Gibbledygook's anti-viral log

Tell us what you are using to treat your MS-- and how you are doing.

Postby CureOrBust » Tue Nov 18, 2008 6:25 pm

Dandelion contains luteolin, an antioxidant, and has demonstrated antioxidant properties without cytotoxicity
I tried a supplement called LutiMax. Its 100mg luteolin, taken 4 times a day. Its said by themselves to be "Highest single dose (100 mg) of luteolin available in the world". It wasn't cheap ($70USD for 30 days worth), but not the most expensive supplement I have ever tried either.

I personally noticed nothing change.
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Postby gibbledygook » Wed Nov 19, 2008 6:43 am

You know Cureo, I tried that supplement several years ago and noticed no improvement either. I actually think that some of these constituents may be best taken via herbs so that the constituents make it through to the blood. I think and this is just a hunch that the quercetin contained within ginkgo is delivered more effectively by ginkgo than quercetin alone.

I might try some dandelion supplements as it looks like it may do something beneficial to astrocytes and if it inhibits kallikrein that would be a boon.

Also some of the others above look interesting and so I've ordered some sample pots.
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby Wonderfulworld » Wed Nov 19, 2008 6:52 am

Hi Gibbledygook
I seem to remember dandelion decreases uric acid - so I avoided that, but I know you are looking at a different angle than uric acid=bad....
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Flu treatments and the vasculature

Postby gibbledygook » Thu Nov 20, 2008 4:05 am

well, I was really, really ill yesterday and decided to take paracetemol with codeine during the day and in the evening. My walking and stiffness was good throughout the day with a ginkgo/salvia dose of 120mg ginkgo and 1020mg salvia every 2- 3hours. I combined the evening codeine and paracetemol dose with 360mg of ginkgo and 1020mg of salvia and some curcumin. I had pretty dreadful spasms through the night but not as bad as the night of paracetamol and phenylephrine and they resolved with extra curcumin. After my morning dose of 120mg gingko and 1020mg salvia today my leg was much much stiffer than yesterday. I noted that on the packet of codeine and paracetamol there is a warning to consult the doctor if on warfarin. Now ginkgo and salvia have similar effects on the blood to warfarin. I also now see that codeine activates mast cells which is probably not what we want:
1: Anesth Analg. 2004 Feb;98(2):364-70, table of contents. Links
Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin.Blunk JA, Schmelz M, Zeck S, Skov P, Likar R, Koppert W.
Department of Anesthesiology, University Hospital, Erlangen, Germany. blunk@physiologie1.uni-erlangen.de

Activation of mast cells and the systemic release of histamine is a common side effect of opioids. Nevertheless, fentanyl and its derivatives show only a slight activation of mast cells with a subsequent liberation of histamine and tryptase. In this study, we used intradermal microdialysis to assess whether this stimulatory effect of opioids on mast cells depends on the activation of opioid receptors. This new approach allowed us to measure the dose-dependent release of histamine and tryptase from mast cells and the subsequent vascular and sensory effect without systemic side effects in volunteers. The opiate codeine and the synthetic opioids meperidine, fentanyl, alfentanil, sufentanil, remifentanil, buprenorphine, and the opioid antagonist naloxone were tested. Only codeine and meperidine induced mast cell activation with the release of tryptase and histamine, leading to protein extravasation, flare reactions, and itch sensations. Because naloxone did not attenuate these effects, it is unlikely that mu-opioid receptors are involved in the activation of mast cells. IMPLICATIONS: Opioid effects on mast cells were assessed using intradermal microdialysis. Mast cell activation was seen with codeine and meperidine; no other opioid induced degranulation. Therefore, histamine release seen at large concentrations of potent micro agonists is caused by an unspecific effect rather than an activation of opioid receptors.

PMID: 14742371 [PubMed - indexed for MEDLINE]

Related ArticlesDifferent patterns of mast cell activation by muscle relaxants in human skin. [Anesthesiology. 2001] Wheal and flare responses to opioids in humans. [Anesthesiology. 1989] ReviewMechanisms of activation of human mast cells and basophils by general anesthetic drugs. [Ann Fr Anesth Reanim. 1993] Azelastine's inhibition of histamine and tryptase release from human umbilical cord blood-derived cultured mast cells as well as rat skin mast cell-induced vascular permeability: comparison with olopatadine. [Allergy Asthma Proc. 2002] ReviewHuman skin mast cells: in vitro and in vivo studies. [Ann Allergy Asthma Immunol. 1999] » See Reviews... | » See All...
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also I see that paracetamol has inhibitory effects on the TRPV1 pathway which is activated by capsaicin, a polyphenol that I have found extremely effective in reducing mast cell activation owing to hayfever and coincidentally good for spasticity.
from wikipedia:
Further research has shown that paracetamol also modulates the endogenous cannabinoid system.[24] Paracetamol is metabolized to AM404, a compound with several actions; most important, it inhibits the uptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide uptake would result in the activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). Furthermore, AM404 inhibits sodium channels, similarly to the anesthetics lidocaine and procaine.[25] Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol, though it has been demonstrated that, after blocking cannabinoid receptors and hence making any action of cannabinoid reuptake irrelevant, paracetamol no longer has any analgesic effect, suggesting its pain-relieving action is indeed mediated by the endogenous cannabinoid system


I also see that paracetamol have blood thinning properties which may explain why one should consult a doctor when taking warfarin:
1: Prostaglandins Leukot Essent Fatty Acids. 2005 Feb;72(2):129-31. Links
In vivo endothelial interaction between ACE and COX inhibitors.Gryglewski RJ, Chlopicki S, Swies J.
Jagiellonian Medical Research Centre, Department of Experimental Pharmacology, Jagiellonian University, Poland 17 Slawkowska, 31-016 Cracow, Poland. mfgrygle@cyf-kr.edu.pl

Here we studied the mechanism of thrombolytic response (THR) induced by angiotensin converting enzyme (ACE-I) in vivo in anaesthetised Wistar rats with extracorporeal circulation. Intravenous injections of ACE-Is, i.e. perindopril or quinapril at non-hypotensive doses of 3-30 microg kg(-1) produced a dose-dependent thrombolysis that was associated with a parallel rise in arterial blood levels of 6-keto-PGF(1 alpha), but not those of TXB(2) or PGE(2). L-NAME at a dose of 5 mg kg(-1) affected significantly neither ACE-I-induced thrombolysis nor prostacyclinemia; however, the pre-treatment with icatibant (0.1-0.5 mg kg(-1)) abolished both effects. The selective COX-1 inhibitor, SC 560 (100-300 microg kg(-1) i.v.), or a would be selective COX-3 inhibitor--paracetamol (acetaminophen, 1-3 mg kg(-1)), both agents induced a transient thrombolysis and slightly potentiated thrombolysis by ACE-Is. In contrast, selective COX-2 inhibitors (rofecoxib>>celecoxib>nimesulide>NS 398) were thrombogenic, and abolished THR and rise in 6-keto-PGF(1 alpha) induced by ACE-Is. Summing up, in our in vivo bioassay system ACE-Is such as quinapril, perindopril or captopril at non-hypotensive doses evoke THR that is mediated by endogenous bradykinin and prostacyclin derived from endothelial COX-2.

PMID: 15626595 [PubMed - indexed for MEDLINE]

Related ArticlesMechanisms of angiotensin-converting enzyme inhibitor induced thrombolysis in Wistar rats. [Thromb Res. 2003] Significance of endothelial prostacyclin and nitric oxide in peripheral and pulmonary circulation. [Med Sci Monit. 2001] Signaling via the angiotensin-converting enzyme enhances the expression of cyclooxygenase-2 in endothelial cells. [Hypertension. 2005] ReviewCyclo-oxygenase-2 inhibitors: when should they be used in the elderly? [Drugs Aging. 2005] ReviewComparison of endothelial pleiotropic actions of angiotensin converting enzyme inhibitors and statins. [Ann N Y Acad Sci. 2001] » See Reviews... | » See All...
link

I think the conclusion must be to go rather more lightly on the ginkgo and salvia when combining with paracetamol and codeine. Certainly today I am backing off until my leg feels better and I am over this damned cold/flu. I simply can't go through the day without the codeine/paracetamol or maybe I should drink whiskey and lemon. Groan, sniff. cough.


This caught my eye:
1: Clin Exp Dermatol. 1996 Jan;21(1):33-7.Links
Effects of H1- and H2-antihistamines on platelet-activating factor and bradykinin-induced inflammatory responses in human skin.Sansom JE, Brooks J, Burton JL, Archer CB.
Department of Dermatology, University of Bristol, UK.

Previous studies show that oral antihistamines affect the weal and flare response to intradermal injections of the inflammatory mediators platelet-activating factor (PAF) and bradykinin (BK). The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on weal and flare responses to PAF and BK in healthy non-atopic human volunteers. The effects of doxepin on PAF responses were investigated, as there is evidence that doxepin may have direct anti-PAF effects in addition to its known antihistaminic actions. Terfenadine significantly reduced weal and flare responses to PAF (mean reduction 53 and 73%, respectively) and flare responses to BK (mean reduction 78%) but had no effect on weal responses to BK. Doxepin significantly reduced both weal and flare responses to PAF (mean reduction 43 and 68%, respectively, at higher doses of PAF). Cimetidine had no effect on weal or flare responses to PAF or BK. These findings suggest that the flare response to intradermal BK is mediated via histamine release while the weal response is not. The effects of the various antagonists of PAF-induced responses suggest that its effects too may be mediated via histamine, the similarity of the effects of terfenadine and doxepin on these responses indicating that the effects of doxepin may be due to its known antihistamine activity rather than to any specific PAF-antagonistic properties. Platelet-activating factor (PAF) is a phospholipid which is released from a wide range of cell types and also from vascular endothelium. PAF is formed by the conversion of ether-linked phospholipids initially to the biologically inactive lyso-PAF and then by acetylation to PAF. Intradermal injection of PAF in human skin causes vasodilatation and increased vascular permeability, producing a weal and flare response with accompanying pruritus. Bradykinin (BK) is a vasoactive polypeptide formed by the action of enzymes known as kallikreins on inactive precursors called kininogens. Its effects include an increase in blood flow and vascular permeability and stimulation of the release of prostaglandins and histamine. On intradermal injection in human skin it causes a weal and flare response with associated pain rather than pruritus. Previous studies have suggested that the weal and flare response to PAF may be mediated in part by histamine release. Given that BK is known to cause histamine release it appears possible that the responses to both compounds may be modified by conventional antihistamines. Experiments based on this premise have found that antihistamines have a pronounced effect on the flare response to PAF but a less marked effect on weal responses. The weal response to BK was unaffected by systemic antihistamines but studies have produced conflicting results with regard to effects on the flare response. The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on PAF- and BK-induced weal and flare responses in healthy, non-atopic human volunteers. Based on the treatment of cold urticaria it has been suggested that doxepin, which has known H1- and H2-antagonistic effects, may in addition show specific anti-PAF activity. We compared the effects of doxepin on PAF-induced intradermal responses with those of terfenadine and cimetidine in this study.

PMID: 8689766 [PubMed - indexed for MEDLINE]
link

1: Eur J Pharmacol. 2001 Oct 19;429(1-3):161-76. Links
Kinin receptors in pain and inflammation.Couture R, Harrisson M, Vianna RM, Cloutier F.
Department of Physiology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale centre-ville, Montréal, Québec, Canada H3C 3J7. couturer@physio.umontreal.ca

Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes. These short-lived peptides, including bradykinin, kallidin and T-kinin, are generated during tissue injury and noxious stimulation. However, emerging evidence also suggests that kinins are stored in neuronal elements of the central nervous system (CNS) where they are thought to play a role as neuromediators in various cerebral functions, particularly in the control of nociceptive information. Kinins exert their biological effects through the activation of two transmembrane G-protein-coupled receptors, denoted bradykinin B(1) and B(2). Whereas the B(2) receptor is constitutive and activated by the parent molecules, the B(1) receptor is generally underexpressed in normal tissues and is activated by kinins deprived of the C-terminal Arg (des-Arg(9)-kinins). The induction and increased expression of B(1) receptor occur following tissue injury or after treatment with bacterial endotoxins or cytokines such as interleukin-1 beta and tumor necrosis factor-alpha. This review summarizes the most recent data from various animal models which convey support for a role of B(2) receptors in the acute phase of the inflammatory and pain response, and for a role of B(1) receptors in the chronic phase of the response. The B(1) receptor may exert a strategic role in inflammatory diseases with an immune component (diabetes, asthma, rheumatoid arthritis and multiple sclerosis). New information is provided regarding the role of sensory mechanisms subserving spinal hyperalgesia and intrapleural neutrophil migration that occur upon B(1) receptor activation in streptozotocin-treated rats, a model of insulin-dependent diabetes mellitus in which the B(1) receptor seems to be rapidly overexpressed. Although it is widely accepted that the blockade of kinin receptors with specific antagonists could be of benefit in the treatment of somatic and visceral inflammation and pain, recent molecular and functional evidence suggests that the activation of B(1) receptors with an agonist may afford a novel therapeutic approach in the CNS inflammatory demyelinating disorder encountered in multiple sclerosis by reducing immune cell infiltration (T-lymphocytes) into the brain. Hence, the B(1) receptor may exert either a protective or detrimental effect depending on the inflammatory disease. This dual function of the B(1) receptor deserves to be investigated further.

PMID: 11698039 [PubMed - indexed for MEDLINE]
color=blue]link[/color]

1: Neurology. 1999 Dec 10;53(9):2087-92. Links
Bradykinin B1 receptor expression and function on T lymphocytes in active multiple sclerosis.Prat A, Weinrib L, Becher B, Poirier J, Duquette P, Couture R, Antel JP.
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, the Multiple Sclerosis Clinic, Montreal, Canada. aprat@po-box.mcgill.ca

BACKGROUND: Lesion development in MS is initiated by migration of inflammatory cells into the central nervous system, a process dependent on endothelial cell-lymphocyte interaction. Bradykinin B1 receptor is a membrane-bound G protein-coupled receptor shown to be upregulated on the surface of various cells types during inflammation. OBJECTIVE: To assess the expression and function of the bradykinin B1 receptor on T lymphocytes from MS patients. METHODS: The authors used multiplex polymerase chain reaction amplification and Western blot techniques to demonstrate B1 receptor expression by T cells. A modified Boyden chamber assay also was used to assess the effect of B1 agonist and antagonist on T cell migration. RESULTS: The authors demonstrated that the expression of B1 receptor was upregulated on T cells derived from peripheral blood of MS patients. Expression of this receptor was upregulated on T cells from patients with secondary progressive MS and relapsing-remitting patients in active relapse. Expression was lower in relapsing remitting patients in remission and least in control subjects, including patients with epilepsy, chronic inflammatory demyelinating polyneuritis, and systemic lupus erythematosus. In vitro treatment of cells from healthy control subjects with tumor necrosis factor-alpha and interferon-gamma also induced the expression of B1 receptors. The authors also found that the significantly higher rate of migration of MS T lymphocytes, compared with control subjects in the Boyden chamber assay, could be prevented by the addition of the selective and stable B1 agonist Sar (D-Phe8) desArg9-BK. CONCLUSION: The authors demonstrate that B1 receptors are upregulated by T lymphocytes during the course of MS and that signaling through this receptor with a B1 agonist can negatively regulate T-cell migration in vitro.

PMID: 10599786 [PubMed - indexed for MEDLINE]
link

I've still got this cold/flu thing going on but now much milder but with frequent moments of high temperature and nausea. I have, I think, discovered that further paring back the salvia and ginkgo is better for the stiffness as this morning I switched to just one ginkgo, three hours later one salvia and three hours later one ginkgo etc. This will mean I take in total 3 ginkgo or 360mg ginkgo and 3 salvia or 3060mg salvia per day. I think that my high dose ginkgo and salvia of the last few months may have altered the vasculature and that I now no longer need as much to notice a difference. The last few nights the spasms have been mild and I've been taking one ginkgo and one salvia about an hour and a half before the spasms kick in. These only last about half an hour and then the spasms die down. It's almost like the medicine is affecting the lesion sites within the first two hours and then the initial irritation dies down. I also note that a curious hypersensitivity of my tongue has died down since reducing the ginkgo. 8)

How to reduce the effects of bradykinin:
1: Eur J Pharmacol. 1995 Jan 5;272(1):87-95. Links
Inhibition of hind-paw edema and cutaneous vascular plasma extravasation in mice by acetylshikonin.Wang JP, Raung SL, Chang LC, Kuo SC.
Department of Medical Research, Taichung Veterans General Hospital, Taiwan.

Acetylshikonin, a naphthoquinone isolated from the Chinese herb medicine, tzu ts'ao, was demonstrated to inhibit the polymyxin B-induced hind-paw edema in normal as well as in adrenalectomized mice. Liver glycogen content was increased in adrenalectomized mice pretreated with dexamethasone, but not with acetylshikonin. Like diphenhydramine, methysergide and isoproterenol, acetylshikonin reduced the plasma exudation evoked in dorsal hind-paw skin by antidromic stimulation of the saphenous nerve, and in passive cutaneous anaphylactic reaction, bradykinin-, substance P-, compound 48/80-, histamine- and serotonin-induced ear edema. Indomethacin was ineffective in these respects. Bradykinin- and substance P-induced plasma exudation were also significantly reduced when [Thi5,8,D-Phe7]bradykinin and [D-Pro2,D-Trp7,9]substance P were coinjected with bradykinin and substance P, respectively. In isolated rat peritoneal mast cell preparation, acetylshikonin produced a concentration-dependent inhibition of histamine and beta-glucuronidase release from mast cells challenged by compound 48/80. In compound 48/80-pretreated mice, acetylshikonin and isoproterenol produced significantly more inhibitory effect on bradykinin- and substance P-induced plasma exudation than did diphenhydramine in combination with methysergide. Pretreatment with diphenhydramine/methysergide in compound 48/80-pretreated mice significantly further reduced the bradykinin- and substance P-induced plasma exudation if [Thi5,8,D-Phe7]bradykinin and [D-Pro2,D-Trp7,9]substance P were coinjected with bradykinin or substance P, respectively. The results suggest that the inhibitory effect of acetylshikonin on the edematous response is due neither to the release of steroid hormones from the adrenal gland nor to the glucocorticoid activity, but probably partly to the suppression of mast cell degranulation and partly to protection of the vasculature from mediator challenge.

PMID: 7536160 [PubMed - indexed for MEDLINE]
link

which plant?
Arnebia hispidissima ethanolic extract, after chromatography, yielded a number of shikonin derivatives, which were identified as arnebin-5, arnebin-6, teracryl shikonin, arnebinone and acetyl shikonin.


Arnebia is a genus of the family Boraginaceae.


Titre du document / Document title
Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human tumor necrosis factor α promoter in vivo
Auteur(s) / Author(s)
STANIFORTH Vanisree ; WANG Sheng-Yang ; SHYUR Lie-Fen ; YANG Ning-Sun ;
Résumé / Abstract
Tumor necrosis factor a (TNF-a) contributes to the pathogenesis of both acute and chronic inflammatory diseases and has been a target for the development of new anti-inflammatory drugs. Shikonins, the naphthoquinone pigments present in the root tissues of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), have been reported to exert anti-inflammatory effects both in vitro and in vivo. In this study, we evaluated the effects of shikonin and its derivatives on the transcriptional activation of human TNF-a promoter in a gene gun-transfected mouse skin system by using a luciferase reporter gene assay. The crude plant extract of L. erythrorhizon as well as derived individual compounds shikonin, isobutyryl shikonin, acetyl shikonin, dimethylacryl shikonin and isovaleryl shikonin showed significant dose-dependent inhibition of TNF-a promoter activation. Among the tested compounds, shikonin and isobutyryl shikonin exhibited the highest inhibition of TNF-a promoter activation and also showed significant suppression of transgenic human TNF-a mRNA expression and protein production. We demonstrated that shikonin-inhibitory response was retained in the core TNF-a promoter region containing the TATA box and a 48-bp downstream sequence relative to the transcription start site. Further our results indicated that shikonin suppressed the basal transcription and activator-regulated transcription of TNF-α by inhibiting the binding of transcription factor IID protein complex (TATA box-binding protein) to TATA box. These in vivo results suggest that shikonins inhibit the transcriptional activation of the human TNF-a promoter through interference with the basal transcription machinery. Thus, shikonins may have clinical potential as anti-inflammatory therapeutics.
link

1: Antimicrob Agents Chemother. 2003 Sep;47(9):2810-6. Links
Shikonin, a component of chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1.Chen X, Yang L, Zhang N, Turpin JA, Buckheit RW, Osterling C, Oppenheim JJ, Howard OM.
Basic Research Program, SAIC-Frederick, Inc, National Cancer Institute-Frederick, Frederick, Maryland 21702-1201, USA.

Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with various biological activities, including inhibition of human immunodeficiency virus (HIV) type 1 (HIV-1). G protein-coupled chemokine receptors are used by HIV-1 as coreceptors to enter the host cells. In this study, we assessed the effects of shikonin on chemokine receptor function and HIV-1 replication. The results showed that, at nanomolar concentrations, shikonin inhibited monocyte chemotaxis and calcium flux in response to a variety of CC chemokines (CCL2 [monocyte chemoattractant protein 1], CCL3 [macrophage inflammatory protein 1alpha], and CCL5 [regulated upon activation, normal T-cell expressed and secreted protein]), the CXC chemokine (CXCL12 [stromal cell-derived factor 1alpha]), and classic chemoattractants (formylmethionyl-leucine-phenylalanine and complement fraction C5a). Shikonin down-regulated surface expression of CCR5, a primary HIV-1 coreceptor, on macrophages to a greater degree than the other receptors (CCR1, CCR2, CXCR4, and the formyl peptide receptor) did. CCR5 mRNA expression was also down-regulated by the compound. Additionally, shikonin inhibited the replication of a multidrug-resistant strain and pediatric clinical isolates of HIV in human peripheral blood mononuclear cells, with 50% inhibitory concentrations (IC(50)s) ranging from 96 to 366 nM. Shikonin also effectively inhibited the replication of the HIV Ba-L isolate in monocytes/macrophages, with an IC(50) of 470 nM. Our results suggest that the anti-HIV and anti-inflammatory activities of shikonin may be related to its interference with chemokine receptor expression and function. Therefore, shikonin, as a naturally occurring, low-molecular-weight pan-chemokine receptor inhibitor, constitutes a basis for the development of novel anti-HIV therapeutic agents.

PMID: 12936978 [PubMed - indexed for MEDLINE]
link
Last edited by gibbledygook on Wed Nov 26, 2008 9:27 am, edited 2 times in total.
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby gibbledygook » Tue Nov 25, 2008 3:44 am

The pared back dose of 3 x 1020mg salvia and 3 x 120mg of ginkgo daily is proving very enjoyable for the legs with much reduced stiffness/spasticity, virtually no pain at night, much reduced night spasms. The bladder remains much more responsive as does the bowel which with a bit of extra acidophilus and a morning coffee is as regular as clockwork now. I feel 100% better than I did this time last year when I was in my 3rd year of antibiotics. I'm almost beginning to feel like I'm normal. However I haven't yet ventured forth on a walk to test my walking ability, last measured at 500 to 600meters. I may attempt the 900 meter walk to the Coffee Republic this afternoon although it is cold out and I haven't quite got rid of a nasty cold/flu bug which had me in bed for several days and on the codeine. I really do think that the combination of salvia and ginkgo is worth a shot for many with MS. I also wonder whether my initial front-loading of large doses (far larger doses than above) of these herbs means that now I need a much lower maintenance dose to feel better. At any rate this is how I feel now and I'm sure I wouldn't have pursued the vascular line of enquiry if I hadn't seen a dramatic improvement on high doses of salvia miltiorrhiza. I expect I've got from A to B far quicker than what my Chinese doctor would have imagined with the dosages he prescribes in those revolting teas. I still haven't even tried his latest concoction!

25/11/08
I just completed a brisk 400 meters outside and this felt much better than my last attempt at walking about a month ago when I only just managed 600meters. The post-walk tingle has lasted much longer than in my experiments on much higher doses of ginkgo/salvia but then again walking was harder on higher doses so maybe I shouldn't worry so much about the post-walk tingle. Tingling may not be so much a sign of existing disease activity but the evidence of lesions. But then why would high dose ginkgo/salvia stop the tingling? So tomorrow when/if it's a bit warmer or earlier in the day I shall attempt a longer walk but first I'm going to pare back even further and take one 1020mg salvia before breakfast, one 120mg ginkgo before lunch, one 1020mg salvia before supper and one 120mg ginkgo last thing at night. I think that this really must be the minimal dose now for me and that occasionally I might increase it to an alternate pill every three hours. I'm nervous of going any lower. One pill every 5 hours is probably about right. Perhaps I should take one ginkgo and one salvia every 5 hours. Well, I'll find out ove the next few days. Then I'll add back the horsechestnut!

26/11/2008
I've just remeasured my walk from yesterday and it looks more like 500meters. I am now going to attempt that twice although I feel a bit feverish. I still have the nastiest cold/flu thing going with endless snot and tissues and ear aches and etc etc.

well, 2 circuits proved a bit much mentally especially after queuing in the shop which probably added another 10 meters or so. So I did another 500 meters today without cane and, I think, without people staring too much as I was relatively smooth. I think that I am definitely going to stick to this sort of vasodilator dose for the time being. I wonder if my enjoyment of the capsaicin was down to its vasodilator activity.

15:30ish
After a bit of nourishment via egg sandwich I felt a bit better and went for another attempt. This time I succeeded! I've just managed all in one and without a cane approximately 1.1kilometers. I even think I wasn't limping too badly by the end although the last 200 meters felt pretty damn difficult. And I also avoided walking in the public bits with all the healthy people in it so felt more relaxed with my slower tempo. I haven't even attempted to walk this far in at least a year or maybe more. Last year was a disaster of relapses in the summer, autumn and early 08 spring so I definitely wasn't having much joy at walking. The last 1 kilometer I managed I promptly fell over. This was during 2007 at some point before the summer relapse. This is definitely it. Ginkgo biloba and salvia miltiorrhiza. :lol:
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby gibbledygook » Wed Nov 26, 2008 10:49 am

In addition to my success in walking over a kilometer today I have also noticed that a split capillary or vein in my hand which I have had for as long as I can remember has vanished. In a certain type of dark light I can make out a hint of diffuse red where it used to be but in bright light I can't see a thing. I used to think it was a birth mark. I have certainly had it for most of my life but now it is gone. So is the split capillary mark on my face which I had lasered ineffectually about 5 years ago. Indeed the laser treatment made it rather worse at one point! Extraordinary. The much lighter dosages of ginkgo and salvia are now producing very nice walking with hardly any spasticity on rising after prolonged sitting, good bladder control, regular bowel, rare movement induced phosphenes, milder spasms at night. Hooray!

6/12/2008
I have major computer problems owing to a trojan horse arrival a few days ago so my posting will be somewhat irregular over these next few weeks. I continue to enjoy much reduced levels of ginkgo/salvia for smoother walking and am playing around with doses of approximately 240mg ginkgo daily with up to 4080mg salvia. However the lower doses seem to result in a tendency to headache. Perhaps this is just a transitory phase as the capillaries reduce back to only a semi-dilated state. Ethanol continues to exert a disturbing effect on the regime and I continue to avoid it as far as possible in these social months. I have also started taking up to 1.5g of butcher's broom which has similar effects on the vasculature as horsechestnut but since introducing it I can't say I have noticed anything either positive or negative. The same can be said to my reintroduction of alpha lipoic acid. Previously when on high dose salvia and ginkgo the addition of alpha lipoic made my leg much stiffer. Now I take up to 750mg of alpha lipoic daily and haven't noticed much.

8/12/2008
I am now taking 3060mg salvia miltiorrhiza and 120mg of ginkgo daily with one pill approximately every 6 hours. I may add quercetin to the salvia and ginkgo. I noticed this am when I added 250mg of alpha lipoic acid about 3 hours after the salvia pill that my walking became stiffer. This is a repeat finding of a few months/weeks ago but in higher doses of each supplement. It's very odd that I find the alpha lipoic acid unhelpful. After all it inhibits all those icam/vcam baddies which allow white blood cells across the blood brain barrier. Maybe the ginkgo and salvia with a dash of curcumin is all I need!! I must say the walking has been feeling MUCH better since I lowered the doses during my recent illness. I haven't retried my kilometer walk as I rather strained my achilles tendon in the left leg and need to get that feeling better before I strain it again.

10/12/2008
I am feeling my way to an assessment of the relative strengths/weaknesses of a 1020mg pill of salvia vs a 120mg pill of ginkgo. My feeling is that 120mg of ginkgo is actually stronger and has somewhat different effects to a 1020mg pill of salvia. I am also now wondering whether combining the two every day is not so sensible so today I am going to stick with just salvia. I noted yesterday that taking 333mg of quercetin at the same time as 1020mg of salvia had no noticeably good/bad effect so will continue experimenting with that. Today I'm going to take 1020mg of salvia every 4 hours with occasional 333mg of quercetin. I continue to take curcumin, scutellaria, vitamin b, d, green tea etc.

11/12/2008
So I think after yesterday that 1020mg of salvia every 4 hours is a bit much and today I am going to lengthen the intervals to 1020mg salvia about every 8 hours or before breakfast, lunch and supper and one extra pill last thing at night. I do think it is better NOT to combine salvia and ginkgo after yesterday when all I took was salvia. Next week I'll try just ginkgo.

This evening I resumed my horsechestnut and butcher's broom experiment, taking 600mg horsechestnut and 500mg of butcher's broom at my 2nd last dose of salvia. Tomorrow I shall try these two varicose vein herbs with the salvia dose and see what happens! My leg generally feels much looser on the lower more spaced out dose and I think one pill every 8 hours is pretty optimal.
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby cheerleader » Sun Dec 14, 2008 10:40 am

Alex...where are you? Dignan has found some more research for our vascular posits. Hope all is well-
Joan

http://www.thisisms.com/ftopic-5671-day ... sc-60.html
http://jnnp.bmj.com/cgi/rapidpdf/jnnp.2008.157164v1
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby gibbledygook » Mon Dec 15, 2008 3:53 am

Wow! Great stuff. I have moved almost without break from nasty flu/cold to gastric flu/vomiting/intestinal pain etc etc AND have been fighting a trojan horse computer virus. Posting has been rather limited as a result. At least there is no sign of a relapse!

I think that horsechestnut and butcher's broom are useful aids to combat venous insufficiency and prevent vascular permeability and I take one of either horsechestnut or butcher's broom with my salvia every 6 to 8 hours. 8)
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby gibbledygook » Tue Dec 16, 2008 1:21 am

Well I'm not so sure about horsechestnut and butcher's broom. Last night I had absolutely terrible spasms which required zanaflex to calm them and a large mouthful of curcumin. This morning my leg is really quite stiff, unlike the mornings after days on just salvia. Mmm. Maybe these are too vasoconstrictive.
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Rhubarb?

Postby gibbledygook » Tue Dec 16, 2008 2:04 am

1: Zhongguo Zhong Xi Yi Jie He Za Zhi. 2006 Feb;26(2):152-6.Links
[Research on acting mechanism of rhubarb on aquaporin-4 in rats with blood-brain barrier injury after acute cerebral hemorrhage][Article in Chinese]


Tang YP, Cai DF, Liu J.
Zhongshan Hospital Affliated to Shanghai Medical College, Fudan University 200032.

OBJECTIVE: To investigate the mechanism of rhubarb in regulating aquaporin-4 in rats with blood-brain barrier damage after acute cerebral hemorrhage (CH). METHODS: CH model was induced by stereospecific injection of auto-blood into caudate nucleus of rats, and the brain water content and neurological defect were detected to evaluate cerebral edema and neurological defect level. Also, the blood-brain barrier damage was observed by Evan's blue staining; the changes of blood-brain barrier tight junction and astrocyte end feet at different time points were observed with electron microscope; and the AQP-4 mRNA and protein expression were measured with RT-PCR and Western blot. RESULTS: Rhubarb showed effects in reducing cerebral edema. Evan's blue result indicated the blood-brain barrier was evidently damaged at the 12th hour after CH, with blood-brain barrier tight junction damaged and astrocyte end feet process swelled obviously, but these changes could be relieved by rhubarb. The AQP-4 mRNA and protein expression in rats increased significantly 24 hrs after modeling (P < 0.05) and reached the peak value at 72 hrs, and decreased gradually after then. Rhubarb also showed inhibiting transcription and translation of AQP-4 gene. CONCLUSION: Rhubarb could alleviate cerebral edema via reducing blood-brain barrier tight junction damage and astrocyte end feet process swelling, which might be realized by the inhibition on transcription and translation of AQP-4 gene.

PMID: 16548359 [PubMed - indexed for MEDLINE]

Related Articles[Effect of local mild hypothermia on expression of aquaporin-4 following intracerebral hemorrhage in rats] [Zhonghua Yi Xue Za Zhi. 2006] Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. [J Neurosurg. 1994] Dexamethasone treatment modulates aquaporin-4 expression after intracerebral hemorrhage in rats. [Neurosci Lett. 2007] ReviewBlood-brain barrier breakdown in septic encephalopathy and brain tumours. [J Anat. 2002] Review[Summarization of the clinical and laboratory study on the rhubarb in treating chronic renal failure] [Zhongguo Zhong Yao Za Zhi. 2002] » See Reviews... | » See All...
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3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby gibbledygook » Tue Dec 16, 2008 3:56 am

I'm hunting around for causes and solutions to tight junction failure. This is a report about the noradrenaline pathway:
1: Eur J Neurosci. 2006 Dec;24(12):3393-400. Links
Degeneration of noradrenergic fibres from the locus coeruleus causes tight-junction disorganisation in the rat brain.Kalinin S, Feinstein DL, Xu HL, Huesa G, Pelligrino DA, Galea E.
Department of Anaesthesiology, University of Illinois at Chicago, Illinois, USA.

Although functional studies demonstrate that noradrenaline controls the permeability of the blood-brain barrier, it has never been determined whether this neurotransmitter regulates the tight junction (TJ) assembly that confers the barrier property to brain microvessels. We thus tested in rats the effect of pharmacological depletion of noradrenaline with the noradrenergic toxin DSP4 (5 mg/kg) on the expression of the TJ proteins zonula occludens-1 (ZO1) and occludin. The effectiveness of the lesion was confirmed by tyrosine hydroxylase immunoreactivity, which showed noradrenergic fibre reduction accompanied by debris and swollen fibres in DSP4-treated brains. Noradrenergic fibre degeneration caused: (i) gliosis; (ii) disappearance of TJ proteins in vascular cell-to-cell contacts (49.9 and 38.3% reductions for occludin and ZO1, respectively); (iii) a 49.2% decrease in total ZO1 protein, measured by Western blot analysis, parallel to a 39.5% decrease in ZO1 mRNA, measured by real-time PCR; and (iv) a relative increase in the beta occludin isoform (62.9%), with no change in total occludin protein or mRNA. The expression of endothelial brain antigen, a marker of a functionally competent brain endothelium, was also reduced. We conclude that damage to the ascending fibres from the locus coeruleus caused TJ disruption and gliosis, a sign of inflammation. These results imply that the locus coeruleus degeneration reported in Alzheimer's and Parkinson's diseases may contribute to these disorders by causing blood-brain barrier dysfunction. Whether the vascular damage is the result of impaired noradrenergic transmission or secondary to the inflammatory reaction remains to be determined.

PMID: 17229089 [PubMed - indexed for MEDLINE]

Related ArticlesNoradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer's disease. [J Neurosci. 2002] Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats. [Eur J Neurosci. 2003] Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice. [Glia. 2003] ReviewThe blood-brain barrier/neurovascular unit in health and disease. [Pharmacol Rev. 2005] ReviewBlood-brain barrier breakdown in septic encephalopathy and brain tumours. [J Anat. 2002] » See Reviews... | » See All...
link

this looks at levels of noradrenaline and other neurotransmitters such as serotonin which appears low:
1: J Neurochem. 2008 Nov 12. [Epub ahead of print] Links
Relationship of CSF neurotransmitter metabolite levels to disease severity and disability in multiple sclerosis.Markianos M, Koutsis G, Evangelopoulos ME, Mandellos D, Karahalios G, Sfagos C.
Department of Neurology, Athens University Medical School, Eginition Hospital, Athens, Greece.

Axonal degeneration and brain tissue loss occur during disease progression in multiple sclerosis (MS) and are expected to influence neurotransmitter activities, with consequences on neurologic and psychiatric symptomatology. We searched for relationships of disease duration, disability, and severity of MS patients to CSF levels of the major metabolites of noradrenaline, dopamine, and serotonin, MHPG, methoxyhydroxyphenylglycol (MHPG), homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA), respectively, in 39 patients with relapsing-remitting (RR) MS in remission, and 26 patients with progressive (PR) MS. Disability and Disease Severity were assessed by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). Compared with the levels of 50 control subjects, MHPG levels were not different in either MS group, correlated negatively to duration of illness and number of relapses in the RRMS group, but not to EDSS score or to MSSS. Homovanillic acid levels were significantly lower only in the PRMS group, with a negative correlation to duration of illness, and a strong negative correlation to EDSS score, but not to MSSS. 5-HIAA was significantly lower in both RRMS and PRMS groups. In the RRMS group, 5-HIAA levels were negatively related to EDSS and to MSSS. Multiple regression analyses revealed a significant association of MHPG to duration of illness, and a strong negative association of 5-HIAA to MSSS rather than to EDSS. The strong negative correlation of MSSS to CSF 5-HIAA levels in RRMS group of patients indicates that deficits in central serotonergic activity are related to the rate of disability accumulation in RRMS, and could be linked to the reported reduction of disease activity by serotonergic drugs.

PMID: 19014375 [PubMed - as supplied by publisher
link

interestingly serotonin regulates the endothelium from wikipedia:
Endothelial cell function and Serotonin
5-hydroxytryptamine evokes endothelial nitric oxide synthase activation and stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.[14]


this article states that noradrenaline downregulates cytokines in the brain:
1: Neurochem Int. 2002 Nov;41(5):357-65. Links
Noradrenergic regulation of inflammatory gene expression in brain.Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E.
Department of Anesthesiology, University of Illinois, Chicago, IL, USA. dlfeins@uic.edu

It is now well accepted that inflammatory events contribute to the pathogenesis of numerous neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease, and AID's dementia. Whereas inflammation in the periphery is subject to rapid down regulation by increases in anti-inflammatory molecules and the presence of scavenging soluble cytokine receptors, the presence of an intact blood-brain barrier may limit a similar autoregulation from occurring in brain. Mechanisms intrinsic to the brain may provide additional immunomodulatory functions, and whose dysregulation could contribute to increased inflammation in disease. The findings that noradrenaline (NA) reduces cytokine expression in microglial, astroglial, and brain endothelial cells in vitro, and that modification of the noradrenergic signaling system occurs in some brain diseases having an inflammatory component, suggests that NA could act as an endogenous immunomodulator in brain. Furthermore, accumulating studies indicate that modification of the noradrenergic signaling system occurs in some neurodiseases. In this article, we will briefly review the evidence that NA can modulate inflammatory gene expression in vitro, summarize data supporting a similar immunomodulatory role in brain, and present recent data implicating a role for NA in attenuating the cortical inflammatory response to beta amyloid protein.

PMID: 12176079 [PubMed - indexed for MEDLINE]

Related ArticlesReviewIntrinsic regulation of brain inflammatory responses. [Cell Mol Neurobiol. 2003] Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and presenilin-1 mutant transgenes. [J Neuroinflammation. 2007] Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease. [Neurobiol Aging. 2007] ReviewStructural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review. [Histol Histopathol. 2004] Noradrenergic depletion increases inflammatory responses in brain: effects on IkappaB and HSP70 expression. [J Neurochem. 2003] » See Reviews... | » See All...
link

It seems to me that we should maybe boost our noradrenaline levels, perhaps with its precursor tyrosine. Likewise a boost to serotonin with its precursors tryptophan or 5htp. I've tried the latter and noticed no difference but now I've got the salvia maybe things will come together. Hope springs eternal!

So here is shown that noradrenaline (norepinephrine is same thing) is low in Ms patients.
1: Mult Scler. 2001 Oct;7(5):327-34. Links

Comment in:
Mult Scler. 2003 Mar;9(2):216; author reply 215.
Autonomic dysfunction in multiple sclerosis is related to disease activity and progression of disability.Flachenecker P, Reiners K, Krauser M, Wolf A, Toyka KV.
Department of Neurology, Julius-Maximilians-Universität Würzburg, Germany.

BACKGROUND: Autonomic dysfunction is frequently observed in patients with multiple sclerosis (MS) but the evolution over time and the relationship to clinical characteristics are not yet established. OBJECTIVES: We investigated the correlation of disease activity and progression of disability with composite scores of cardiovascular autonomic dysfunction and serum levels of catecholamines in a cross-sectional study of patients with clinically active and clinically stable MS. In a longitudinal study of clinically active MS patients, we performed cardiovascular reflex tests for up to 2 years. METHODS: Twenty-six patients with clinically active relapsing-remitting MS, age 33.0 +/- 7.3 years, and nine patients with clinically stable MS, age 41.3 +/- 10.9 were studied. Twenty-four healthy volunteers served as controls. Standard autonomic tests were repeated at 3, 6, 12, 18 and 24 months in 18 of the 26 active patients participating in a placebo-controlled trial with interferon-beta-1a. Parasympathetic dysfunction was assessed by heart rate response to the Valsalva manoeuvre, deep breathing and active change of posture, while sympathetic dysfunction was analysed by blood pressure response to active change of posture and to sustained handgrip, and by measuring levels of norepinephrine and epinephrine in serum obtained in the supine position. RESULTS: In the cross-sectional study, the number of patients with at least one abnormal sympathetic test was higher in the 'active' patient group (39%) than in healthy controls (8%, P< 0.02) or 'stable' patients (0%, P< 0.04), while no difference was seen in the parasympathetic score. Median catecholamine levels were significantly lower in 'active' MS patients than in those with stable disease (norepinephrine, 204 ng/l (interquartile range 158-310 ng/l) vs 363 ng/l (269-507 ng/l), P<0.02 and epinephrine, 23 ng/l (16-28 ng/l) vs 32 ng/l (24-107 ng/l), P<0.04). In the subgroup of patients studied longitudinally, parasympathetic but not sympathetic dysfunction increased slightly during the follow-up period, with a significant correlation to the increase in clinical disability (r=0.7, P<0.002). No difference was seen for any of the autonomic scores between patients treated with interferon-beta (n=12) and those receiving placebo (n=6). During acute exacerbations, only parasympathetic dysfunction tended to increase in parallel with a deterioration in the EDSS. CONCLUSIONS: Parasympathetic dysfunction was closely related to the progression of disability in patients with MS. In contrast, sympathetic dysfunction was associated to the clinical activity of MS. This is in line with previous observations suggesting that the autonomic nervous system may be intimately linked with the disordered immune regulation in MS.

PMID: 11724449 [PubMed - indexed for MEDLINE
link

and in the 3rd term norepinephrine is higher along with vitamin d and cortisol:
1: J Clin Endocrinol Metab. 2001 Oct;86(10):4933-8. Links
IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times.Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S, Crane M, Kanik KS, Chrousos GP.
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ije@gunet.georgetown.edu

Clinical observations indicate that some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, frequently remit during pregnancy but exacerbate, or have their onset, in the postpartum period. The immune basis for these phenomena is poorly understood. Recently, excessive production of IL-12 and TNF-alpha was causally linked to rheumatoid arthritis and multiple sclerosis. We studied 18 women with normal pregnancies in their third trimester and during the early postpartum period. We report that during the third trimester pregnancy, ex vivo monocytic IL-12 production was about 3-fold and TNF-alpha production was approximately 40% lower than postpartum values. At the same time, urinary cortisol and norepinephrine excretion and serum levels of 1,25-dihydroxyvitamin were 2- to 3-fold higher than postpartum values. As shown previously, these hormones can directly suppress IL-12 and TNF-alpha production by monocytes/macrophages in vitro. We suggest that a cortisol-, norepinephrine-, and 1,25-dihydroxyvitamin-induced inhibition and subsequent rebound of IL-12 and TNF-alpha production may represent a major mechanism by which pregnancy and postpartum alter the course of or susceptibility to various autoimmune disorders.

PMID: 11600565 [PubMed - indexed for MEDLINE]

Related ArticlesDoes differential neuroendocrine control of cytokine production govern the expression of autoimmune diseases in pregnancy and the postpartum period? [Mol Med Today. 1997] ReviewHormonal regulation of tumor necrosis factor-alpha, interleukin-12 and interleukin-10 production by activated macrophages. A disease-modifying mechanism in rheumatoid arthritis and systemic lupus erythematosus? [Ann N Y Acad Sci. 1999] The effect of estradiol, but not progesterone, on the production of cytokines in stimulated whole blood, is concentration-dependent. [Neuro Endocrinol Lett. 2003] Stress-induced versus preovulatory and pregnancy hormonal levels in modulating cytokine production following whole blood stimulation. [Neuroimmunomodulation. 2005] ReviewHormones, pregnancy, and autoimmune diseases. [Ann N Y Acad Sci. 1998] » See Reviews... | » See All...
link

time for some berberine?
1: Eur J Pharmacol. 2008 Jul 28;589(1-3):163-72. Epub 2008 Jun 3. Links
On the mechanism of antidepressant-like action of berberine chloride.Kulkarni SK, Dhir A.
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. skpu@yahoo.com <skpu@yahoo.com>

Berberine, an alkaloid isolated from Berberis aristata Linn. has been used in the Indian system of medicines as a stomachic, bitter tonic, antiamoebic and also in the treatment of oriental sores. Evidences have demonstrated that berberine possesses central nervous system activities, particularly the ability to inhibit monoamine oxidase-A, an enzyme involved in the degradation of norepinephrine and serotonin (5-HT). With this background, the present study was carried out to elucidate the antidepressant-like effect of berberine chloride in different behavioural paradigms of despair. Berberine (5, 10, 20 mg/kg, i.p.) inhibited the immobility period in mice in both forced swim and tail-suspension test, however, the effect was not dose-dependent. Berberine (5 and 10 mg/kg, i.p.) also reversed the reserpine-induced behavioral despair. Berberine (5 mg/kg, i.p.) enhanced the anti-immobility effect of subeffective doses of various typical but not atypical antidepressant drugs in forced swim test. Berberine (5 mg/kg, i.p.) following its acute administration in mice resulted in increased levels of norepinephrine (31%), serotonin (47%) and dopamine (31%) in the whole brain. Chronic administration of berberine (5 mg/kg, i.p.) for 15 days significantly increased the levels of norepinephrine (29%), serotonin (19%) as well as dopamine (52%) but at higher dose (10 mg/kg, i.p.), there was no change in the norepinephrine (12%) levels but a significant increase in the serotonin (53%) and dopamine (31%) levels was found. The antidepressant-like effect of berberine (5 mg/kg, i.p.) in forced swim test was prevented by pretreatment with l-arginine (750 mg/kg, i.p.) or sildenafil (5 mg/kg, i.p.). On the contrary, pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, i.p.) or methylene blue (10 mg/kg, i.p.) potentiated the effect of berberine (2 mg/kg, i.p.) in the forced swim test. Pretreatment of mice with (+)-pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma1 receptor agonist, produced synergism with subeffective dose of berberine (2 mg/kg, i.p.). Pretreatment with various sigma receptor antagonists viz. progesterone (10 mg/kg, s.c.), rimcazole (5 mg/kg, i.p.) and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047; 1 mg/kg, i.p.) reversed the anti-immobility effects of berberine (5 mg/kg, i.p.). Berberine at lower dose did not affect the locomotor activity and barbiturate-induced sleep time. It produced mild hypothermic action in rats and displayed analgesic effect in mice. Taken together, theses findings demonstrate that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin and dopamine). Further, nitric oxide pathway and/or sigma receptors are involved in mediating its antidepressant-like activity in mouse forced swim test.

PMID: 18585703 [PubMed - indexed for MEDLINE]
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3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby gibbledygook » Tue Dec 16, 2008 8:08 am

Today I waited for 3 hours after my salvia dose to test the horsechestnut and 2 hours after taking the horsechestnut I noticed my bad motor leg was much stiffer. Mmm. It undoubtedly has vasoconstrictive effects which must mean that it isn't good for the MS even though it also reduces vascular permeability. But we have way too much endothelin 1 which is already a potent vasoconstrictor.

I am now testing rheum officinale or rhubarb root which looks promising in terms of healing the endothelium. It should also be good for bowel function which has become less good since reducing the salvia doses.

Wow! Well I took 600mg of rhubarb root, 600mg of berberine and 1020mg of salvia 2 hours after the horsechestnut when the leg felt much stiffer and some 2 hours later my motor function leg feels much less stiff! Amazing.
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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A superoxide dismutase setback

Postby gibbledygook » Wed Dec 24, 2008 1:41 am

I'm afraid that I am having a mini-relapse. On the 17th/18th December I started taking 500mg of superoxide dismutase in addition to the salvia, curcumin, vit d etc. There were quite a few alcoholic drinks in circulation as well. After about 4 days I stopped taking the superoxide dismutase as I feared my walking was deteriorating and yesterday there can have been no doubt. Today I am just taking plenty of curcumin and scutellaria with alpha lipoic acid at night as it makes my legs too stiff during the day. I am also being a little cautious with the salvia and took only 2040mg yesterday which I may repeat today. It seems that the superoxide dismutase and me do not get on at all. This is my 2nd relapse associated with the consumption of this antioxidant. Of course it could be something else entirely but it is a little strange that as soon as I start taking it I start feeling considerably worse. ho hum. bah humbug. At least this doesn't appear to be a major relapse and I doubt that I will need steroids. I am never going to take superoxide dismutase again.
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby gibbledygook » Mon Dec 29, 2008 12:07 pm

My mini-relapse is over after consumption of plenty of curcumin, scutellaria and inosine with a bit of alpha lipoic acid and salvia at night. I am using very little salvia now and at night as I suspect this may be a better time to take it with less pressure on the vein walls. I am now trying to unearth stuff on why I react badly to superoxide dismutase which looks like it can interrupt sp and cgrp mediated vasodilation. This research is also interesting as it brings back the question of the afferent nerves which I think may be involved in our endothelial dysfunction.


1: Cardiovasc Res. 2008 Apr 1;78(1):139-47. Epub 2008 Jan 17. Links
A reactive oxygen species-mediated component in neurogenic vasodilatation.Starr A, Graepel R, Keeble J, Schmidhuber S, Clark N, Grant A, Shah AM, Brain SD.
Cardiovascular Division, King's College London, Franklin-Wilkins Building, Waterloo Campus, London SE1 9NH, UK.

AIMS: Activation of the transient receptor potential vanilloid receptor 1 (TRPV1) leads to release of potent microvascular vasodilator neuropeptides. This study was designed to investigate in vivo mechanisms involved in TRPV1-mediated peripheral vasodilatation. METHODS AND RESULTS: Wildtype (WT) and TRPV1 knockout (KO) mice were investigated in a model of peripheral vasodilatation. Blood flow was measured by laser Doppler flowmetry under anaesthesia and following local application of the TRPV1 agonist capsaicin. A sustained (60 min) increase in blood flow was observed in WT but not TRPV1 KO mouse ears. This response was resistant to blockers of classic vasodilators but inhibited in pharmacogenetic experiments that targeted blockade of the substance P (SP) and calcitonin gene-related peptide (CGRP) pathways. The TRPV1-mediated vasodilatation was also attenuated by treatment with superoxide dismutase and the hydrogen peroxide scavenger catalase, but not by deactivated enzymes, supporting a novel role for reactive oxygen species (ROS) generation. Furthermore, neurogenic vasodilatation was observed neither in the presence of the selective NADPH inhibitor apocynin, nor in gp91 phox KO mice, under conditions where prostaglandin E1-induced vasodilatation occurred. Finally, a role of neuropeptides in initiating a ROS-dependent component was verified as superoxide dismutase, catalase, and apocynin inhibited SP and CGRP vasodilatation. CONCLUSION: These studies provide in vivo evidence that ROS are involved in mediating TRPV1- and neuropeptide-dependent neurogenic vasodilatation. An essential role of NADPH oxidase-dependent ROS is revealed that may be of fundamental importance to the neurogenic vasodilator component involved in circulatory homeostasis and the pathophysiology of certain cardiovascular diseases.

PMID: 18203709 [PubMed - indexed for MEDLINE]

Related ArticlesLoss of capsaicin-induced meningeal neurogenic sensory vasodilatation in diabetic rats. [Neuroscience. 2007] Mustard oil induces a transient receptor potential vanilloid 1 receptor-independent neurogenic inflammation and a non-neurogenic cellular inflammatory component in mice. [Neuroscience. 2004] Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin. [Mol Pain. 2007] ReviewReactive oxygen species in the cerebral circulation: are they all bad? [Antioxid Redox Signal. 2006] ReviewThe vanilloid receptor and hypertension. [Acta Pharmacol Sin. 2005] » See Reviews... | » See All... Patient Drug Information
Indomethacin (Indocin®) Indomethacin is used to relieve moderate to severe pain, tenderness, swelling, and stiffness caused by osteoarthritis (arthritis caused by a breakdown of the lining of the joints), rheumatoid arthritis (arthritis caused ... » read more ...
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Postby gibbledygook » Sat Jan 03, 2009 9:46 am

Calcification may be at the root of the stenoses. People with MS suffer more from osteoporosis:

J Neurol Sci. 2008 Oct 7. [Epub ahead of print] Links
The role of osteopontin: A shared pathway in the pathogenesis of multiple sclerosis and osteoporosis?Altıntaş A, Saruhan-Direskeneli G, Benbir G, Demir M, Purisa S.
Istanbul University Cerrahpasa School of Medicine, Department of Neurology, Istanbul, 34098, Turkey.

Osteopontin (OPN) was suggested to have a role in the pathophysiology of MS and in bone metabolism. However, we formerly reported increased presence of osteoporosis in MS patients independent of corticosteroid treatment, there is only limited information about the mechanism of bone loss. In this study, we investigated the role of OPN on bone mineral density in MS patients. Thirty-three relapsing-remitting (RR), 12 secondary progressive (SP), and 5 primary progressive (PP) MS patients and 30 healthy controls were prospectively enrolled. Students' t test, chi-square test, and Pearson correlations were used. The mean OPN level was 155.4+/-81.8 ng/ml in controls, and 15.9+/-36.2 ng/ml in MS patients (p<0.001).No statistical difference was observed among RR, SP and PPMS patients (p=0.162). No relationship was found between OPN levels and age at onset of disease (p=0.830), gender (p=0.785), MS subtypes (p=0.330), disease duration (p=0.744), or EDSS scores (p=0.633).About 34% of MS patients versus 10.3% of controls had osteoporosis (p=0.017).Osteopontin levels showed no significant correlation with osteoporosis in controls, but were lower in MS patients with osteoporosis in femur neck (r=0.85, p=0.010).The cumulative dose of corticosteroid treatment did not correlate with OPN levels (p=0.285).In conclusion, our results suggest that OPN may have a role as a shared cytokine in pathogenesis of MS and osteoporosis.

PMID: 18845306 [PubMed - as supplied by publisher]

Related ArticlesReviewMitoxantrone: a review of its use in multiple sclerosis. [CNS Drugs. 2004] Risk of bone loss in men with multiple sclerosis. [Mult Scler. 2004] Plasma osteopontin levels in multiple sclerosis. [J Neuroimmunol. 2005] Long-term effects of intravenous high dose methylprednisolone pulses on bone mineral density in patients with multiple sclerosis. [Eur J Neurol. 2005] ReviewWhat is new in the treatment of multiple sclerosis? [Drugs. 2000] » See Reviews... | » See All...
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1: J Neuroimmunol. 2005 Jan;158(1-2):231-9. Links
Plasma osteopontin levels in multiple sclerosis.Comabella M, Pericot I, Goertsches R, Nos C, Castillo M, Blas Navarro J, Río J, Montalban X.
Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron (HUVH), Escola d'Infermeria 2a planta, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain. mcomabel@vhebron.net

Osteopontin (OPN) is a pleiotropic integrin binding protein with functions in cell-mediated immunity, inflammation, tissue repair, and cell survival. Recent studies have shown that OPN may play an important role in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis (MS). Here, we investigated the plasma levels of OPN in 221 MS patients and 36 healthy controls using an enzyme-linked immunoassay. The MS group comprised of 71 patients with primary and transitional progressive MS (PP/TP-MS), 35 patients with secondary progressive MS (SPMS), and 115 patients with relapsing-remitting MS (RRMS)[46 patients during clinical remission, 26 patients during relapse, and 43 patients treated with interferon-beta (IFNbeta)]. Levels of OPN in plasma were elevated in SPMS patients compared with healthy controls, RRMS patients in remission, and PP/TP-MS patients. Patients with RRMS during relapse presented higher OPN levels than patients with RRMS during clinical remission. When MS patients were classified based on progression of neurological disability, an inverse relation between levels of OPN and disability progression was observed only in patients with relapsing MS. In RRMS patients receiving therapy with IFNbeta, OPN plasma levels were similar to RRMS patients during remission. These findings suggest that OPN is involved in both acute and chronic disease activity, thus expanding the role of OPN in MS pathogenesis suggested by previous studies. Furthermore, the different profiles of OPN levels found in acute relapses and chronic progression and its apparent lack of influence in primary progressive MS phenotypes raise interesting questions on the actual role of OPN in the pathogenesis of MS.

PMID: 15589058 [PubMed - indexed for MEDLINE]

Related ArticlesTNF-alpha converting enzyme (TACE) protein expression in different clinical subtypes of multiple sclerosis. [J Neurol. 2006] Elevated osteopontin levels in active relapsing-remitting multiple sclerosis. [Ann Neurol. 2003] Osteopontin gene haplotypes correlate with multiple sclerosis development and progression. [J Neuroimmunol. 2005] ReviewManagement of worsening multiple sclerosis with mitoxantrone: a review. [Clin Ther. 2006] ReviewClinically isolated syndromes: predicting and delaying multiple sclerosis. [Neurology. 2007] » See Reviews... | » See All...
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from wikipedia:
Secreted phosphoprotein 1 (osteopontin, bone sialoprotein I, early T-lymphocyte activation 1), also known as SPP1 and commonly referred to as osteopontin, is a human gene.[1] Osteopontin is a glycoprotein first identified in 1986 in osteoblasts. The prefix of the word "osteo" indicates that the protein is expressed in bone. The suffix "-pontin" is derived from "pons," the Latin word for bridge, and signifies osteopontin's role as a linking protein. Osteopontin is an extracellular structural protein and therefore an organic component of bone. Synonyms for this protein include sialoprotein I and 44K BPP (bone phosphoprotein).


Osteopontin is biosynthesized by a variety of tissue types including preosteoblasts, osteoblasts, osteocytes, extraosseous cells in the inner ear, brain, kidney, deciduum, placenta, odontoblasts, some bone marrow cells, hypertrophic chondrocytes, macrophages, smooth muscle, skeletal muscle myoblasts and endothelial cells. Synthesis of osteopontin is stimulated by calcitriol (1,25-dihydroxy-vitamin D3).

Osteopontin has been implicated as an important factor in bone remodeling.[2] Specifically, research suggests it plays a role in anchoring osteoclasts to the mineral matrix of bones.[3]

The organic part of bone is about 20% of the dry weight, and counts in, other than osteopontin, collagen type I, osteocalcin, osteonectin, bone sialo protein and alkaline phosphatase. Collagen type I counts for 90% of the protein mass. The inorganic part of bone is the mineral hydroxyapatite, Ca10(PO4)6(OH)2. Loss of this mineral may leads to osteoporosis, as the bone is depleted for calcium if this is not supplied in the diet.

Osteopontin (OPN) is expressed in various immune cells, including macrophages, neutrophils, dendritic cells, and T and B cells, with its timing of expression being in variety. Several levels of modulation in immune responses are recognized.[4] It has, in first, chemostatic property to promote cell recruitment to sites of inflammation. In second, it has function as an adhesion protein for cell attachment and wound healing. In third, OPN mediates cell activation and cytokine production, and in fourth, it promotes cell survival by regulating apoptosis.[4] The following examples are found.[4]

1. Chemotaxis. OPN plays an important role in neutrophil recruitment in alcoholic liver disease. [5] [6] OPN is important for the migration of neutrophil in vitro.[7] OPN recruits inflammatory cells to arthritis joints in the collagen-induced arthritis model of rheumatoid arthritis.[8] [9]

2. Adhesion of cells and wound healing. Receptors for OPN include some types of integrins [10] [11] [12] and CD44 variants.[13] [14] [15] These receptors mediate cell adhesion, migration, and survival in various cell types. That OPN interacts with multiple cell surface receptors which are ubiquitously expressed makes it an active player in many physiological and pathological processes including wound healing, bone turnover, tumorigenesis, inflammation, ischemia and immune responses.[4]

3. Cell activation and cytokine production. Activated T cells are promoted by IL-12 to differentiate towards the Th1 type, producing cytokines (IL-12, IFNγ). OPN inhibits production of the Th2 cytokine IL-10, which leads to enhanced Th1 response. OPN influences cell-mediated immunity and has Th1 cytokine functions. It enhances B cell immunoglobulin production and proliferation.[4]

4. Apoptosis. OPN is an important anti-apoptotic factor in many circumstances. OPN blocks the activation-induced cell death of macrophages and T cells as well as fibroblasts and endothelial cells exposed to harmful stimuli.[16] [17] OPN prevents non-programmed cell death in inflammatory colitis.[18]

It has been shown that osteopontin drives IL-17 production.[19]. Osteopontin is overexpressed in a variety of cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer, ovarian cancer, melanoma and mesothelioma. It may contribute to kidney stone formation and both glomerulonephritis and tubulointerstitial nephritis and is also found in atheromatous plaques within arteries.

Manipulation of plasma OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, osteoporosis and some forms of stress.[4]

Research has implicated osteopontin in excessive scar-forming and a gel has been developed to inhibit its effect


Vitamin k reduces calcification and is vital for coagulation. I believe there are coagulation issues in MS. I'm not quite sure where I'm going with all this but I think it entirely plausible that there is a build-up of calcium in parts of the vein walls within the CNS. Minimizing this might involve taking vitamin k supplements which are, according to the Life Extension Foundation's latest magazine, great for preventing osteporosis. This would also balance out the effects of the blood thinning herbs/warfarin.

1: J Vasc Surg. 2008 Jan;47(1):55-62. Links
The relationship between serum levels of vascular calcification inhibitors and carotid plaque vulnerability.Kadoglou NP, Gerasimidis T, Golemati S, Kapelouzou A, Karayannacos PE, Liapis CD.
Department of Vascular Surgery, Medical School, University of Athens, 124 Vosporou Street, Athens, Greece. nikoskad@yahoo.com

OBJECTIVE: Osteopontin (OPN) and osteoprotegerin (OPG) are well-known vascular calcification inhibitors, which have been recently demonstrated to correlate with inflammation and cardiovascular events incidence. The aim of this cross-sectional study is to survey whether OPN and OPG are involved in carotid plaque vulnerability. For this reason, we assessed serum OPN and OPG levels in patients with carotid stenosis, and we explored their relationship with carotid plaque echogenicity and subsequent cerebrovascular ischemic events. METHODS: A total of 164 Whites were selected from a large cohort of 297 subjects to participate. In particular, 114 patients (61 men, 53 women), aged 55 to 80, had recently-diagnosed ICA stenosis higher than 50%. A group of 50 age-, sex-, and body mass index (BMI)-matched healthy individuals served as healthy controls. Patients with renal failure, hypothyroidism, osteoporosis, and lipid-lowering therapy were excluded. Images of both carotids were obtained from all participants using a high-resolution color duplex ultrasound and the gray-scale median (GSM) score was calculated. Brain computed tomography (CT), and magnetic resonance imaging (MRI) scans when CT was questionable, were performed on all patients with carotid stenosis. Clinical parameters, lipid and glycemic indexes, hsCRP, fibrinogen, white blood cells (WBC) count, OPN, and OPG were measured. Independent t test, one-way ANOVA, Pearson correlation, and multiple regression analysis were used for statistical analysis. RESULTS: Among patients with carotid stenosis, 60 had history of ipsilateral stroke or TIA and positive CT or MRI findings (group A), while 54 had no neurological symptoms and negative CT and MRI scan (group B). Overall, patients with carotid stenosis showed worse lipid profile and increased waist circumference, blood pressure, hsCRP, fibrinogen, WBC count, OPN, and OPG levels compared with healthy subjects (group C) (P <.05). Statistical analysis revealed that group A had significantly lower levels of GSM than group B (57.41 +/- 38.19 vs 76.32 +/- 36.72; P = .008) and higher levels of hsCRP, OPN, and OPG than groups B and C (P < .05). Concerning the latter, biochemical markers group B showed only elevated OPG levels compared with group C (P = .038). Notably, GSM was considerably associated with serum OPN and OPG and waist circumference in patients with carotid atherosclerosis in univariate (r = -0.333; P = .032, r = -0.575; P < .001, r = -0.590; P =.006, respectively) and multiple regression analysis (R(2) = 0.445; P =.006). CONCLUSIONS: The present study demonstrated elevated serum OPN and OPG levels in patients with carotid stenosis and documented an independent association between these biochemical markers, GSM and carotid-induced symptomatology. Therefore bone-matrix proteins combined with GSM could be potential markers for vulnerable carotid plaques.

PMID: 18178454 [PubMed - indexed for MEDLINE]
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wikipedia bits on vitamin k

The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al.[17], Nelsestuen et al.[18], and Magnusson et al.[19]) isolated the vitamin K-dependent coagulation factor prothrombin (Factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that while warfarin-treated cows had a form of prothrombin that contained 10 glutamate amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues which were chemically identified as gamma-carboxyglutamate, or Gla. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.
The biochemistry of how Vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world. Within the cell, Vitamin K undergoes electron reduction to a reduced form of Vitamin K (called Vitamin K hydroquinone) by the enzyme Vitamin K epoxide reductase (or VKOR).[20] Another enzyme then oxidizes Vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase[21][22] or the Vitamin K-dependent carboxylase. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize Vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. Vitamin K epoxide is then re-converted to Vitamin K by the Vitamin K epoxide reductase. These two enzymes comprise the so-called Vitamin K cycle.[23] One of the reasons why Vitamin K is rarely deficient in a human diet is because Vitamin K is continually recycled in our cells.

Warfarin and other coumarin drugs block the action of the Vitamin K epoxide reductase.[24] This results in decreased concentrations of Vitamin K and Vitamin K hydroquinone in the tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of Warfarin will give the desired degree of suppression of the clotting, Warfarin treatment must be carefully monitored to avoid over-dosing. See Warfarin.


[edit] Gla-proteins
At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting protein Z. The bone Gla-protein osteocalcin, the calcification inhibiting matrix gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown. Gas6 can function as a growth factor that activates the Axl receptor tyrosine kinase and stimulates cell proliferation or prevents apoptosis in some cells. In all cases in which their function was known, the presence of the Gla-residues in these proteins turned out to be essential for functional activity.

Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.

Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus.[25] These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2-5 Gla residues.[26]


Perhaps statins work due to their anti-calcification processes:

1: Curr Pharm Des. 2007;13(35):3622-36. Links
Emerging indications for statins: a pluripotent family of agents with several potential applications.Paraskevas KI, Tzovaras AA, Briana DD, Mikhailidis DP.
Department of Clinical Biochemistry, Royal Free Hospital, London, UK.

Statins are pluripotent agents exhibiting multiple non-lipid-lowering actions. Besides their established role in the management of hypercholesterolemia, statins may also have beneficial actions in other pathological conditions, namely: a) osteoporosis and osteoporosis-related bone fractures, b) cancer, c) solid organ transplantation, d) cerebrovascular events (transient ischemic attack and stroke episodes), e) various neurological disorders, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, f) cardiac arrhythmias and heart failure, g) renal diseases, h) rheumatoid arthritis, i) autoimmune diseases, j) sepsis, and k) allergic asthma. We reviewed the literature searching for studies that support or oppose the use of statins in each proposed indication. In some of these emerging indications, a role for statin treatment is more firmly set; for others, current evidence is more controversial. Future trials may reveal more convincing evidence that will make statin use necessary in the therapeutic management of several diseases.

PMID: 18220799 [PubMed - indexed for MEDLINE]
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I'm adding vitamin K to my shopping list NOW!
1: Thromb Haemost. 2008 Oct;100(4):593-603. Links
Matrix Gla-protein: the calcification inhibitor in need of vitamin K.Schurgers LJ, Cranenburg EC, Vermeer C.
VitaK, Maastricht University, Universiteitssingel 50, Maastricht, The Netherlands. l.schurgers@bioch.unimaas.nl

Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. With the aid of conformation-specific antibodies MGP species in both tissue and the circulation have been detected in the healthy population, and significant differences were found in patients with cardiovascular disease (CVD). Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection. These assays may have potential value for identifying patients as well as apparently healthy subjects at high risk for CVD and/or cardiovascular calcification and for monitoring the treatment of CVD and vascular calcification.

PMID: 18841280 [PubMed - indexed for MEDLINE]

Related ArticlesPost-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. [J Thromb Haemost. 2007] Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. [Arterioscler Thromb Vasc Biol. 2005] ReviewMolecular mechanisms mediating vascular calcification: role of matrix Gla protein. [Nephrology (Carlton). 2006] The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification. [J Vasc Res. 2008] ReviewVitamin K-dependent proteins, warfarin, and vascular calcification. [Clin J Am Soc Nephrol. 2008] » See Reviews... | » See
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3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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