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Minocycline is an excellent Anti-inflammatory
 Moderated by: Prof Trevor Marshall Page:    1  2  3  4  5  Next Page Last Page  
 

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Prof Trevor Marshall
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 Posted: Thu Feb 16th, 2012 14:48

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The trickle of information about how the antibiotics used in the MP are actually affecting the disease process is swelling into a flood:


There is a new paper out: "Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition"

http://www.ncbi.nlm.nih.gov/pubmed/22306153

"RESULTS: Minocycline significantly reduced the inflammatory response in LPS-challenged monocytes, decreasing LPS-induced transcription of pro-inflammatory tumor-necrosis factor alpha (TNF-α), interleukin-1 beta, interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), and the LPS-stimulated TNF-α, IL-6 and PGE(2) release. Minocycline inhibited LPS-induced activation of the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), NF-κB, LPS-induced TNF-α factor (LITAF) and the Nur77 nuclear receptor. Mechanisms involved in the anti-inflammatory effects of minocycline include a reduction of LPS-stimulated p38 mitogen-activated protein kinase (p38 MAPK) activation and stimulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway."

(thanks to Bane for finding this for me)

Now we are not as interested in the TLR4 pathway as with the TLR2, but both are active within the cytoplasm. 

All of the mechanisms listed in this paper are significant in the chronic disease process, and my colleagues have been keeping their eye on them. Many more pieces of the clinical puzzle are now falling into place,

Let's use this thread to bring together the best papers describing the action of Minocycline in the human body :)

..Trevor..

Jigsaw
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 Posted: Thu Feb 16th, 2012 16:16

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Here are some of uncertain quality. The most relevant is the one on PXR function by Dubrac which reports that PXR  activates SOCS1 (suppressor of cytokine signalling 1). This could account for some of the effects reported above for mino.


Clinical Trial of Doxycycline for Matrix Metalloproteinase-9 Inhibition in Patients With an Abdominal Aneurysm: Doxycycline Selectively Depletes Aortic Wall Neutrophils and Cytotoxic T Cells -- Lindeman et al. 119 (16): 2209 -- Circulation
The influence of tetracyclines on T cell activatio... [Clin Exp Immunol. 1995] - PubMed result

Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction -- Giuliani et al. 78 (1): 135 -- Journal of Leukocyte Biology

 Modulation of T Lymphocyte Function by the Pregnane X Receptor -- Dubrac et al. 184 (6): 2949 -- The Journal of Immunology
 Antibiotic appears safe for stroke patients and good companion for tPA, study suggests
 Minocycline inhibits the growth of glioma by induc... [Autophagy. 2011] - PubMed - NCBI

Last edited on Thu Feb 16th, 2012 16:24 by Jigsaw



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Bane
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 Posted: Thu Feb 16th, 2012 17:57

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Minocycline protects SH-SY5Y cells from 6-hydroxydopamine by inhibiting both caspase-dependent and -independent programmed cell death.
http://www.ncbi.nlm.nih.gov/pubmed/22108958
This study investigated these alternative pathways in SH-SY5Y cells, a human dopaminergic cell line, challenged with 6-hydroxydopamine (6-OHDA). Minocycline exhibited neuroprotection and inhibition of the toxin-induced caspase-3-like activity, DNA fragmentation, and chromatin condensation, hallmarks of apoptosis.


Inactivation of the Human Vitamin D Receptor by Caspase-3
http://endo.endojournals.org/content/150/2/679.abstract
In conclusion, our results demonstrate that the human VDR is a target of caspase-3 and suggest that activation of caspase-3 may limit VDR activity.

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Does minocycline, an antibiotic with inhibitory effects on microglial activation, sharpen a sense of trust in social interaction?
http://www.ncbi.nlm.nih.gov/pubmed/21956241
METHODS:Forty-nine healthy volunteers were administered minocycline or placebo over four days, after which they played (1) a trust game, in which they decided how much to trust an anonymous partner, and (2) a dictator game, in which they decided how to divide resources between themselves and an anonymous partner.

CONCLUSIONS:These results suggest that minocycline led to more rational decision-making strategies, possibly by increasing emotion regulation. Since minocycline is a well-known inhibitor of microglial activation, our findings may open a new optional pathway for treating mental states in which a component of rational decision making is impaired.

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Minocycline produced antidepressant-like effects on the learned helplessness rats with alterations in levels of monoamine in the amygdala and no changes in BDNF levels in the hippocampus at baseline.
http://www.ncbi.nlm.nih.gov/pubmed/21967886
"LH rats showed significantly higher serotonin turnover in the orbitofrontal cortex and lower levels of brain-derived neurotrophic factor (BDNF) in the hippocampus than control rats. However, these alterations in serotonin turnover and BDNF expression remained unchanged after treatment with minocycline. On the contrary, minocycline treatment of LH rats induced significant increases in the levels of dopamine and its metabolites in the amygdala when compared with untreated LH rats. Taken together, minocycline may be a therapeutic drug for the treatment of depression"

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Minocycline as potent anticonvulsant in a patient with astrocytoma and drug resistant epilepsy.
http://www.ncbi.nlm.nih.gov/pubmed/22265576
"We present the case of a patient with marked reduction in seizure frequency during minocycline therapy with severe symptomatic epilepsy due to an astrocytoma"

Last edited on Thu Feb 16th, 2012 18:54 by Bane

Bane
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 Posted: Thu Feb 16th, 2012 18:41

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Cryotherapy and topical minocycline as adjunctive measures to control pain after third molar surgery: an exploratory study.
http://www.ncbi.nlm.nih.gov/pubmed/21802812

CONCLUSIONS: Data from this exploratory study suggest that adjunctive therapy to decrease postoperative pain-cryotherapy or topical minocycline-might be effective at moderating the patient's highest pain levels after third molar surgery. The topic should be studied further in a multicenter, prospective, randomized trial.

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Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2412862/

"Minocycline blocked LPS-stimulated inflammatory cytokine secretion in the BV-2 microglia-derived cell line and reduced LPS-induced Toll-like-receptor-2 (TLR2) surface expression on brain microglia. Moreover, minocycline facilitated the recovery from sickness behavior (i.e., anorexia, weight loss, and social withdrawal) and prevented anhedonia in adult mice challenged with LPS. Furthermore, the minocycline associated recovery from LPS-induced sickness behavior was paralleled by reduced mRNA levels of Interleukin (IL)-1β, IL-6, and indoleamine 2, 3 dioxygenase (IDO) in the cortex and hippocampus. Finally, in aged mice, where exaggerated neuroinflammation was elicited by LPS, minocycline pretreatment was still effective in markedly reducing mRNA levels of IL-1β, TLR2 and IDO in the hippocampus"

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Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells.
http://www.ncbi.nlm.nih.gov/pubmed/21282105

"These findings provide a novel mechanism for minocycline induced suppression of CD4(+) T cell activation and may better inform the application of minocycline as an immunomodulatory agent"


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Minocycline Modulates Neuroinflammation Independently of Its Antimicrobial Activity in Staphylococcus aureus-Induced Brain Abscess
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1988870/

Minocycline exerts beneficial immune modulatory effects in several noninfectious neurodegenerative disease models; however, its potential to influence the host immune response during central nervous system bacterial infections, such as brain abscess, has not yet been investigated. Using a minocycline-resistant strain of Staphylococcus aureus to dissect the antibiotic’s bacteriostatic versus immune modulatory effects in a mouse experimental brain abscess model, we found that minocycline significantly reduced mortality rates within the first 24 hours following bacterial exposure. This protection was associated with a transient decrease in the expression of several proinflammatory mediators, including interleukin-1β and CCL2 (MCP-1). Minocycline was also capable of protecting the brain parenchyma from necrotic damage as evident by significantly smaller abscesses in minocycline-treated mice. In addition, minocycline exerted anti-inflammatory effects when administered as late as 3 days following S. aureus infection, which correlated with a significant decrease in brain abscess size. Finally, minocycline was capable of partially attenuating S. aureus-dependent microglial and astrocyte activation. Therefore, minocycline may afford additional therapeutic benefits extending beyond its antimicrobial activity for the treatment of central nervous system infectious diseases typified by a pathogenic inflammatory component through its ability to balance beneficial versus detrimental inflammation.

Last edited on Thu Feb 16th, 2012 18:59 by Bane

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 Posted: Thu Feb 16th, 2012 19:27

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Minocycline Helps Developmental Delay

http://www.youtube.com/watch?v=t3PF-pOMzc8

Prof Trevor Marshall
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 Posted: Thu Feb 16th, 2012 20:10

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..Just a few notes to explain what I have done in-silico

I did manage to partially confirm the in-vitro study which said that Minocyline and Cilindamycin were PXR receptor agonists.

There were measuring expression of CYP3A4, which is supposed to come wholly from PXR expression, but which may not IMO (there are 52 nuclear receptors, many of them with unknown function).

I found that Minocycline docked with high affinity in a very similar position to a known agonist, but Clindamycin is a much larger molecule, and must require a different configuration of PXR's prolific binding pocket, if it does indeed dock at all.
 

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 Posted: Thu Feb 16th, 2012 21:22

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Just a reminder of PXR-AR cross talk (if I'm understanding this paper right, activated PXR should reduce AR transcribed AMP's?).
http://www.ncbi.nlm.nih.gov/pubmed/20599793

paper title: Cross-talk between androgen receptor and pregnane and xenobiotic receptor reveals existence of a novel modulatory action of anti-androgenic drugs.

Abstract
The androgen receptor (AR) is a member of nuclear receptor superfamily (NRs) and plays a critical role in prostate cancer development and progression. Therefore, anti-androgens that repress AR activity remain a critical mainstay for prostate cancer therapy. However, molecular mechanisms by which anti-androgens exert their therapeutic effects are not clearly elucidated and hence are a major area of scientific pursuit. Here, we demonstrate that another member of NRs, pregnane and xenobiotic receptor (PXR), not only acts as a molecular sensor of anti-androgens but also influences the outcome of therapeutic regimen with anti-androgenic drugs via a novel AR-PXR cross-talk. Using 'gain- and loss-of-function' studies, we identified a distinct role of PXR as a potent repressor of AR-regulated transcription. Our study implicates PXR as a key determinant of anti-androgen action since down-regulation of PXR diminishes the potency of the anti-androgenic drugs and enhances transcriptional actions of androgens. In addition, our subcellular localization studies revealed that ligand-activated AR induces nuclear localization of PXR and the two receptors colocalize at discrete sites in nucleus and mitotic chromatin. Finally, we report a distinct antagonist-induced interaction between AR and PXR defining a hitherto unidentified mode of action of AR antagonist. In this perspective, the study may help in designing and development of novel AR antagonists offering improved avenues in prostate cancer therapy.



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Jigsaw
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 Posted: Fri Feb 17th, 2012 01:28

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This bookmarking seems to have been miscoded in my previous post

Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction



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 Posted: Fri Feb 17th, 2012 06:17

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Jigsaw,
My confusion here is that I thought we were using sub inhibitory levels of Minocycline to avoid such immune system effects. In this study, in fact, 200 mg/day were administered as 100 mg b.i.d. Furthermore, I wonder what would be the effect of strong olmesartan mediated VDR activation on such studies. Perhaps our 100 mg Minocycline dose schedule will have a commensurate immunomodulating effect, or not. Is there some thought of trying 100 mg Mino b.i.d for extra CNS palliation?

Best regards as ever,
Mike



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Jigsaw
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 Posted: Fri Feb 17th, 2012 19:23

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  I have thought the sub-inhibitory levels were to turn off the bacterial protein synthesis to release their control of the immune system just enough to achieve some bacterial killing: but not so much that the bacterial breakdown products over-activated our TLRs and gave us excessive IP. 
  The immuno-suppressive effect through PXR I see as something that has evolved to protect us against the chance that some xenobiotic might be too harmful to our microbiome for our comfort.
  I think that strong VDR mediated activation would make sudden high dose minocycline dangerous.

Last edited on Fri Feb 17th, 2012 19:27 by Jigsaw



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mvanwink5
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 Posted: Fri Feb 17th, 2012 20:13

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Jigsaw,
The ribosome interference MP thought is clear, but that it is not just bacterial replication that is being targeted, but also their ability to interfere with the immune system, is a new thought for me. My memory of MPKB abx discussion does not mention the targeting of bacterial immune system interference. Thank you for pointing that out. Maybe I just missed it.

Are you saying that the PXR immunosuppression pathway suggested by the paper requires too high a Minocycline dose to provide heavy CNS immune activation protection for the MP protocol or just that 100mg b.i.d is just too high for the MP? I'm just pondering the MS and ALS folk's issues with immune action that is too heavy, and 100 mg/day just does not seem to be providing adequate help (for some reports)?
Thanks again,
Mike



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Jigsaw
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 Posted: Fri Feb 17th, 2012 22:23

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I am saying that the high levels of mino coupled with immune activation through the VDR by 25d depletion and olmesartan could lead to runaway IP. If the mino dosage was slowly increased it might work. However it might be an unstable situation. Unliganded PXR is a repressor of its target and becomes an activator on ligand binding. Also it can go from activator to repressor by the action of inflammatory cytokines (the ones it suppresses through SOCS1), at least in liver and intestine.
 Phosphorylation and Protein-protein Interactions in PXR-mediated CYP3A Repression
Pregnane X receptor is required for interleukin-6 mediated down-regulation of cytochrome P450 3A4 in human hepatocytes

This may be part of why people find that mino varies in its exacerbating or palliative effects on IP.



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mvanwink5
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 Posted: Sat Feb 18th, 2012 00:55

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Jigsaw,
The take away from these papers might be that it is not likely a smart way to purposely repress PXR as a central palliation strategy as the PXR is deeply regulated for essential and multiple purposes. If a particular drug really clobbers it, it is not likely to be a good strategy because of the side issues. Further, one should not be surprised to find such palliation via the PXR is unreliable (and such unreliability seems to be borne out by MP cohort reports). Would you say that is fair?

Best regards,
Mike



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Prof Trevor Marshall
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 Posted: Sat Feb 18th, 2012 01:32

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It is worth remembering that the primary agonist for PXR, the classic agonist, is Rifampin, which was isolated from bacteria which were observed to be pathogenic to Mycobacteria tuberculosis.

PXR activation may not be all bad, as it upregulates glutathione metabolites (normally depressed in Th1 disease). Like all bodily metabolism, everything tends to be not so black and white as we have pictured it in the past. The Interactome is complex, still a semi-infinite space to science...

The problem with understanding the action of physiological (clinical) minocycline concentrations on the bacterial Ribosome is that I was never really convinced that it targeted 30S very effectively. Unlike Clindamycin, and the macrolides, which clearly affect the ability of 50S to do its job, the papers describing minocycline's modes of action on 30S, described by the Max Planck Ribosomal researchers were less convincing (primarily due to the low binding affinities and multiple putative binding sites). Additionally, mino in the bloodstream has to cross the cell wall, and then the vacuole exoskeleton, before it gets to the persistent microbiota, and both transitions would likely result in a concentration gradient (just as I explained for 25-D and Olmesartan in the last  web-conference).

..Trevor..
 

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 Posted: Sat Feb 18th, 2012 04:11

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Minocycline modulates antigen-specific CTL activity through inactivation of mononuclear phagocytes in patients with HTLV-I associated neurologic disease

http://www.ncbi.nlm.nih.gov/pubmed/22335964
http://en.wikipedia.org/wiki/Human_T-lymphotropic_virus_1
http://en.wikipedia.org/wiki/Tropical_spastic_paraparesis
http://en.wikipedia.org/wiki/Degranulation

The activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contribute to central nervous system inflammation in various neurological diseases. In HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), MPs are reservoirs of HTLV-I, and induce proinflammatory cytokines and excess T cell responses. The virus-infected or activated MPs may play a role in immuneregulation and disease progression in patients with HTLV-I-associated neurological diseases. Results: Phenotypic analysis of CD14+ monocytes in HAM/TSP patients demonstrated high expression of CX3CR1 and HLA-DR in CD14lowCD16+ monocytes, compared to healthy normal donors (NDs) and asymptomatic carriers (ACs), and the production of TNF-alpha and IL-1beta in cultured CD14+ cells of HAM/TSP patients. CD14+ cells of HAM/TSP patients also showed acceleration of HTLV-I Tax expression in CD4+ T cells. Minocycline, an inhibitor of activated MPs, decreased TNF-alpha expression in CD14+ cells and IL-1beta release in PBMCs of HAM/TSP patients. Minocycline significantly inhibited spontaneous lymphoproliferation and degranulation/IFN-gamma expression in CD8+ T cells of HAM/TSP patients. Treatment of minocycline also inhibited IFN-gamma expression in CD8+ T cells of HAM/TSP patients after Tax11-19 stimulation and downregulated MHC class I expression in CD14+ cells. Conclusion: These results demonstrate that minocycline directly inhibit the activated MPs and that the downregulation of MP function can modulate CD8+ T cells function in HAM/TSP patients. It is suggested that activated MPs may be a therapeutic target for clinical intervention in HAM/TSP.

Last edited on Sat Feb 18th, 2012 04:17 by Bane

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 Posted: Sat Feb 18th, 2012 08:04

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Concentration-dependent effects of antimicrobials on Staphylococcus aureus toxin-mediated cytokine production from peripheral blood mononuclear cells.

http://www.ncbi.nlm.nih.gov/pubmed/21980070

BACKGROUND:

Toxins contribute to the pathogenicity of Staphylococcus aureus infections by inducing a dysregulated inflammatory response. This study evaluated the impact of anti-staphylococcal antibiotic exposures over an increasing concentration range on cytokine production from peripheral blood mononuclear cells (PBMCs) after S. aureus toxin exposures.

RESULTS:

At concentrations approximating serum C(max), tigecycline decreased IL-6 by 52%-57% and IFN-γ production by 43%-53% compared with toxin alone (P ≤ 0.05) and linezolid inhibited TNF-α by 12%-35% and IL-8 by 25%-42% (P ≤ 0.02). However, trimethoprim/sulfamethoxazole increased TNF-α and IL-8 production (P = 0.002). Clindamycin, daptomycin, vancomycin and azithromycin had no consistent significant effect at approximate serum C(max) concentrations. All antibiotics had a concentration-dependent effect on cytokine production, with tigecycline, clindamycin and trimethoprim/sulfamethoxazole being the most potent inhibitors of cytokine production at concentrations exceeding 25 mg/L.

CONCLUSIONS:

S. aureus toxins stimulate production of inflammatory cytokines in PBMCs. Antimicrobials with high tissue penetration, including tigecycline, clindamycin, trimethoprim/sulfamethoxazole and linezolid, reduced cytokine production, which, along with their antimicrobial effects, may have importance in the therapeutic outcome of severe infections.

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Comparison of the Effects of Human β-defensin 3, Vancomycin, and Clindamycin on Staphylococcus aureus Biofilm Formation.

http://www.ncbi.nlm.nih.gov/pubmed/22229614

Despite improvements in surgical techniques and implant design in orthopedic surgery, implantation-associated infections are still a challenging problem for surgeons. In 2006, trace quantities of human β-defensin 3 (hBD-3) were found in human bone tissue and bone cells. Human β-defensin 3 is a 45-amino-acid peptide that is considered the most promising class of defensin antimicrobial peptides and may help in the prevention and treatment of implantation-associated infections. Studies of the effectiveness of hBD-3 against Staphylococcus aureus showed that hBD-3 was more potent at low concentrations than other antibiotics. The effect of hBD-3 on S aureus biofilms has not been reported. We studied the effect of hBD-3, vancomycin, and clindamycin on S aureus biofilms and on the survival of the bacteria in the biofilms. Staphylococcus aureus biofilms were examined with confocal scanning laser microscopy. Staining with LIVE/DEAD BacLight viability stain (Molecular Probes Europe BV, Leiden, The Netherlands) differentiated between live and dead bacteria within the biofilms, and extracellular polymeric substances (slime) from the biofilms was evaluated after staining with calcofluor white (Sigma Chemical Company, Rocky Hill, New Jersey). Human β-defensin 3 and clindamycin reduced the S aureus biofilm area. Human β-defensin 3 was significantly more effective against bacteria from the S aureus biofilms than was clindamycin. Vancomycin did not reduce the S aureus biofilm area.

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Effects of minocycline on accumulation of cyclic AMP in cerebral cortex of rat. A comparison with lithium.

http://www.ncbi.nlm.nih.gov/pubmed/8413842

"Minocycline and lithium dose-dependently inhibited noradrenaline-stimulated formation of cAMP in slices of cortex, but only lithium inhibited the formation of cAMP induced by forskolin. In contrast to lithium, minocycline did not affect either noradrenaline- or Ca(2+)-stimulated activity of adenylate cyclase in a preparation of cortical membranes"


A comparative study on the effects of tetracyclines and lithium on the cyclic AMP second messenger system in rat brain.

http://www.ncbi.nlm.nih.gov/pubmed/7708928

This study was aimed at investigating the effects of demeclocycline (DMC), minocycline (MC), and lithium (Li) in vitro on cyclic AMP (cAMP) accumulation in rat cerebral cortex stimulated by noradrenaline, forskolin, and ouabain. 2. DMC, MC, and Li dose-dependently reduced noradrenaline-stimulated cAMP formation in cortical slices, but only Li inhibited the cAMP formation induced by forskolin. 3. In contrast to Li, DMC and MC did not affect noradrenaline-stimulated adenylate cyclase activity in cortical membranes. 4. In cortical slices, ouabain stimulated the cAMP production (required the presence of extracellular Ca2+ and was blocked by verapamil). Ouabain-stimulated cAMP accumulation in cortical slices was inhibited by DMC, MC, and Li. 5. DMC and MC do not seem to interact directly with the adenylate cyclase as reported for Li. It is concluded that the tetracyclines, DMC and MC, affect the cAMP signaling system in rat brain by mechanisms that differ from that of Li. The decreased receptor agonist-stimulated cAMP production in cortical slices in the presence of DMC and MC may be due to the Ca(2+)-chelating ability of these tetracyclines.

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 Posted: Sat Feb 18th, 2012 16:42

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an oldie...

Acne Drug Prevents HIV Breakout

http://www.hopkinsmedicine.org/news/media/releases/Acne_Drug_Prevents_HIV_Breakout

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Janice Clements on the discovery of minocycline for treating HIV-related cognitive disorders

http://www.youtube.com/watch?v=RvpJ9itcyXo


Minocycline Does Not Improve HIV-Associated Neurocognitive Disorder

http://www.natap.org/2011/CROI/croi_110.htm

The ACTG researchers suggested several reasons why minocycline may not have improved cognitive function in this trial: (1) minocycline may be ineffective in treating HIV-associated neurocognitive disorders, (2) treatment was too brief, (3) the 100-mg dose is not high enough to penetrate the central nervous system adequately, (4) cognitive impairment in these people may be caused by factors not addressed by minocycline, such as comorbid conditions or medication side effects, or (5) minocycline-induced neuroprotection may be reflected only in cerebrospinal fluid markers or by neuroimaging. The investigators are evaluating neuroprotection markers in cerebrospinal fluid markers now.


Minocycline fails to modulate cerebrospinal fluid HIV infection or immune activation in chronic untreated HIV-1 infection: results of a pilot study

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117676/

"For those meeting entry criteria, this also served as the baseline visit, and they starting minocycline 100 mg twice daily orally for the next 8 weeks. At four and eight weeks, and after a 6-week washout period off minocycline, subjects underwent repeated evaluation similar to the baseline, including LP and CSF analysis. Treatment adherence was assessed at each on-study visit by direct questioning and pill count"


Minocycline treatment for HIV-associated cognitive impairment: results from a randomized trial.

http://www.ncbi.nlm.nih.gov/pubmed/21900636

OBJECTIVE:
We conducted a study of minocycline to assess its safety, tolerability, and efficacy for the treatment of HIV-associated cognitive impairment.

METHODS:
HIV-1-infected individuals with progressive neurocognitive decline were enrolled in a double-blind, placebo-controlled study of minocycline. Participants were randomized to receive minocycline 100 mg or matching placebo orally every 12 hours. The primary efficacy measure was change in a neuropsychological test composite z score (NPZ-8) from baseline to week 24. Measures of safety included the frequency of adverse events and changes over time in laboratory tests. After 50% of participants completed the double-blind phase, an interim analysis of futility for the primary outcome measure was performed, and our Data and Safety Monitoring Board recommended early study termination.

RESULTS:
A total of 107 HIV-1-infected individuals with cognitive impairment were enrolled. The minocycline group did not show improvement in the primary outcome measure (NPZ-8) (mean 24-week change = 0.12) compared to placebo (mean 24-week change = 0.17) (95% confidence interval = [-0.26, 0.39], p = 0.70). There were few severe adverse events or laboratory abnormalities in either treatment group.

CONCLUSION:
Minocycline was safe and well-tolerated in individuals with HIV-associated cognitive impairment, but cognitive improvement was not observed. Classification of evidence. This interventional study provides Class II evidence for the safety, tolerability, and efficacy of minocycline for the treatment of HIV-associated cognitive impairment.

Last edited on Sat Feb 18th, 2012 17:17 by Bane

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 Posted: Sat Feb 18th, 2012 17:28

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Minocycline Inhibition of Monocyte Activation Correlates with Neuronal Protection in SIV NeuroAIDS

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071838/


Results

Minocycline treatment decreased plasma virus and pro-inflammatory CD14+CD16+ and CD14loCD16+ monocytes, and reduced their expression of CD11b, CD163, CD64, CCR2 and HLA-DR. There was reduced recruitment of monocyte/macrophages and productively infected cells in axillary lymph nodes. There was an inverse correlation between brain NAA/Cr (neuronal injury) and circulating CD14+CD16+ and CD14loCD16+ monocytes. Minocycline treatment in vitro reduced SIV replication CD16 expression on activated CD14+CD16+ monocytes, and IL-6 production by monocytes following LPS stimulation.


Conclusion

Neuroprotective effects of minocycline are due in part to reduction of activated monocytes, monocyte traffic. Mechanisms for these effects include CD16 regulation, reduced viral replication, and inhibited immune activation.

Prof Trevor Marshall
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 Posted: Sat Feb 18th, 2012 18:53

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But how do the monocytes penetrate this mythical "blood-brain barrier" :) ?
 

Jigsaw
Research Team


Joined: Thu Jul 13th, 2006
Location: Australia
Posts: 979
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 Posted: Sat Feb 18th, 2012 20:37

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The take away from these papers might be that it is not likely a smart way to purposely repress PXR as a central palliation strategy as the PXR is deeply regulated for essential and multiple purposes. If a particular drug really clobbers it, it is not likely to be a good strategy because of the side issues. Further, one should not be surprised to find such palliation via the PXR is unreliable (and such unreliability seems to be borne out by MP cohort reports). Would you say that is fair?

   
I have not thought about the possibility of repressing PXR as such, or how it could be done. I think it may be constitutive. IMO what can happen is that PXR can be programmed to act as a suppressor or as an activator of its target genes. Minocycline would also have double roles (rapid suppression of cytokines via PXR and SOCS1 and slow depletion of microbial defences by partial inhibition of their protein synthesis). With pressure from anti-microbial peptides arising from VDR activation, the latter effect could allow enough microbial damage to trigger enhanced inflammatory cytokine activity via TLRs. Having inflammatory cytokines dominant  could induce inversion of the role of PXR from activator to suppressor of SOCS1 production and the inflammation (IP) would become endemic. Removal of the mino would allow the microbes to restore their defences and the IP could ease as the source of TLR activators dried up. The preceding is part of a scenario I posted as "A mino drama in 4 Acts".  Coffee, mino & rebound IP - Prof. Marshall's Members' Only Topics - MEMBER DISCUSSION - The Marshall Protocol Study Site
   I don't think it is fair to say that palliation via PXR, if that is the way mino is really working) is unreliable if you learn to use it properly.

Last edited on Sat Feb 18th, 2012 20:44 by Jigsaw



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