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Some Risks with the use of Benicar and other ARBs with CFIDS/GWI Patients 

In 1997,  GA Rook[1] and Z. Zumla[2], University College London Medical School - UK,   suggested regimens that induce a systemic Th1 bias[3]. CFIDS is generally recognized as being a disease where the immune response favors Th2[17]. Ang II promotes a switch towards the Th1 response[21] thus decreasing it promotes a switch to the Th2 response.

Recently, Trevor Marshall, PhD (Electrical Engineering), has been stating[20] the opposite from accepted findings that CFIDS is a Th1 bias illness based on Vitamin 1,25D levels[18] and been advocating shifting towards Th2 from Th1 by decreasing Ang II. Medical staff of MarhsallProtocol.com has been asserting that CFIDS is a Th1 illness[19]. The arrival of Angiotensin Receptor Blockers (ARBs) with their apparent safety presented the opportunity to test this later interesting approach. ARBs having significant impact on inflammations indicators appears to be a significant additional clinical benefit[4] [5] [6], especially if statins are used concurrently[7] [8]. Anecdotal reports indicate significant improvement of symptoms with many CFIDS/GWI patients regardless of manipulation of Vitamin D levels[9]. Two ARBs, Candesartan and Telmisartan are particularly attractive because of their ability to cross the blood-brain-barrier[10]  [11]. Telmisartan has the greatest half-life of ARBs and thus have the  simplest dosage regimen. Recently, adverse side-effects with some patients has resulted in a careful review of the literature and found a significant risk that should be monitored for all CFIDS/GWI/FM patients taking ARBs.

It is well recognized that patients with CFIDS and related illnesses frequently suffer from aldosterone insufficiency[12] [13]. Safety testing of ARBs have been done on two populations: normal healthy patients and hypertensive patients. Hypertensive patients have higher levels of plasma renin activity and serum aldosterone levels than normal patients[14].

There are few studies on the long term impact of ARBs, one of these studies[15] found for Benicar (olmesartan):

“This study also found an increase in PRA and a decrease in plasma Ang I, Ang II and aldosterone levels during the long-term administration of olmesartan.”

The charts below shows the decreases observed over time.

A recent study[16]  on long term Benicar was done on patients with mild to moderate hypertension -- that is patients with above average levels of aldosterone.

Summary

The appropriateness of further shifting CFIDS/GWI patients further in favor of a Th2 response is very questionable especially since the basis of it is a measurement of Vitamin 1,25D. The drop of aldosterone levels is a significant concern for the treatment of CFIDS/GWI patients due to the low levels normally seen with them. A severe drop in aldosterone levels may result in (or induce) Addison Disease or other conditions. Patients should be screened for the aldosterone levels prior to commencing any ARB and at least every quarter while prescribed. If the dosage of benicar exceeds the FDA MRHD of 40mg/day, monthly testing of aldosterone levels may be advised for patients.

Incidences of this Addison Disease are being reported today, one patient experience is described at http://creatocracy.org/

Long term use of ARBs must be carefully evaluated against the potential impacts and risk of reduced plasma Ang I, Ang II and aldosterone levels in the patients being administered to.

Ken Lassesen, M.S.


[1] Department of Bacteriology, Department of Medicine, University College London Medical School, London W1P 6DB, UK

[2] Academic Infectious Diseases Unit, Department of Medicine, University College London Medical School, London W1P 6DB, UK

[3] Rook GA, Zumla A. Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile? Lancet. 1997 Jun 21;349(9068):1831-3.

[4] Fliser D, Buchholz K, Haller H; EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis (EUTOPIA) Investigators. Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation. 2004 Aug 31;110(9):1103-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15313950

[5] Sironi L, Gelosa P, Guerrini U, Banfi C, Crippa V, Brioschi M, Gianazza E, Nobili E, Gianella A, de Gasparo M, Tremoli E.  Anti-inflammatory effects of AT1 receptor blockade provide end-organ protection in stroke-prone rats independently from blood pressure fall.  J Pharmacol Exp Ther. 2004 Dec;311(3):989-95. http://www.ncbi.nlm.nih.gov/entr ez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15302895

[6] Neri Serneri GG, Boddi M, Modesti PA, Coppo M, Cecioni I, Toscano T, Papa ML, Bandinelli M, Lisi GF, Chiavarelli M. Comment on:Cardiac angiotensin II participates in coronary microvessel inflammation of unstable angina and strengthens the immunomediated component.

Circ Res. 2004 Jun 25;94(12):1530-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15131005

[7] Li Z, Iwai M, Wu L, Liu HW, Chen R, Jinno T, Suzuki J, Tsuda M, Gao XY, Okumura M, Cui TX, Horiuchi M. Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker, valsartan, on atherosclerosis. Hypertension. 2004 Nov;44(5):758-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15452025

[8] Danilo Fliser, MD; Konrad Buchholz, MD; Hermann Haller, MD, for the EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis (EUTOPIA) Investigators  Antiinflammatory Effects of Angiotensin II Subtype 1 Receptor Blockade in Hypertensive Patients With Microinflammation Circulation. 2004;110:1103-1107 http://circ.ahajournals.org/cgi/content/abstract/110/9/1103

[9] http://MarshallProtocol.com  advocates severe reduction of Vitamin D levels. Individuals who did not reduce the level of Vitamin D and individuals who increases Vitamin D levels to at least the bottom of the current optimal level of no less than 78 nmol/l (31 ng/ml) report less adverse symptoms appearing.

[10] Unger T. Blood pressure lowering and renin-angiotensin system blockade. J Hypertens Suppl. 2003 Jul;21 Suppl 6:S3-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14513945

[11] Unger T. Inhibiting angiotensin receptors in the brain: possible therapeutic implications. Curr Med Res Opin. 2003;19(5):449-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=13678486

[12] Kato Y, Kamijima S, Kashiwagi A, Oguri T. [Chronic fatigue syndrome, a case of high anti-HHV-6 antibody titer and one associated with primary hyperaldosteronism]

Nippon Rinsho. 1992 Nov;50(11):2673-8.        

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1337563

[13] De Lorenzo F, Hargreaves J, Kakkar VV.Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clin Auton Res. 1997 Aug;7(4):185-90.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9292244

[14] Hughes GS Jr, Oexmann MJ, Margolius HS, Epstein S, Bell NH Normal vitamin D and mineral metabolism in essential hypertension. Am J Med Sci. 1988 Oct;296(4):252-9  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3057908

[15] Ichikawa S, Takayama Y.  Long-term effects of olmesartan, an Ang II receptor antagonist, on blood pressure and the renin-angiotensin-aldosterone system in hypertensive patients. Hypertens Res. 2001 Nov;24(6):641-6. http://www.jstage.jst.go.jp/article/hypres/24/6/641/_pdf

[16] Brunner HR. Clinical efficacy and tolerability of olmesartan.Clin Ther. 2004;26 Suppl A:A28-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15291377

[17] Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004 Feb;135(2):294-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14738459

Ferguson E, Cassaday HJ. Theoretical accounts of Gulf War Syndrome: from environmental toxins to psychoneuroimmunology and neurodegeneration. Behav Neurol. 2001-2002;13(3-4):133-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12446953

Patarca R. Cytokines and chronic fatigue syndrome. Ann N Y Acad Sci. 2001 Mar;933:185-200.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12000020

Immunotherapy of Chronic Fatigue Syndrome: Therapeutic Interventions Aimed at Modulating the Th1/Th2 Cytokine Expression Balance, Journal of Chronic Fatigue Syndrome: Multidisciplinary Innovations in Research, Theory, and Clinical Practice, Editorial base

Paul Cheney on Th1 / Th2 Date: 7 december 2000 http://www.cfsresearch.org/cfs/cheney/19nf.htm

Klimas N. et al. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol. 1990; 28: 1403-10.

Chronic Fatigue Syndrome State of the Science Conference The U.S. Department of Health and Human Services Chronic Fatigue Syndrome Coordinating Committee October 23-24, 2000 Arlington, Virginia http://www4.od.nih.gov/orwh/state-of-science.pdf

[18] "We found that you can measure a hormone (in the blood) resulting from the Th1 inflammation produced by these tiny bacteria, and that it is elevated in Sarcoidosis patients. It is also often elevated in CFS patients, indicating that the inflammation of CFS is often very similar to that of Sarcoidosis." The Marshall Protocol for Treating Chronic Fatigue Syndrome: Interview with Trevor Marshall, Ph.D. http://www.immunesupport.com/library/showarticle.cfm/id/5784

[19] "I think most, if not all, of the CFS patients who have tested so far have been Th1 dominant." Meg Mangin R.N. Research Team on MarshallProtocol.com
http://www.marshallprotocol.com/view_topic.php?id=1495&forum_id=31&highlight=Th2

[20] "I will now state that CFS is a Th1 immune disease, bacterial in origin, and that it responds to the same antibacterial therapy as we developed for sarcoidosis. ."Trevor G Marshall, Director Autoimmunity Research Foundation, Thousand Oaks, California http://www.chronicfatiguesupport.com/library/showarticle.cfm/ID/5825/e/1/T/CFIDS_FM/
http://bmj.bmjjournals.com/cgi/eletters/329/7457/112-b#66977

[21] Tedgui and Mallat, Hypertension: A Novel Regulator of Adaptive Immunity in Atherosclerosis? Hypertension.2004; 44: 257-258. http://hyper.ahajournals.org/cgi/ content/full/hypertensionaha;44/3/257 

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