Re: More on VDR's Relationship to 1,25-D

[Guest guest]

Actually this is an excellent citation that seems to substantiate my

fears about MP (I just rearrange the sentence structure for clarity)

" we show that 1,25-dihydroxyvitamin D3 " induced " diverse combination

of cationic antimicrobial peptides " to repel assaults from numerous

infectious agents including bacteria, viruses, fungi, and parasites. "

My fear is that MP turns off the immune system response -- thus two

things happen:

* you feel better BECAUSE THERE ARE NOT THE SYMPTOMS of an immune

response (thing of allergies --- the allergen is not causing the

response, the immune system is).

* the infections are able to rapidly grow because of the absence of a

response repelling them.

- I have seen people that did not herx from 300mg of an antibiotic

prior to MP, herx severely from 5 mg after being on MP for 6 months.

There is no objective evidence or publication (or product warning)

that benicar potenates any antibiotics which leaves Vitamin D (which

does have impact -- in fact it was historically used as an antibiotic

before patented antibiotics came along).

Last colon cancer -- which is cited, has a 40% lower incidence with

645IU of 25D supplementation which confirms the positive aspects of

vitamin D. Higher dosages in later studies drop the rate even more.

http://www.cnn.com/2003/HEALTH/conditions/12/09/cancer.vitamind.ap/

http://www.mercola.com/2002/may/29/vitamin_d.htm

http://www.mercola.com/2004/jan/3/vitamin_d_cancer.htm

> For those interested in the Vitamin D receptor and its relationship

> to 1,25-D, here is another article;

>

> FASEB J. 2005 Jul;19(9):1067-77.

>

> Human cathelicidin antimicrobial peptide (CAMP) gene is a direct

> target of the vitamin D receptor and is strongly up-regulated in

> myeloid cells by 1,25-dihydroxyvitamin D3.

>

> Gombart AF, Borregaard N, Koeffler HP.

>

> Department of Medicine, Division of Hematology/Oncology, Cedars-

Sinai

> Medical Center, Geffen School of Medicine at UCLA, Los

Angeles,

> California 90048, USA. gombarta@c...

>

> The innate immune system of mammals provides a rapid response to

> repel assaults from numerous infectious agents including bacteria,

> viruses, fungi, and parasites. A major component of this system is

a

> diverse combination of cationic antimicrobial peptides that include

> the alpha- and beta-defensins and cathelicidins. In this study, we

> show that 1,25-dihydroxyvitamin D3 and three of its analogs induced

> expression of the human cathelicidin antimicrobial peptide (CAMP)

> gene.

> PMID: 15985530 [PubMed - in process]

[Guest guest]

> " we show that 1,25-dihydroxyvitamin D3 " induced " diverse

combination

> of cationic antimicrobial peptides " to repel assaults from right

numerous

> infectious agents including bacteria, viruses, fungi, and

parasites. "

>

> My fear is that MP turns off the immune system response

This study shows that D3 can induce CAMP expression, but it doesn't

imply that a lack of D3 turns off the immune system. CAMP, like

many other parts of the immune system, can be induced by several

different factors, as the study mentions:

" The induction of CAMP expression by cytokines and growth factors

has been reported in a number of tissues; but 1,25(OH)2D3 and its

analogs are strikingly potent in myeloid cells. The induction was

less striking in the HaCat and HT-29 cell lines, but combining

vitamin D3 treatment with other compounds known to activate CAMP

expression may increase expression. Treatment of cultured

keratinocytes or composite keratinocyte grafts with LPS or IL-1

{alpha} induced CAMP expression (61) ; on the other hand, TNF-

{alpha}, Il-4, Il-6, IL-8, IL-10, and INF-{gamma} did not. The

growth factor insulin-like growth factor-1 that is important in

wound healing was found to induce both the CAMP mRNA and protein in

primary human keratinocytes; TGF{alpha} and proinflammatory

cytokines IL-1ß, IL-6, and TNF-{alpha} were not (62) . In epithelial

cells of the colon, hCAP18 expression is restricted to

differentiated cells in the human colon and ileum (58 , 63) .

Consistent with this, hCAP18 expression was induced by

differentiation of colon epithelial cell lines and by short chain

fatty acids independent of differentiation, but not by

proinflammatory mediators including IL-1{alpha}, IL-6, TNF-{alpha},

INF-{gamma}, LPS, or PMA (58 , 63) . "

[Guest guest]

Absolutely correct --- what we can say is that one part of the immune

system will NOT be induced. The consequences of other things NOT

induced is obvious from the following studies...

http://www.cnn.com/2003/HEALTH/conditions/12/09/cancer.vitamind.ap/

* 645IU of D intake --> 40% drop in Colon Cancer

From:

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

cmd=Retrieve & db=PubMed & list_uids=2572900 & dopt=Abstract

" Risk of colon cancer was reduced by:

* 75% for 27-32 ng/ml

* 80% for 33-41 ng/ml of serum 25-OHD.

Risk of getting colon cancer decreased three-fold in people with a

serum 25-OHD concentration of 20 ng/ml or more. "

Which implies that someone intentionally going for low D levels and

dropping their 25D level below 20ng/ml is increasing their colon

cancer risk by THREE FOLD.

> This study shows that D3 can induce CAMP expression, but it doesn't

> imply that a lack of D3 turns off the immune system. CAMP, like

> many other parts of the immune system, can be induced by several

> different factors, as the study mentions:

[Guest guest]

Hi Ken,

Don't worry about that. Here is the specific pathway by which Benicar

blocks inflammation. Benicar only blocks the Angiotensin II, type 1

receptor.

When this pathway is open, adapted bacterial cell surface proteins

bind to AT-II.

This in turn activates NF-KappaB in the cytoplasm of monocytes,

macrophages, and dendritic cells,which causes the phagocytes to emit

Messenger RNA (mRNA); the genetic coding which directs the

transcription of chemokines and cytokines. These include IL-1beta, IL-

6, IL-8, MCP, CAM, CAM1, FN-gamma, and TNF-Alpha (2-9).

Differing Blockade Methods (Corticosteroids vs Benicar)

Corticosteroids (like prednisone) block NF-KappaB completely

(all pathways), in effect totally disabling the phagocytes, whereas

Angiotensin receptor (Benicar) blockade only shuts down this one

channel by which NF-KappaB can be induced to set off its inflammatory

cascade.

The advantage of blockade by Benicar is that the body has other

channels such as Toll-like and other receptors, available through

which to mount a sufficient immune defense via NF-KappaB,if required.

Bacteria metabolize Angiotensin, and it is likely that they

either use parts of it to camouflage themselves, and/or to interfere

with the process of phagocytosis.

Phagocytes can get out to fight pathogens through other doors;

it's just that the bugs adapted to the A-II receptor cannot get in

through that door.

I hope this gives some clarification.

Pippit

> > For those interested in the Vitamin D receptor and its

relationship

> > to 1,25-D, here is another article;

> >

> > FASEB J. 2005 Jul;19(9):1067-77.

> >

> > Human cathelicidin antimicrobial peptide (CAMP) gene is a direct

> > target of the vitamin D receptor and is strongly up-regulated in

> > myeloid cells by 1,25-dihydroxyvitamin D3.

> >

> > Gombart AF, Borregaard N, Koeffler HP.

> >

> > Department of Medicine, Division of Hematology/Oncology, Cedars-

> Sinai

> > Medical Center, Geffen School of Medicine at UCLA, Los

> Angeles,

> > California 90048, USA. gombarta@c...

> >

> > The innate immune system of mammals provides a rapid response to

> > repel assaults from numerous infectious agents including

bacteria,

> > viruses, fungi, and parasites. A major component of this system

is

> a

> > diverse combination of cationic antimicrobial peptides that

include

> > the alpha- and beta-defensins and cathelicidins. In this study,

we

> > show that 1,25-dihydroxyvitamin D3 and three of its analogs

induced

> > expression of the human cathelicidin antimicrobial peptide (CAMP)

> > gene.

> > PMID: 15985530 [PubMed - in process]

[Guest guest]

hi Pippit,

> When this pathway is open, adapted bacterial cell surface proteins

> bind to AT-II.

I just reviewed the only paper I know of on this topic... if I'm not

too much in a rush, it lists only two bacterial species as known to

express an AT-II receptor.

> This in turn activates NF-KappaB in the cytoplasm of monocytes,

> macrophages, and dendritic cells

How so? When a bacterium binds a host molecule, this has no

immediate direct effect on the host other than to deprive the host

of that molecule. Any immediate, direct signaling by such binding

would take place within the bacteria, not within the host cell

proper.

> [During use of benicar/olmesartan] phagocytes can get out to fight

pathogens through other doors;

> it's just that the bugs adapted to the A-II receptor cannot get in

> through that door.

Maybe... but, it apparantly has not been shown that

benicar/olmesartan in fact blocks the bacterial AT-II receptor

(whose existence, again, is so far directly evidenced for only 2

bacterial species, according to the paper I'm reading). Nor is it

certain that the latter receptor has an immunoevasive function, tho

that it is, is probably a good hypothesis.

[Guest guest]

Actually to correct you (AGAIN), " Benicar only blocks the Angiotensin

II, type 1 receptor. " is incorrect. It affects many things --

including aldosterone which can be very dangerous for some CFIDSers.

" This study also found an increase in PRA and a decrease in plasma

Ang I, Ang II and aldosterone levels during the long-term

administration of olmesartan. "

Ichikawa S, Takayama Y. Long-term effects of olmesartan, an Ang II

receptor antagonist, on blood pressure and the renin-angiotensin-

aldosterone system in hypertensive patients. Hypertens Res. 2001

Nov;24(6):641-6. The FULL text and CHARTS are at

http://www.jstage.jst.go.jp/article/hypres/24/6/641/_pdf

Do you have some evidence to ignore this study?

Also " Bacteria metabolize Angiotensin " is a very sweeping statement --

my understanding is that they are all over the place in what they

use. The set of bacteria and virus for CFIDS are pretty well

established. Can you find any studies indicating this for MYCOPLASMA

FERMENTUS, CHLAYMEDIA or RICKETTSIA ? I believe that there are bugs

that adapt to " every possible door " -- so unless you know exactly

which bugs are involved, you are throwing dice.

> Hi Ken,

>

> Don't worry about that. Here is the specific pathway by which

Benicar

> blocks inflammation. Benicar only blocks the Angiotensin II, type 1

> receptor.

> Bacteria metabolize Angiotensin, and it is likely that they

> either use parts of it to camouflage themselves, and/or to

interfere

> with the process of phagocytosis.

>

> Phagocytes can get out to fight pathogens through other doors;

> it's just that the bugs adapted to the A-II receptor cannot get in

> through that door.

>

> I hope this gives some clarification.

>

> Pippit

[Guest guest]

My my, Ken, didn't we get up on the wrong side of the bed.

I answered the question you asked, and accurately. I didn't say that

Benicar didn't affect other things. All I was saying was that unlike

prednisone and other corticosteroids it doesn't block ALL immune

pathways " shut down the whole immune system " as you put it, (which is

what you said you were worried about).

I read the study you posted about the long-term effects of Olmesartan

and the researchers didn't place any negative value judgments on the

data they gave. Yes, they said that Aldosterone levels decreased in

15 patients after 1 year (data not provided), and I am aware that CFS

patients need to watch Aldosterone, but they did not conclude that

the levels they saw were necessarily unsafe nor that it posed any

great risk.

This study shows very nicely how at lower doses in shorter time-

frames BP is less stable, while at higher doses and taken for longer

periods it reaches a point at which it achieves homeostasis.

The study showed that BP stabilized at 4 months. It stated, " Mean SBP

and DBP decreased significantly (p<0.001) from baseline to week 12-16

and remained stable thereafter with no further changes during long-

term administration. "

They admit there is more that needs to be studied on the effect AT2

stimulation has on various tissues, and on the RAS. This study was

done. Its latest revision was on August 27, 2001. The MP has done

just what the study suggested, picking up where this earlier study

leaves off.

They concluded, " The present study confirmed the favorable

antihypertensive effect and tolerability of Olmesartan, a novel AT1

receptor antagonist, in hypertensive patients. The study also

demonstrated that plasma Ang.I and Ang.II levels were decreased by

long-term treatment wih Olmesartan. Although further investigation

will be necessary to determine the actual effects on the RAS produced

by long-term treatment with AT1 receptor antagonists such as

Olmesartan, the findings in our study improve the understanding of

the interaction between AT1 antagonists and the RAS. "

I've been continuing to read in-depth on this topic, and it is clear

that although there are a number of scientists looking into and

shedding further light on this process, the RAS is a highly complex

system and that not even the top scientists in the world have it all

figured out yet in 2005.

Sure, it is highly possible that bugs may be getting in through other

pathways besides the ATII, Type 1 receptor, but what you're reasoning

is heading back to is the approach you feared in the first place

which was to shut down the whole immune system, and I don't think

that's the answer.

What the MP does is to allow some pathways to stay open so that

Phagocytes can still access and kill those bacteria that do get in,

while it blocks one known point of entry, making it inaccessible to

the nasty little things. The pulsed antibiotic combinations address

those creatures that have gotten in, both directly (bacteriocidally)

and indirectly, (bacteriostatically), by not allowing them to

transcribe their cell proteins, and assist the person's own immune

system in finding and killing them.

It may well be discovered that Benicar has other actions through

which it addresses these bugs, or that the combination of Benicar and

the other MP meds do.

There may be other pathways addressed in the future besides the ATII,

Type 1 receptor in which these organisms are blocked and/or killed,

and there may very well be other foodstuffs bacteria metabolize in

addition to Angiotensin, but we have to take this one step at a time.

There is alot of uncharted territory out there, some of which has

never been documented, or only partly.

As always, myself and a number of other people who take a special

interest in this are keeping our ear to the floor. I will look into

the species you mentioned to see what comes up.

Pippit

> > Hi Ken,

> >

> > Don't worry about that. Here is the specific pathway by which

> Benicar

> > blocks inflammation. Benicar only blocks the Angiotensin II, type

1

> > receptor.

> > Bacteria metabolize Angiotensin, and it is likely that they

> > either use parts of it to camouflage themselves, and/or to

> interfere

> > with the process of phagocytosis.

> >

> > Phagocytes can get out to fight pathogens through other

doors;

> > it's just that the bugs adapted to the A-II receptor cannot get

in

> > through that door.

> >

> > I hope this gives some clarification.

> >

> > Pippit

[Guest guest]

Hi Pippit,

I did understand your comment about Benicar 'only' blocking AII type

1 receptors to be in the context of a comparison with cortisone,

rather than claiming that this is the only impact Benicar has on the

body. I figured you could clarify that yourself, which you've done.

What the literature tells me about Benicar's effect on the immune

system is simply that macrophages behave differently when their AII

type 1 receptors are blocked. They are less responsive to

chemotaxis, and their phagocytic activity is diminished. Here are

some references (I'm quoting selectively, but you can access full

text at the links):

http://www.jci.org/cgi/content/full/110/12/1763

Unexpected news in renal fibrosis

J. Clin. Invest. 110:1763-1764 (2002). doi:10.1172/JCI200217399.

Copyright ©2002 by the American Society for Clinical Investigation

" Indeed, analysis of macrophage function by Nishida et al. (11)

revealed that macrophages lacking Agtr1a have reduced migratory

capacity and decreased phagocytic activity, a characteristic that

could also be elicited in wild-type macrophages by the angio-tensin

II receptor antagonist losartan. "

http://tinyurl.com/cyc3g

J. Clin. Invest. 110:1859-1868 (2002). doi:10.1172/JCI200215045.

Copyright ©2002 by the American Society for Clinical Investigation

Absence of angiotensin II type 1 receptor in bone marrow–derived

cells is detrimental in the evolution of renal fibrosis

" In vivo assays revealed a significantly impaired phagocytic

capability in Agtr1–/– macrophages. In vivo treatment of Agtr1+/+

mice with losartan reduced phagocytic capability of Agtr1+/+

macrophages to a level comparable to that of Agtr1–/– macrophages.

Thus, during urinary tract obstruction, the Agtr1 on bone marrow–

derived macrophages functions to preserve the renal parenchymal

architecture, and this function depends in part on its modulatory

effect on phagocytosis. "

Here's a reference that's specific for resitance to infection, with

paragraph breaks added for readability:

Clin Diagn Lab Immunol. 2000 Jul;7(4):635-40.

Angiotensin II increases host resistance to peritonitis.

Rodgers K, Xiong S, Espinoza T, Roda N, Maldonado S, diZerega GS.

Livingston Research Institute, University of Southern California

School of Medicine, Los Angeles, California 90033, USA.

krodgers@...

" Studies by other laboratories have shown that angiotensin II (AII)

can affect the function of cells which comprise the immune system.

" In the present study, the effect of AII on the function of

peritoneal macrophages and peripheral blood monocytes was assessed.

In vitro exposure (4 h prior to assay) of peritoneal macrophages

from mice and rats to AII increased the percentage of cells that

phagocytosed opsonized yeast and the number of yeast per macrophage.

" Furthermore, AII increased the respiratory burst capacity of

peritoneal macrophages from mice and rats and peripheral blood

mononuclear cells from humans. Because of these observations, the

effect of AII on host resistance to bacterial infection was

assessed.

" Intraperitoneal administration of AII was shown to increase host

resistance (reduced abscess formation) in an animal model of

bacterial peritonitis. Studies were then conducted to assess whether

parenteral administration of AII, a clinically relevant route, could

affect peritoneal host resistance in a manner similar to that

observed after peritoneal administration. These studies showed that

subcutaneous administration of AII throughout the postinfection

interval increased the level of host resistance to bacterial

peritonitis. "

Can you provide even one published finding that shows that

pathogens, rather than the immune cells we've evolved to protect

ourselves from them, are inhibited by Benicar?

Thanks,

> > > Hi Ken,

> > >

> > > Don't worry about that. Here is the specific pathway by which

> > Benicar

> > > blocks inflammation. Benicar only blocks the Angiotensin II,

type

> 1

> > > receptor.

> > > Bacteria metabolize Angiotensin, and it is likely that

they

> > > either use parts of it to camouflage themselves, and/or to

> > interfere

> > > with the process of phagocytosis.

> > >

> > > Phagocytes can get out to fight pathogens through other

> doors;

> > > it's just that the bugs adapted to the A-II receptor cannot

get

> in

> > > through that door.

> > >

> > > I hope this gives some clarification.

> > >

> > > Pippit

[Guest guest]

Hello Pippit:

There arer 2 things in your post to Ken I want to address:

What you wrote is copied below:

The MP in general:

IMO, It would seem to me that 2 or more years on drugs that are used

to modulate the immune system (no matter what they are), while taking

other drugs proported to either to kill, or assist the body in

killing pathogenic bacteria should be sufficiently a long enough

time if indeed that's what happening.

It seems to me, in light of the fact that no one has been reported to

be off Benicar (including the founders of the protocol) that the

regiment is more like what the low dose abx regiment is like for

cystic fibrosis (low dose zith) which keeps the bacteria in colonies -

ANd I'm no saying that's a bad thing - because therapies that make

you feel better and extend life, I view as a good thing... evebn if

it's a life long therapy.

Point 2.. LOW dose abx.

I know that some abx under the MIC will kill variants of certain

bacteria (I supplied those papers to your group originally). And

usually 2 abx are used in concert - one to kill the classical, and

the other to kill it's variant. But the application of this theroy

was not to use just low dose abx in the way they are used for AIDS

(minimum doses to control bacteria in a supressed host). While slow

growing

bacteria don't form resistance so quickly - that's not true for the

faster replicators.

ALso- there seems to be enough evidence, IMO that PH plays a

significant role as to where abx can enter a cell compartment

(intracellular bacteria) no matter what dose one is taking.

BENICAR:

As far as Benicar goes- I think every know enough now to know that

drug is like a andora's box. It just affects the body in so many

ways (and most seem to be beneficial)... and I think there'll be alot

of light shed on thit's mechanisms in the next few years.

No one right know know exactly how it modulates the immune system.

Pippit- how long have you been on Benicar (if you are) and at what

dose, and what happens if you try to wean off?

I am not trying to be challenging- it's just that we talk about

relapsing if one goes off abx (for other therapies) - or abx that

aren't working - and I'd like to discuss why people may relapse if

they wean off Benicar.

Barb

REFERENCED POST IN PART

Pippit wrote in part:

What the MP does is to allow some pathways to stay open so that

Phagocytes can still access and kill those bacteria that do get in,

while it blocks one known point of entry, making it inaccessible to

the nasty little things.

The pulsed antibiotic combinations address

those creatures that have gotten in, both directly (bacteriocidally)

and indirectly, (bacteriostatically), by not allowing them to

transcribe their cell proteins, and assist the person's own immune

system in finding and killing them.

It may well be discovered that Benicar has other actions through

which it addresses these bugs, or that the combination of Benicar and

the other MP meds do.

There may be other pathways addressed in the future besides the ATII,

Type 1 receptor in which these organisms are blocked and/or killed,

and there may very well be other foodstuffs bacteria metabolize in

addition to Angiotensin, but we have to take this one step at a time.

There is alot of uncharted territory out there, some of which has

never been documented, or only partly.

As always, myself and a number of other people who take a special

interest in this are keeping our ear to the floor. I will look into

the species you mentioned to see what comes up.

Pippit

> > > Hi Ken,

> > >

> > > Don't worry about that. Here is the specific pathway by which

> > Benicar

> > > blocks inflammation. Benicar only blocks the Angiotensin II,

type

> 1

> > > receptor.

> > > Bacteria metabolize Angiotensin, and it is likely that

they

> > > either use parts of it to camouflage themselves, and/or to

> > interfere

> > > with the process of phagocytosis.

> > >

> > > Phagocytes can get out to fight pathogens through other

> doors;

> > > it's just that the bugs adapted to the A-II receptor cannot get

> in

> > > through that door.

> > >

> > > I hope this gives some clarification.

> > >

> > > Pippit

[Guest guest]

Hi Barb,

In reference to the length of time it should take to eradicate the

bacteria; I think there are so many possible combinations of

bacteria, some more resistent than others (especially when you're

talking about the cell wall deficient type and ones that shape-shift

back and forth into different forms), that it's really impossible to

make a hard and fast rule for duration of treatment.

I would love it if they were all gone in 2 years (and I'm sure

everyone else would too), but although I haven't been on long-term

high-dose regimens I have been on short-courses of high dose

antibiotics before I knew that what I had was more than a short-term

infection, and I herxed so badly it was dangerous. I also know

several others who did not do well on high-dose (either they herxed

too severely or they relapsed afterwards).

These things are not that easy to kill completely on high or low-dose

regimens. I suspect it may have to do with how adapted the species

you have are to the phagocytes and how good they are at circumventing

the abx in various other ways.

Who knows, maybe we will find out that some species need to be killed

with low-dose and others with high-dose. The problem is we don't all

know what's in there. I am really hoping that new, more sophisticated

bacterial testing methods will come out soon. That would make the

determination alot easier.

Alot of people have been on the Brown Protocol for 10 years. They're

better, but not completely.

Your point about PH makes sense.

One woman that I know of(and there may be more) has gone off Benicar

and is still off it. So far she hasn't relapsed. I believe she said

she's been off of it for about 4 months now. She has both CFS and

Lyme. This is very encouraging for everybody with one or both of

these diseases, because so far this is a success story.

I would not try to do that right now because it's very important at

this time in my life that I finish my education so that I can re-

enter the workforce in my field of study.

At some point I don't mind trying it, but I want to have that out of

the way first.

It would really be nice to see a number of these top scientists put

their heads together.

Pippit

> > > > Hi Ken,

> > > >

> > > > Don't worry about that. Here is the specific pathway by which

> > > Benicar

> > > > blocks inflammation. Benicar only blocks the Angiotensin II,

> type

> > 1

> > > > receptor.

> > > > Bacteria metabolize Angiotensin, and it is likely that

> they

> > > > either use parts of it to camouflage themselves, and/or to

> > > interfere

> > > > with the process of phagocytosis.

> > > >

> > > > Phagocytes can get out to fight pathogens through other

> > doors;

> > > > it's just that the bugs adapted to the A-II receptor cannot

get

> > in

> > > > through that door.

> > > >

> > > > I hope this gives some clarification.

> > > >

> > > > Pippit