Wednesday, 30 September 2015

Potassium Channel Opener bombs in MS

Villoslada P, Rovira A, Montalban X, Arroyo R, Paul F, Meca-Lallana V, Ramo C, Fernandez O, Saiz A, Garcia-Merino A, Ramió-Torrentà L, Casanova B, Oreja-Guevara C, Muñoz D, Martinez-Rodriguez JE, Lensch E, Prieto JM, Meuth SG, Nuñez X, Campás C, Pugliese M; NeuroAdvan study. Effects of diazoxide in multiple sclerosis: A randomized, double-blind phase 2 clinical trial. Neurol Neuroimmunol Neuroinflamm. 2015 Sep 10;2(5):e147.

OBJECTIVE: The aim of this study was to test the safety of diazoxide and to search for signs of efficacy in patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS: In this multicenter, randomized, placebo-controlled, double-blind trial (treatment allocation was concealed), 102 patients with RRMS were randomized to receive a daily oral dose of diazoxide (0.3 and 4 mg/d) or placebo for 24 weeks (NCT01428726). The primary endpoint was the cumulative number of new T1 gadolinium-enhancing lesions per patient, recorded every 4 weeks from week 4 to week 24. Secondary endpoints included brain MRI variables such as the number of new/enlarging T2 lesions and the percentage brain volume change (PBVC); clinical variables such as the percentage of relapse-free patients, relapse rate, and change in the Expanded Disability Status Scale score; and safety and tolerability.
RESULTS: Diazoxide was well-tolerated and it produced no serious adverse events other than 1 case of Hashimoto disease. At the 2 doses tested, diazoxide did not improve the primary endpoint or the MRI and clinical variables related to the presence of new lesions or relapses. Patients treated with diazoxide showed reduced PBVC compared with the placebo group, although such changes could be confounded by the higher disease activity of the treated group and the vascular effects of diazoxide.
CONCLUSION: At the doses tested, oral diazoxide did not decrease the appearance of new lesions evident by MRI. The effects in slowing the progression of brain atrophy require further validation.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with RRMS, diazoxide (0.3 and 4 mg/d) does not significantly change the number of new MRI T1 gadolinium-enhancing lesions.



Diazoxide (INN; brand name Proglycem) is a potassium channel activator, which causes local relaxation in smooth muscle by increasing membrane permeability to potassium ions. This switches off voltage-gated calcium ion channels, preventing calcium flux across the sarcolemma and activation of the contractile apparatus. Diazoxide is used as a vasodilator in the treatment of acute hypertension. In this study they find no effect on inhibiting relapsing MS.

There is a thought that targeting potassium channels can block lymphocyte function.


I wonder why they would expect this...the answer is clear ......the dreaded EAE.

However, if you look at the EAE data (above), diazoxide is not really stopping the immune response, as animals are getting EAE. 


So why would you want to target relapsing MS? 
People should get MS attacks if the animal data is correct and this is what happened.

However ,the drug may influence neurodegeneration and be neuroprotective. Enhance potassium levels and it blocks too much nerve signalling..which can cause excitoxicity (nerves fire themselves to damage). The
 brain volume loss may have been protected in MS. 


So in my opinion a different trial design may have found a difference. 

Virgili N, Mancera P, Wappenhans B, Sorrosal G, Biber K, Pugliese M, Espinosa-Parrilla JF. K(ATP) channel opener diazoxide prevents neurodegeneration: a new mechanism of action via antioxidative pathway activation. PLoS One. 2013 ;8(9):e75189. 


However, this study is unlikely to be repeated as it is seen as a failure...a failure of EAE? or a failure to see what EAE can show?...

However, as we (the EAEers not TeamG) are doing EAE experiments that make it hard to dissociate immunosuppression from neuroprotection. Until people wake up and change how they do and interpret EAE experiments, this confusion and resultant failure will continue. 

Should I shut up....as this does not send out a good message about......as I am sure you will appreciate. I may suffer the consequences....However, firstly, it is an opinion and may be wrong. 

Secondly if nothing is said, nothing will change and it is more ammunition for the EAE bashers. 

People can argue otherwise if they like and say everything is great, but the truth is we have not delivered drugs to PPMSers/SPMSers. 

People can argue their case and I may be full of mushroom food, but I will say the graph above is there for everyone to see. what's your interpretation.

P.S. Note the top graph starts a 1 not 0 this is to make the small differences look bigger.

P.P.S. Yes I'm Mr. Grumpy today

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