You’re had Neuroprotectives for Years…You just don’t know it

We are desparate to produce neuroprotective drugs and todays paper reports what we have be saying from years and that you may have them already, but you just have to show it.

In 2000 we showed that cannabinoids are symptom control agents because it blocks nerves becoming over excited. This process can be damaging to nerves and therefore cannabinoids should be protective for nerves. We showed that in the beasties in 2003 and virutally everyone else generated supportive data is MS and non MS models, but unfortunately the trial in MS didn’t work….and with that was the end of the road for our cannabinoid research. This is because shit sticks and the trial failure meant no one wanted to fund this research.

However, people in the trial did not progress and other aspect that was a problems was that the trial was loaded with people who could not respond quickly. When you looked at people who were likely to progress more quickly, it was shown that there was a positive effect……Sadly Shit Sticks and the trial is simply viewed as a failure.

I wonder if baclofen treatment has similar effect, but there is no data.

Now we come to the subject of this current paper and it is nice to be proved wrong.

This work looks at the ingredient on which fampridine is based. This targets a calcium ion channel…a different one to that targeted by nimodipine and what is does is that it allows the nerve to work harder. Therefore it can damatically improve the walking ability of some people with MS. ProfG and Myself wondered whether this would be damaging to the nerve. We sugested that we could test this, but Biogen didn’t want us to go there. However todays report suggest that we

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.Dietrich M, Koska V, Hecker C, Göttle P, Hilla AM, Heskamp A, Lepka K, Issberner A, Hallenberger A, Baksmeier C, Steckel J, Balk L, Knier B, Korn T, Havla J, Martínez-Lapiscina EH, Solà-Valls N, Manogaran P, Olbert ED, Schippling S, Cruz-Herranz A, Yiu H, Button J, Caldito NG, von Gall C, Mausberg AK, Stettner M, Zimmermann HG, Paul F, Brandt AU, Küry P, Goebels N, Aktas O, Berndt C, Saidha S, Green AJ, Calabresi PA, Fischer D, Hartung HP, Albrecht P. Brain. 2020 Apr 15. pii: awaa062. doi: 10.1093/brain/awaa062. [Epub ahead of print]

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer (outer layer of the retinal where the nerve heads of the the axons in the nerve are located) was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.

The you have it in people who were treated with fampridine to improve their walking, it was looked to see if there was any influence on nerve damage. This is occurring throughout the brain and spinal cord, but it is easiest to see in the eye. As the vision pathway is affected nerves drop out. Now you may not notice this because you have capacity in the visual pathway to loose nerves. In people treated with fampridine they lost less nerves. Importantly this was seen in people where the inflammatory response was being blocked with fingolimod, I bet without it you may not see this because as all you would notice is the disease worsening and you would not seen if the value of the fampridine…..Finally I say the penny is dropping you need neuroprotective and DMT and to show a difference there needs to be enough capacity in the nervous system to show benefit. One wonders what would happen in Hand Function?

Now you need to do a formal study, will Biogen fund a study of dimethyl fumarate and fampridine?

One wonders what would happen in Hand Function?

Well the “Lord Giveth and the Lord Taketh Away”

Effects of modified-release fampridine on upper limb impairment in patients with Multiple Sclerosis. Marion S, Leonid C, Belinda B, Joanne D, Elise H, Leeanne C, Richard M. Mult Scler Relat Disord. 2020 Jan 28;40:101971. doi: 10.1016/j.msard.2020.101971. [Epub ahead of print]

BACKGROUND: Modified-release 4-aminopyridine (fampridine-MR) is used in the symptomatic treatment of walking disability in patients with multiple sclerosis (MS).  Its potential for use in other MS symptoms remains unproven and its mode of action in this context is uncertain. Interest is growing in the use of upper limb outcome measures in clinical trials in patients with Multiple Sclerosis, particularly in advanced or progressive disease.  This study tests the following hypotheses: (1) Fampridine-MR improves upper limb function in patients with MS and upper limb impairment.  (2) Treatment with fampridine-MR is associated with measurable alterations in objective electrophysiological parameters (evoked potentials and transcranial magnetic stimulation (TMS)) which may predict response to drug treatment.

METHODS:Study population: patients with MS of any disease subtype, duration and severity who have symptomatic impairment of one or both upper limbs.  A healthy control group was included for validation of clinical and electrophysiological measures.  Study design: randomised double blind placebo-controlled trial.  Treatment details: participants allocated to either fampridine-MR 10 mg bd or placebo of identical appearance for 8 weeks.  Primary outcome: performance on 9-hole peg test (9HPT) after 4 weeks.  Secondary outcomes: persistence of effect on 9HPT; grip strength; visual acuity and contrast sensitivity; modified fatigue impact scale score; sensory discrimination capacity; visual, somatosensory and motor evoked potentials; resting motor threshold; paired-pulse TMS; peripheral nerve conduction studies.

RESULTS: 40 patients with MS (60% female, median age 52, median disease duration 13.5 years, median EDSS 6.0) were enrolled.  Treatment with fampridine-MR was not associated with any change in upper limb function as measured by the clinical primary or secondary outcomes.  Treatment with fampridine-MR was also not associated with any difference in electrophysiological measures of upper limb function.  This held true after adjustment for hand dominance, disease duration and severity.  Four patients withdrew from the trial because of lack of efficacy or side-effects; all were in the placebo arm.  Three patients were admitted to hospital during the study period; one with MS exacerbation (placebo group), one with syncope (drug group) and one with UTI (drug group); otherwise there were no serious adverse events.

CONCLUSION: Treatment with fampridine-MR was well-tolerated but did not produce clinical benefit in terms of upper limb function, vision or fatigue, nor was there any measurable effect on objective electrophysiological parameters.

I wonder what neuroprotective drug would show an effect in 4 years…Remember Trials kill useful drugs.