aches and headaches

mino + HCQ and had massive eye aches and headaches

mino + HCQ + fluconazole had massive eye aches and headaches

I used doxy + HCQ and had massive eye aches and headaches

I used ......xxxxxxxx + xxxxxxxx and had massive eye aches and headaches !!!!!

Sorry, I had meant to be helpful but when I started looking through the log I keep, this is what I read!

I also got vertigo attacks but that was with and without mino, with babesia treatment and even before any abx treatment so... I am not going to be very helpful again

Nelly

[infections] Patrice : HCQ/Mino/fluconazole -

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.BarbREFERENCES: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.scarabOBJECTIVES: 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]

[Guest guest]

Barb:

Yes, that is the combination that I’m

taking. I’m also taking Vantin twice daily. I’m hitting

this like a freight train.

I’m almost day 30 into the

Fluconazole. My Infectious Dz. Dr.

wants me to do at least 2 months and probably more.

I don’t seem to be having any drug

interactions. No vertigo or nausea. Just fatigue but that is my

constant companion anyway, so very hard to evaluate whether it’s truly

worse or not.

The high dose of Fluconazole was selected

based on the Schart study & suggested by my ID Dr. We know that

Fluconazole doesn’t kill borrelia, but possibly starves out it’s

nutrients.

My ID Dr. has a handful of patients on this

protocol, not enough time for data to roll in on whether it’s effective

or not.

Although my Igenex test came back

glaringly positive, I’m not even sure I have Lyme. I have all the

hallmark features of Mixed Connective Tissue Disease & I have a lot of

antibodies in my blood that could’ve cross reacted with the Lyme

bands.

In answer to your final question, the jury

is out as to whether it is helping or not. , who is in frequent

contact with my ID Dr.

states that patients are

experiencing most noted improvement after day 30 of the protocol.

Hope this helps. Patrice

From: Barb Peck

[mailto:egroups1bp@...]

Sent: Monday, March 14, 2005 10:11

AM

infections

Subject:

[infections] Patrice : HCQ/Mino/fluconazole -

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]

[Guest guest]

>, who is in frequent contact with my ID Dr. states that patients are experiencing most noted >improvement after day 30 of the protocol.

Sorry, Patrice, but is always "confident that this or that will be the answer" so to be taken with a grain of salt, IMO.

I took fluconazole for 74 days and it did not help at all.

Nelly

[Guest guest]

Well, I’m not relying on

exclusively for my information. I’m lucky enough to go to a very

progressive ID Dr.

here in Kansas City,

who happens to know. I rely on my ID Dr.’s information/advice, as

well as my own research when making these decisions.

I’m always skeptical of anyone that

thinks “this or that” will be the answer. I think sometimes

we get so desperate that we’re willing to believe or try anything.

I always weigh benefits vs. risks. That’s one reason why I would

NOT embark on the Marshall Protocol. Felt that dosage of Benicar was way

too risky. This protocol is pretty benign without a lot of risk.

The Schardt study, despite being small, is

somewhat encouraging.

There certainly are people cured of

chronic Lyme. Ever wonder if the failures really have something else

going on?

From: Nelly Pointis

[mailto:janel@...]

Sent: Monday, March 14, 2005 11:39

AM

infections

Subject: Re:

[infections] Patrice : HCQ/Mino/fluconazole -

>, who is in frequent contact with

my ID Dr. states that patients are experiencing

most noted >improvement after day 30 of the protocol.

Sorry, Patrice, but is always " confident

that this or that will be the answer " so to be taken with a

grain of salt, IMO.

I took fluconazole for 74 days and it did not help at

all.

Nelly

[Guest guest]

>There certainly are people cured of chronic Lyme. Ever wonder if the failures really have something else going on?

Patrice,

I NEVER stop WONDERING, that's why I took fluconazole for so long, and it didn't help at all! I have been looking in all directions for a hell of a long time

Nelly

From: Nelly Pointis [mailto:janel@...] Sent: Monday, March 14, 2005 11:39 AMinfections Subject: Re: [infections] Patrice : HCQ/Mino/fluconazole -

>, who is in frequent contact with my ID Dr. states that patients are experiencing most noted >improvement after day 30 of the protocol.

Sorry, Patrice, but is always "confident that this or that will be the answer" so to be taken with a grain of salt, IMO.

I took fluconazole for 74 days and it did not help at all.

Nelly

[Guest guest]

Do you feel the Fluconazole was risky or

did you harm?

To be honest, even though the ID Dr. has told me

I have Lyme, I have my doubts. I think there’s so much about these

autoimmune diseases and CFS/Lyme, etc. that we just don’t know.

From: Nelly Pointis

[mailto:janel@...]

Sent: Monday, March 14, 2005 11:59

AM

infections

Subject: Re:

[infections] Patrice : HCQ/Mino/fluconazole -

>There certainly are

people cured of chronic Lyme. Ever wonder if the failures really have

something else going on?

Patrice,

I NEVER stop WONDERING,

that's why I took fluconazole for so long, and it didn't help at all! I have

been looking in all directions for a hell of a long time

Nelly

From: Nelly Pointis

[mailto:janel@...]

Sent: Monday, March 14, 2005 11:39

AM

infections

Subject: Re: [infections]

Patrice : HCQ/Mino/fluconazole -

>, who is in frequent contact with

my ID Dr. states that patients are experiencing

most noted >improvement after day 30 of the protocol.

Sorry, Patrice, but is always " confident

that this or that will be the answer " so to be taken with a

grain of salt, IMO.

I took fluconazole for 74 days and it did not help at

all.

Nelly

[Guest guest]

No, I did not test for candida. My ID Dr. believes the

Fluconazole is effective b/c it starves out the nutrients of the spirochetes,

according to Schardts theory. He really doesn’t believe it’s

effective b/c it flushes out any underlying candida issues, but he’s the

1st to admit, he is not 100% sold on this Fluconazole therapy but he

does have a handful of patients that are empirically doing well on it. This ID Dr. is very

mainstream. He’s an academic professor & associated w/an Academic

Institution. He’s not radical in his approach & he truly thinks this

is very worthy of consideration.

From: Barb Peck

[mailto:egroups1bp@...]

Sent: Monday, March 14, 2005 12:17

PM

infections

Subject:

[infections] Patrice : HCQ/Mino/fluconazole -

Patrice:

Yes thanks - this is very helpfull.

Did you test for Candida before beginning?

Barb

PATRICE WROTE

Barb:

Yes, that is the combination that I'm

taking. I'm also taking Vantin

twice daily. I'm hitting this like a freight

train.

I'm almost day 30 into the Fluconazole. My Infectious Dz. Dr.

wants

me to do at least 2 months and probably more.

I don't seem to be having any drug

interactions. No vertigo or

nausea. Just fatigue but that is my constant

companion anyway, so

very hard to evaluate whether it's truly worse or

not.

The high dose of Fluconazole was selected based on

the Schart study &

suggested by my ID Dr. We know that

Fluconazole doesn't kill

borrelia, but possibly starves out it's

nutrients.

My ID

Dr. has a handful of patients on this protocol,

not enough time

for data to roll in on whether it's effective or

not.

Although my Igenex test came back glaringly

positive, I'm not even

sure I have Lyme. I have all the hallmark

features of Mixed

Connective Tissue Disease & I have a lot of

antibodies in my blood

that could've cross reacted with the Lyme

bands.

In answer to your final question, the jury is out

as to whether it is

helping or not. , who is in frequent

contact with my ID Dr.

states that patients are experiencing most noted

improvement after

day 30 of the protocol.

Hope this helps. Patrice

[Guest guest]

Trying to respond to Lgrasso of Hawaii but

mail gets returned.

From: Barb Peck

[mailto:egroups1bp@...]

Sent: Monday, March 14, 2005 12:17

PM

infections

Subject:

[infections] Patrice : HCQ/Mino/fluconazole -

Patrice:

Yes thanks - this is very helpfull.

Did you test for Candida before beginning?

Barb

PATRICE WROTE

Barb:

Yes, that is the combination that I'm

taking. I'm also taking Vantin

twice daily. I'm hitting this like a freight

train.

I'm almost day 30 into the Fluconazole. My Infectious Dz. Dr.

wants

me to do at least 2 months and probably more.

I don't seem to be having any drug

interactions. No vertigo or

nausea. Just fatigue but that is my constant

companion anyway, so

very hard to evaluate whether it's truly worse or

not.

The high dose of Fluconazole was selected based on

the Schart study &

suggested by my ID Dr. We know that

Fluconazole doesn't kill

borrelia, but possibly starves out it's

nutrients.

My ID

Dr. has a handful of patients on this protocol,

not enough time

for data to roll in on whether it's effective or

not.

Although my Igenex test came back glaringly

positive, I'm not even

sure I have Lyme. I have all the hallmark

features of Mixed

Connective Tissue Disease & I have a lot of

antibodies in my blood

that could've cross reacted with the Lyme

bands.

In answer to your final question, the jury is out

as to whether it is

helping or not. , who is in frequent

contact with my ID Dr.

states that patients are experiencing most noted

improvement after

day 30 of the protocol.

Hope this helps. Patrice

[Guest guest]

I hear ya, Nelly. Our treatment logs have some striking similarities.

Thanks for all your great posts, I read them even when I'm not alert

enough to respond in a helpful way.

> I have used:

>

> mino 100 mg and 200 mg and had massive eye aches and headaches

> mino + HCQ and had massive eye aches and headaches

> mino + HCQ + fluconazole had massive eye aches and headaches

>

> I used doxy + HCQ and had massive eye aches and headaches

>

> I used ......xxxxxxxx + xxxxxxxx and had massive eye aches and

headaches !!!!!

>

> Sorry, I had meant to be helpful but when I started looking

through the log I keep, this is what I read!

>

> I also got vertigo attacks but that was with and without mino,

with babesia treatment and even before any abx treatment so... I am

not going to be very helpful again

>

>

> Nelly

> [infections] Patrice :

HCQ/Mino/fluconazole -

>

>

>

>

> 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.scarabelli@s...

>

> 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]

>

>

>

>

>

>

>

>

>

>

[Guest guest]

Patrice wrote in part: " Well, I'm not relying on exclusively

for my information. I'm lucky enough to go to a very progressive ID

Dr. here in Kansas City, who happens to know... "

I think you seem like a very savvy customer, Patrice. Having been

less than savvy in the past myself, I share Nelly's skepticism, but

I agree with you, there's a case for giving this a shot.

We are in unexplored territory. Because none of us has map we do

tend to depend a lot on each other's reports. So it's great when

someone like you takes the time to document what you're doing, what

you hope to accomplish, and how it works out.

There are some people who are kind of perenially enthusiastic. I

think I sometimes get grumpy because it's like someone's always

saying 'over here! over here!' when there's not much there.

But over time, you learn to qualify the enthusiasm others may have

with your own reasoned consideration. I know you do that, it's clear

from your posts.

Patrice wrote, in part: " There certainly are people cured of chronic

Lyme. Ever wonder if the failures really have something else going

on? "

I don't think we're at a point with Lyme, where we can even

speculate meaningfully about the reasons for treatment failure.

The fact is, it's an insane uphill battle for most of us to get

treated at all. Our treatment is often both delayed and truncated

because of a dysfunctional response to our disease by our respective

health care 'systems.'

Look at the studies documenting treatment failure. They'll use one -

just one - IV antibiotic for 3 weeks, and if you're not better

antibiotic treatment has 'failed'. If we treated TB that way, no one

would ever get better.

It seems to me that the only obvious, undisputed failure is the

failure of modern medicine to pay these diseases the attention they

so desperately need and deserve.

> Well, I'm not relying on exclusively for my information.

I'm lucky

> enough to go to a very progressive ID Dr. here in Kansas City, who

> happens to know. I rely on my ID Dr.'s information/advice, as

well as my

> own research when making these decisions.

>

>

>

> I'm always skeptical of anyone that thinks " this or that " will be

the

> answer. I think sometimes we get so desperate that we're willing

to believe

> or try anything. I always weigh benefits vs. risks. That's one

reason why

> I would NOT embark on the Marshall Protocol. Felt that dosage of

Benicar

> was way too risky. This protocol is pretty benign without a lot

of risk.

>

>

>

> The Schardt study, despite being small, is somewhat encouraging.

>

>

>

> There certainly are people cured of chronic Lyme. Ever wonder if

the

> failures really have something else going on?

>

>

>

> _____

>

> From: Nelly Pointis [mailto:janel@p...]

> Sent: Monday, March 14, 2005 11:39 AM

> infections

> Subject: Re: [infections] Patrice :

HCQ/Mino/fluconazole -

>

>

>

> >, who is in frequent contact with my ID Dr. states that

patients are

> experiencing most noted >improvement after day 30 of the

protocol.

>

>

>

> Sorry, Patrice, but is always " confident that this or that

will be the

> answer " so to be taken with a grain of salt, IMO.

>

>

>

> I took fluconazole for 74 days and it did not help at all.

>

>

>

> Nelly

>

>

>

>

>

>

>

[Guest guest]

Believe me ; I have gotten quite jaded

since becoming ill. I was an RN and a Biostatistician for a major drug

company that got sucked into the “establishment” way of

thinking. It’s not until becoming ill myself that I start to loosen

my standards & become very willing to give anything within reason a shot.

Believe me, waiting for something to come through the Pharmaceutical pipeline

is not a reassuring thought & my best hope is that the answer is something

out here that already exists. But again, I do ALWAYS weigh benefit

vs. risk & go from there. I found the Benicar stuff way too risky for

my comfort, yet I do take a responsible dose of an ARB for inflammation control.

I don’t think I will ever be

susceptible to the “placebo effect” b/c I’m way too skeptical

of any proposed “cures” out there. If I get better, it won’t

be psychological. And I have some very objective labs that will help in

that process.

It helps that I’ve known my ID

doctor professionally for over 20 years and always had a great deal of respect

for him. He’s truly a scientist and thinks outside the box.

He’s got an Academic position at a major teaching hospital and isn’t

afraid to advocate for what he feels is right.

One thing my ID Dr. said to me at my last

visit that I found curious is that he said that I don’t seem as sick as

his other Lyme patients. Ironically, my IGENEX labs came back indicating

that I was a helluva lot sicker than most of his Lyme patients. I had to argue

that I do indeed feel sick but because of my young children and their

dependence on a mother, sometimes it’s just a matter of sheer will of

putting one foot in front of another to make it through each day.

However, after much speculative discussion with this Dr., we came to the

conclusion that the HCQ has indeed been very beneficial to me. I will

probably NEVER go off that drug, unless of course, I develop the very rare

consequence of retinal toxicity.

At this point, I don’t have any hesitancy

about this HCQ/Mino/Fluconazole approach (as well as Vantin) because I’m

tolerating it all just fine. Tomorrow marks day 30 of Fluconazole.

I have thus far resisted the

Rheumatological approach to control of this disease (except for HCQ which is

considered an acceptable DMARD). Believe me, sometimes, it’s

tough. When I see people that have had severe debilitating RA run around

with about 30 times more energy than I have due to some of the newer

biologicals, it’s hard not to throw in the towel and go that route.

I don’t want to start that debate, however.

Patrice

From: Schaafsma

[mailto:compucruz@...]

Sent: Monday, March 14, 2005 8:12

PM

infections

Subject:

[infections] Re: Patrice : HCQ/Mino/fluconazole -

Patrice wrote in part: " Well, I'm not relying

on exclusively

for my information. I'm lucky enough to go

to a very progressive ID

Dr. here in Kansas

City, who happens to know... "

I think you seem like a very savvy customer,

Patrice. Having been

less than savvy in the past myself, I share

Nelly's skepticism, but

I agree with you, there's a case for giving this a

shot.

We are in unexplored territory. Because none of us

has map we do

tend to depend a lot on each other's reports. So

it's great when

someone like you takes the time to document what

you're doing, what

you hope to accomplish, and how it works out.

There are some people who are kind of perenially

enthusiastic. I

think I sometimes get grumpy because it's like

someone's always

saying 'over here! over here!' when there's not

much there.

But over time, you learn to qualify the enthusiasm

others may have

with your own reasoned consideration. I know you

do that, it's clear

from your posts.

Patrice wrote, in part: " There certainly are

people cured of chronic

Lyme. Ever wonder if the failures really

have something else going

on? "

I don't think we're at a point with Lyme, where we

can even

speculate meaningfully about the reasons for

treatment failure.

The fact is, it's an insane uphill battle for most

of us to get

treated at all. Our treatment is often both

delayed and truncated

because of a dysfunctional response to our disease

by our respective

health care 'systems.'

Look at the studies documenting treatment failure.

They'll use one -

just one - IV antibiotic for 3 weeks, and if

you're not better

antibiotic treatment has 'failed'. If we treated

TB that way, no one

would ever get better.

It seems to me that the only obvious, undisputed

failure is the

failure of modern medicine to pay these diseases

the attention they

so desperately need and deserve.

> Well, I'm not relying on exclusively

for my information.

I'm lucky

> enough to go to a very progressive ID Dr.

here in Kansas City,

who

> happens to know. I rely on my ID Dr.'s

information/advice, as

well as my

> own research when making these decisions.

>

>

>

> I'm always skeptical of anyone that thinks

" this or that " will be

the

> answer. I think sometimes we get so

desperate that we're willing

to believe

> or try anything. I always weigh

benefits vs. risks. That's one

reason why

> I would NOT embark on the Marshall

Protocol. Felt that dosage of

Benicar

> was way too risky. This protocol is

pretty benign without a lot

of risk.

>

>

>

> The Schardt study, despite being small, is

somewhat encouraging.

>

>

>

> There certainly are people cured of chronic

Lyme. Ever wonder if

the

> failures really have something else going on?

>

>

>

> _____

>

> From: Nelly Pointis [mailto:janel@p...]

> Sent: Monday, March 14, 2005 11:39 AM

> infections

> Subject: Re: [infections]

Patrice :

HCQ/Mino/fluconazole -

>

>

>

> >, who is in frequent contact with my

ID Dr. states that

patients are

> experiencing most noted >improvement after

day 30 of the

protocol.

>

>

>

> Sorry, Patrice, but is always

" confident that this or that

will be the

> answer " so to be taken with a grain of

salt, IMO.

>

>

>

> I took fluconazole for 74 days and it did not

help at all.

>

>

>

> Nelly

>

>

>

>

>

>

>

[Guest guest]

I've never taken HCQ, but am curious if you ever tried drinking a ton of water when you had the headaches. I had a lot of headaches from doxy but I worked my dose up slowly over years so it wasn't bad. Still I did sometimes have killer headaches from it. Someone posted that he thought a lot of the headaches from herxing was due to dehydration, and I told him he was crazy because I always drank a glass of water with my doxy. But then I paid attention, and it turned out he was right. If I drank 2 glasses of water then I never got the headache again.

doris

----- Original Message -----

From: Nelly Pointis

mino 100 mg and 200 mg and had massive eye aches and headaches

mino + HCQ and had massive eye aches and headaches

mino + HCQ + fluconazole had massive eye aches and headaches

I used doxy + HCQ and had massive eye aches and headaches

I used ......xxxxxxxx + xxxxxxxx and had massive eye aches and headaches !!!!!

Sorry, I had meant to be helpful but when I started looking through the log I keep, this is what I read!

[Guest guest]

On Monday, March 14, 2005, at 11:13 PM, Patrice wrote:

> One thing my ID Dr. said to me at my last visit that I found curious

> is that he said that I don’t seem as sick as his other Lyme patients. 

> Ironically, my IGENEX labs came back indicating that I was a helluva

> lot sicker than most of his Lyme patients.

Which are sicker, people with a lot of antibody response, or people

with not so much? I'm not really sure, but I'm a lot more disabled than

my son and his IGeneX tests indicate he has more antibodies. I think my

immune system was giving up by the time I got my test.

- Kate D.

[Guest guest]

Kate, Patrice,

If we are talking serologies, I'd second Kate's opinion. When my husband and myself got tested by WB in 99, I was a lot sicker than he was (we both got bitten by dozens of ticks at the same time in 93) and my WB was completely neg (not one band) whereas he had 3 positive bands incl the OspC (in Europe 2 specific bands is enough for diagnosis).

I have since had 2 + PCRs for Borrelia and one for Babesia, one from MDLs one from a vet lab in Spain.

I have just got off the phone from speaking with a desperate mother of a 14 year-old who has been very, very sick for a few months, serologies negative. She herself has Lyme, is not as sick as her boy yet has positive serologies.

Co-infections playing a part in seronegativity for Bb?

Nelly

Re: [infections] Re: Patrice : HCQ/Mino/fluconazole -

On Monday, March 14, 2005, at 11:13 PM, Patrice wrote:

One thing my ID Dr. said to me at my last visit that I found curious is that he said that I don’t seem as sick as his other Lyme patients. Ironically, my IGENEX labs came back indicating that I was a helluva lot sicker than most of his Lyme patients.Which are sicker, people with a lot of antibody response, or people with not so much? I'm not really sure, but I'm a lot more disabled than my son and his IGeneX tests indicate he has more antibodies. I think my immune system was giving up by the time I got my test.- Kate D.

[Guest guest]

I’m not sure either Kate. My

Dr. and I looked at the whole picture, killer cell assay’s etc. I’m

also sure variables such as how long you’ve been on antibiotics, your

age, physical condition at time of onset, hormonal imbalances, at what point

during the disease you were tested, how the specimen was handled, what lab

performed the test & genetic make up influence this question, as well.

Patrice

From: Kate

[mailto:KateDunlay@...]

Sent: Tuesday, March 15, 2005 3:09

PM

infections

Subject: Re:

[infections] Re: Patrice : HCQ/Mino/fluconazole -

On Monday, March 14, 2005, at 11:13 PM, Patrice wrote:

One thing my

ID Dr. said to me at my last visit that I found curious is that he said that I

don’t seem as sick as his other Lyme patients. Ironically, my

IGENEX labs came back indicating that I was a helluva lot sicker than most of

his Lyme patients.

Which are sicker, people with a lot of antibody response, or people with not so

much? I'm not really sure, but I'm a lot more disabled than my son and his

IGeneX tests indicate he has more antibodies. I think my immune system was

giving up by the time I got my test.

- Kate D.

[Guest guest]

Good point, Kate. Antibody tests are useless in this respect, and in

most respects. They confirm exposure, that's about it.

Some people think newer tests like the QRIBB or whatever it's called

are improving the picture somewhat, but there's still quite a bit of

uncertainty about those.

What's unfortunate, in my opinion, is that so many make the

unthinking leap from antibodies to bugs. A whole lot of things have

to be happening to get those recognized Bb antibodies up to

detectable levels, but active symptomatic Lyme is not one of them.

You can have very severe borreliosis and have nearly none, because

the bugs are not being successfully identified. Conversely, if your

system were doing a bang-up job of deploying effective antibodies

against the bugs, you would never have gotten a high enough load to

be sick in the first place.

I see has responded, hopefully he's in better brain shape than

me and can explain some of this better.

Thinking good thoughts for you and your son,

>

> Which are sicker, people with a lot of antibody response, or

people with not so much? I'm not really sure, but I'm a lot more

disabled than my son and his IGeneX tests indicate he has more

antibodies. I think my immune system was giving up by the time I got

my test.

>

> - Kate D.