MMP-9s KILL the activity of ALL IFN-Betas.
It is a VERY GOOD IDEA to lower MMP-9s if taking an Ifn-Beta drug.
If you want to maximize Avonex (or any beta interferon), lowering MMP-9s will prevent it from being degraded by being cleaved into parts thus killing its Activity/Effectiveness. http://www.cnsforum.com/commenteditem/f ... fault.aspx
Also getting the most activity from the least amount of near natural (human) interferon like Avonex will usually result in MUCH LESS neutralizing antibody formation (2-5% vrs 20-26%).http://www.ncbi.nlm.nih.gov/pubmed/18035202
Clin Ther. 2007 Sep;29(9):2031-48.Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis.
Schwid SR, Panitch HS.SourceDepartment of Nuerology, University of Rochester, Rochester, New York 14642, USA. Steven.Schwid@urmc.rochester.edu
BACKGROUND: Interferon (IFN)-beta therapy represents an important advance in the management of relapsing multiple sclerosis (MS), but information about the relative benefits and risks of available preparations is limited.
OBJECTIVE: This report describes the full results of the Evidence of Interferon Dose-response-European North American Comparative Efficacy (EVIDENCE) study, combining analyses that were previously reported in separate publications for different phases of the study.
METHODS: The EVIDENCE study was a multicenter, randomized, assessor-blinded comparison of 2 IFN-beta dosing regimens. In the study, patients with relapsing MS were randomly assigned to SC IFN-beta1a 44 lag TIW (Rebif, Serono Inc., Geneva, Switzerland) or IM IFN-betala 30 mug QW (Avonex, Biogen Idec, Cambridge, Massachusetts) for 1 to 2 years. The primary clinical end point during the comparative phase was the proportion of patients who remained free from relapses; secondary and tertiary clinical end points included the annualized relapse rate and time to first relapse, re- spectively. All clinical and magnetic resonance imaging (MRI) evaluations were performed by blinded assessors. In the crossover phase of the study, patients who were originally randomized to low-dose QW treatment switched to the high-dose TIW treatment for an additional 8 months. Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase.
RESULTS: A total of 677 patients were enrolled in the study and evenly randomized to treatment; 605 patients completed the comparative phase and 439 completed the crossover phase. During the comparative phase, a significantly higher proportion of patients in the high-dose TIW treatment group remained free from relapses when compared with patients in the low-dose QW treatment group (adjusted odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.023). The high-dose TIW regimen was also associated with a significant reduction in the annualized relapse rate (-17%; P = 0.033) and a prolonged time to first relapse (hazard ratio, 0.70; P = 0.002). MRI measures of disease activity were significantly reduced in the high-dose TIW group compared with the low-dose QW treatment. During the crossover phase, a 50% reduction in mean relapse rates was observed in patients who converted from low-dose QW treatment to high-dose TIW treatment (P < 0.001), with significant concomitant reductions in MRI activity. Injection-site reactions were significantly more common with high-dose TIW treatment than with low-dose QW treatment (85% vs 33%; P < 0.001). Neutralizing antibody formation was more common with high-dose TIW treatment than with low-dose QW treatment (26% vs 3%; P < 0.001).
CONCLUSIONS: The comparative phase of the EVIDENCE study found that treatment of MS with SC IFN-beta1a 44 microg TIW was associated with a significant reduction in clinical and imaging measures of disease activity over 1 to 2 years, when compared with IM IFN-betala 30 microg QW treatment. The crossover phase found that patients who changed from low-dose QW treatment to high-dose TIW treatment experienced enhanced benefits of treatment without a substantial increase in adverse events.
PMID:18035202[PubMed - indexed for MEDLINE] Things that reduce MMP-9s (AKA gelatinase B)
***NOTE*** ( gelatinase B = MMP-9
..........................REDUCES MMP-9shttp://www.ncbi.nlm.nih.gov/pubmed/18926575VIT D3
(Grape Skin Extract) ...REDUCES MMP-9s
(NOT GRAPE SEED EXTRACT)http://www.ncbi.nlm.nih.gov/pubmed/14627504GREEN TEA EXTRACT
(EGCGs)... REDUCES MMP-9shttp://www.ncbi.nlm.nih.gov/pubmed/10719174ALPHA LIPOIC ACID (R-lipoic/ R-Dihdro-LipoicAcid)
... REDUCES MMP-9shttp://www.ncbi.nlm.nih.gov/pubmed/12458042NAC N-Acetyl-L-Cysteine
STATIN DRUGS (i.e Zocor
) .....REDUCES MMP-9shttp://www.ncbi.nlm.nih.gov/pubmed/12370451Omega-3s (ie Fish oil)
(Pine bark extract)..REDUCES MMP-9s http://www.ncbi.nlm.nih.gov/pubmed/14990359Chondroitin sulfate (CS) and CS plus glucosamine sulfate (GS)
Interferon Betas 1a/1b...........REDUCES MMP-9s
(of course Steroids ....REDUCES MMP-9s)
I have lots more information on this MMP - MS - INTERFERON-beta connection and will elaborate it if there is some interest in this subject here. For the real techie stuff check the link shown belowhttp://home.ix.netcom.com/~jdalton/Yongrev.pdf
(see fig 2 and narrative on page 505)
BIOLOGY AND PATHOLOGY OF
THE NERVOUS SYSTEMhttp://home.ix.netcom.com/~jdalton/Matr ... inases.pdf
Matrix metalloproteinases and their multiple roles in
Lancet Neurol. 2003 Dec;2(12):747-56.
Functional roles and therapeutic targeting of gelatinase B and chemokines in
Opdenakker G, Nelissen I, Van Damme J.
GO, IN, and JVD are at the Rega Institute for Medical Research, University
Multiple sclerosis (MS) is a demyelinating disease of the CNS of unknown
cause. Pathogenetic mechanisms, such as chemotaxis, subsequent activation of
autoreactive lymphocytes, and skewing of the extracellular proteinase
balance, are targets for new therapies.
Matrix metalloproteinase gelatinase B (MMP-9) is upregulated in MS and was
recently shown to degrade interferon beta, one of the drugs used to treat
Consequently, the effect of endogenously produced interferon beta or
parenterally given interferon beta may be increased by gelatinase B
inhibitors. Blockage of chemotaxis or cell adhesion molecule engagement, and
inhibition of hydoxymethyl-glutaryl-coenzyme-A reductase to lower expression
of gelatinase B, may become effective treatments of MS, alone or in
combination with interferon beta. This may allow interferon beta to be used
at lower doses and prevent side-effects.
PMID: 14636780 [PubMed - in process]
1: Brain. 2003 Jun;126(Pt 6):1371-81.
Gelatinase B/matrix metalloproteinase-9 cleaves interferon-beta and is a
target for immunotherapy.
Nelissen I, Martens E, Van den Steen PE, Proost P, Ronsse I, Opdenakker G.
Rega Institute for Medical Research, Laboratory of Molecular Immunology,
University of Leuven, Leuven, Belgium.
Parenteral administration of interferon (IFN)-beta is one of the currently
approved therapies for multiple sclerosis. One characteristic of this
disease is the increased production of gelatinase B, also called matrix
metalloproteinase (MMP) 9. Gelatinase B is capable of destroying the
blood-brain barrier, and of cleaving myelin basic protein into
immunodominant and encephalitogenic fragments, thus playing a functional
role and being a therapeutic target in multiple sclerosis. Here we
demonstrate that gelatinase B proteolytically cleaves IFN-beta, kills its
activity, and hence counteracts this cytokine as an antiviral and
immunotherapeutic agent. This proteolysis is more pronounced with
IFN-beta-1b than with IFN-beta-1a. Furthermore, the tetracycline
minocycline, which has a known blocking effect in experimental autoimmune
encephalomyelitis, an in vivo model of acute inflammation in multiple
sclerosis, and other MMP inhibitors prevent the in vitro degradation of
IFN-beta by gelatinase B. These data provide a novel mechanism and rationale
for the inhibition of gelatinase B in diseases in which IFN-beta has a
beneficial effect. The combination of gelatinase B inhibitors with better
and lower pharmacological formulations of IFN-beta may reduce the
side-effects of treatment with IFN-beta, and is therefore proposed for
multiple sclerosis therapy and the immunotherapy of viral infections.
PMID: 12764058 [PubMed - indexed for MEDLINE]
1: Neuroscientist 2002 Dec;8(6):586-95
Matrix metalloproteinases and neuroinflammation in multiple sclerosis.
Department of Neurology, University of New Mexico Health Sciences Center,
Albuquerque, New Mexico 87131, USA.
Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral proteases that are important in normal development, angiogenesis, wound repair, and a wide range of pathological processes. Growing evidence supports a key role of the MMPs in many neuroinflammatory conditions, including meningitis, encephalitis, brain tumors, cerebral ischemia, Guillain-Barre, and multiple sclerosis (MS).
The MMPs attack the basal lamina macromolecules that line the blood vessels, opening the blood-brain barrier (BBB). They contribute to the remodeling of the blood vessels that causes hyalinosis and gliosis, and they attack myelin. During the acute inflammatory phase of MS, they are involved in the injury to the blood vessels and may be important in the disruption of the myelin sheath and axons. Normally under tight regulation, excessive proteolytic activity is detected in the blood and cerebrospinal fluid in patients with acute MS. Because they are induced in immunologic and nonimmunologic forms of demyelination, they act as a final common pathway to exert a "bystander" effect. AGENTS THAT BLOCK THE ACTION OF THE MMPS HAVE BEEN SHOWN TO REDUCE THE DAMAGE TO THE BBB AND LEAD TO SYMPTOMATIC IMPROVEMENT IN SEVERAL ANIMAL MODELS OF NEUROINFLAMMATORY DISEASES, INCLUDING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS. SUCH AGENTS MAY EVENTUALLY BE USEFUL IN THE CONTROL OF EXCESSIVE PROTEOLYSIS THAT CONTRIBUTES TO THE PATHOLOGY OF MS AND OTHER NEUROINFLAMMATORY CONDITIONS.
PMID: 12467380 [PubMed - in process]