Re: Cell-Targeted Anti-Inflammation drugs.

[Guest guest]

I posted those guys once last fall. Its a cool idea to specifically

target the macrophage, which is the biggest producer of " cytokines " in

the most accustomed sense (interleukins, INFs, TNFs), and perhaps also

of the mediators whose synthesis aspirin inhibits (which I think are

mostly/all prostaglandins).

And the tech could be useful for concentrating various other

substances in macrophages. Some antimicrobials like rifampicin and

azithromycin concentrate spectacularly in macrophages on their own

tho. However, due to pH-mediated concentration (I dont have a real

grasp of the exact mechanism) they may be heavily sequestered within

lysosomes, whereas cytosol may (or may not) be a more critical locus

of pathogens.

IMO, tetracyclines could be interesting to use with this tech, as

toxicity limits their dosage in humans. They are oft-cited as

concentrating 2-4x in cells on their own, but I have a review article

claiming this is sorta questionable, and of course 2-4 isnt a very big

number. But see below.

Problems with particulate drug delivery are these:

1. at what rate do these things get into tissue, where many target

cells may be, as opposed to blood?

2. with toxic drugs, theres the difficulty that particulates tend to

get concentrated in the tissues of the reticuloendothelial system

(liver, lungs, and spleen) because circulating drug particles are

phagocytosed by the fixed tissue phagocytes there. Hence while

particulates can improve the drug concentration ratio in target cells

vs in serum and humor generally, there can be potentially unacceptable

superconcentrations in those reticuloendothelial organs.

For example, I think liver toxicity is a limiting factor with

tetracyclines, so particulated tetracyclines probably wont ever fly.

<Jaep@L...> wrote:

>

>

> This looks good ,

>

> Cell-Targeted Anti-Inflammation drugs..

>

> Coated NSAIDS are aggressively engulfed by a macrophage cell line in

> culture. I like the sound of that ..or is it sales talk.. Anyone

with any

> experience of this?

>

> http://www.biodeliverysciences.com/applications/nsaids.html

> --

[Guest guest]

That was a really thorough, interesting answer to J's post.

Thanks very much, (and J for asking)!

> >

> >

> > This looks good ,

> >

> > Cell-Targeted Anti-Inflammation drugs..

> >

> > Coated NSAIDS are aggressively engulfed by a macrophage cell

line in

> > culture. I like the sound of that ..or is it sales talk..

Anyone

> with any

> > experience of this?

> >

> > http://www.biodeliverysciences.com/applications/nsaids.html

> > --

[Guest guest]

Thanks , I don't grasp the mechanism either, I think & talk in principles , I don't think many if any have an intimate knowledge of how the IS works , I see the problem with mono therapy [tetracylines probably wont ever fly] that's why drug combos are so much more effective , especially if the drugs involved work in different ways ...Take a look at this article ..its a very convincing picture on combos ..the pity is the work is not taken up if you like ..its not adopted for further study ...its just one more piece of information in a sea of information ...we need a good co-ordinator...

Antifungals: Doing the two step

SOURCE:

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Antifungal activity of the sodium-channel blocker amiodarone is mediated by the disruption of calcium homeostasis.

People with compromised immune systems, such as patients with cancer or AIDS, are often susceptible to severe fungal infections that require long-term treatment. Unfortunately, prolonged use of conventional antifungal agents, such as azoles, can lead to the fungus becoming resistant to therapy. However, a potential solution to this problem has now emerged from a surprising source.

The sodium-channel blocker amiodarone is already approved by the US FDA to treat severe disturbances in the heart's natural rhythm, known as arrhythmias. Last year, researchers investigating its mechanism of action in yeast cells unexpectedly discovered amiodarone's antifungal ability. Now, a study in the Journal of Biological Chemistry outlines the two-step mechanism by which amiodarone disrupts yeast cells, and shows that combining the heart drug with azoles provides an unexpectedly effective means of eliminating fungi.

Rajini Rao and colleagues used the baker's yeast Saccharomyces cerevisiae as a model to investigate amiodarone's toxicity. As previous work had indicated that amiodarone administration evoked changes in cellular calcium concentrations, the researchers decided to analyse its effect in yeast cells lacking key Ca2+ transporters, including pumps, channels and exchangers. Some of these mutants proved to be particularly sensitive to amiodarone, which hinted that Ca2+ transport might be important in mediating the toxic effects of the drug.

To further investigate this, a luminescence assay was used to monitor changes in intracellular Ca2+ concentrations in response to amiodarone. A two-step response to amiodarone was seen, in which a sharp initial peak in cytosolic Ca2+ was followed by a more gradual rise in Ca2+ concentrations. Interestingly, mutant cells with higher sensitivity to amiodarone showed sharper rises in cytosolic calcium, further supporting a role for calcium in the amiodarone response.

But where does this amiodarone-induced calcium come from? The researchers showed that amiodarone administration initially causes calcium to flow into the cell from the outside, followed by a more gradual release from internal stores, including the vacuole. They suggest that it is this second sustained rise in calcium that eventually becomes toxic to amiodarone-treated cells. The mechanism by which amiodarone causes cell death by disrupting calcium homeostasis is entirely different to the mechanism used by conventional azole antifungals, which slow cell growth by targeting the ergosterol biosynthetic pathway.

In humans, high doses or prolonged treatment with amiodarone can cause serious side effects, including damage to the lungs and thyroid. The dose required for amiodarone alone to combat fungi is therefore likely to be toxic. Rao and colleagues reasoned that because of their differing mechanisms of action, supplementing an azole with amiodarone could create an effective antifungal treatment, while at the same time preventing the development of resistance. Indeed, they showed that a combination of low-dose amiodarone and the azole miconazole cut survival of yeast cells to less than 10%, compared with almost 100% survival in the presence of the same concentrations of either drug alone. Similar findings were shown with the pathogenic yeasts Candida albicans and Cryptococcus neoformans, for which amiodarone combined with fluconazole killed almost 100% of cells.

Combining amiodarone with an azole could therefore provide a promising new way of treating fungal infections in individuals with depressed immune systems. Furthermore, this new information about amiodarone's mechanism could help researchers to explain, and eventually prevent, its side effects when used to treat heart problems.

Clare Ellis

References

1. Gupta, S. S. et al. Antifungal activity of amiodarone is mediated by disruption of calcium homeostasis. J. Biol. Chem. 2003 May 16 (DOI:10.1074/JBC.N303300200)

2. Courchesne, W. E. Characterization of a novel, broad-based fungicidal activity for the antiarrhythmic drug amiodarone. J. Pharmacol. Exp. Therap. 300, 195–199 (2002)

3. Courchesne, W. E. & Ozturk, S. Amiodarone induces a caffeine-inhibited, MID1-dependent rise in free cytoplasmic calcium in Saccharomyces cerevisiae . Mol. Microbiol. 47, 223–234 (2003)

-----Original Message-----From: infections [mailto:infections ]On Behalf Of HodologicaSent: 18 April 2005 21:18infections Subject: [infections] Re: Cell-Targeted Anti-Inflammation drugs.

I posted those guys once last fall. Its a cool idea to specificallytarget the macrophage, which is the biggest producer of "cytokines" inthe most accustomed sense (interleukins, INFs, TNFs), and perhaps alsoof the mediators whose synthesis aspirin inhibits (which I think aremostly/all prostaglandins).And the tech could be useful for concentrating various othersubstances in macrophages. Some antimicrobials like rifampicin andazithromycin concentrate spectacularly in macrophages on their owntho. However, due to pH-mediated concentration (I dont have a realgrasp of the exact mechanism) they may be heavily sequestered withinlysosomes, whereas cytosol may (or may not) be a more critical locusof pathogens. IMO, tetracyclines could be interesting to use with this tech, astoxicity limits their dosage in humans. They are oft-cited asconcentrating 2-4x in cells on their own, but I have a review articleclaiming this is sorta questionable, and of course 2-4 isnt a very bignumber. But see below.Problems with particulate drug delivery are these: 1. at what rate do these things get into tissue, where many targetcells may be, as opposed to blood?2. with toxic drugs, theres the difficulty that particulates tend toget concentrated in the tissues of the reticuloendothelial system(liver, lungs, and spleen) because circulating drug particles arephagocytosed by the fixed tissue phagocytes there. Hence whileparticulates can improve the drug concentration ratio in target cellsvs in serum and humor generally, there can be potentially unacceptablesuperconcentrations in those reticuloendothelial organs.For example, I think liver toxicity is a limiting factor withtetracyclines, so particulated tetracyclines probably wont ever fly.<Jaep@L...> wrote:> > > This looks good ,> > Cell-Targeted Anti-Inflammation drugs..> > Coated NSAIDS are aggressively engulfed by a macrophage cell line in> culture. I like the sound of that ..or is it sales talk.. Anyone with any> experience of this?> > http://www.biodeliverysciences.com/applications/nsaids.html> --

[Guest guest]

Cool article, , thanx.

> >

> >

> > This looks good ,

> >

> > Cell-Targeted Anti-Inflammation drugs..

> >

> > Coated NSAIDS are aggressively engulfed by a macrophage cell

line in

> > culture. I like the sound of that ..or is it sales talk..

Anyone

> with any

> > experience of this?

> >

> > http://www.biodeliverysciences.com/applications/nsaids.html

> > --

>

>

>

>

>

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