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Thread: what kind of spinal injury ( disorder) would 4-ap help most

  1. #1
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    what kind of spinal injury ( disorder) would 4-ap help most

    - What type of sci would or could be mostreceptive to 4-ap?

  2. #2
    Chris, 4-AP works by increasing the excitability of demyelinated or dysmyelinated (abnormally myelinated) axons. It also increases the amount of neurotransmitters released by a action potential that arrives at the synaptic terminal. So, from this perspective, if you don't have demyelinated or dysmyelinated axons, you won't show much improvement. It may reduce spasticity (because it increases neurotransmitter release of both excitotory and inhibitory synapses below the injury site). It has been reported to reduce neuropathic pain in some earlier trials. It also has been reported to improve erections and orgasms.

    The response to 4-AP is highly variable for this reason and one of the main reasons why it is so difficult to design a rigorous clinical trial to prove its efficacy for formal clinical trial standards. For example, clinical trials require that you choose a particular outcome measure at the primary outcome of the trial, the outcome that has to reach a criterion if the trial result is to be considered as evidence for efficacy. If you choose sexual function, spasticity, motor function, sensory function, or pain... Each of these might occur in only one of out 10 people. Your trial would not reach clinical significance.

    Early on, I thought that it might be possible to screen patients with a dose of 4-AP, find out what response they have and then carry out a stratified trial that segregated patients by their initial response to the drug, and then do a randomized double-blind crossover trial to show that the drug works. However, this is frowned upon because pre-exposure to 4-AP would invalidate a person for the trial, i.e. they would know from previous experience what it felt like to take 4-AP and therefore the blind may be broken.

    This is a problem that may well crop up again with many of the other therapies for spinal cord injury. Sigh.

    Wise.

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    how do you know if you have demyeilinated axons?

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    Rationale

    If the drug does not have "lasting" effects after it wears off, what would be the rationale for Dr. Kao to prescribe the drub after the sural nerve graft?

    Eric Texley

  5. #5
    Angus, there is currently few ways of telling whether a person has demyelinated axons after spinal cord injury. If the axons are conducting but slowly, it may be possible to do a somatosensory evoked potential or motor evoked potential to assess the conduction velocity. However, an easier way to tell may be through use of 4-AP. Wise.

  6. #6
    Eric,

    I don't know why Dr. Kao is using 4-AP. I was surprised when I heard that he was using it. My guess is that Dr. Kao may have been influenced by Harry Goldsmith and J. C. De La Torre's early report of improved regeneration in animals bridged with omentum transplants... they used 4-AP in the mixture. Many scientists are skeptical about the results of that study.

    Wise.


    • Goldsmith HS and de la Torre JC (1992). Axonal regeneration after spinal cord transection and reconstruction. Brain Res. 589 (2): 217-24. Summary: Following complete transection of the spinal cord, cats were separated into 2 groups to undergo: (i) surgical reconstruction of the disconnected cord using a neuroactive agent mixed into a collagen matrix bridge and omental transposition and (ii) cord transection-only. After 90 days, animals were killed and the brain and spinal cord were removed for immunohistochemistry. Two weeks prior to sacrifice, spinal cord blood flows were measured and the retrograde axonal tracer Fluoro- Gold was injected below the transection site. Gross inspection of the spinal cords at autopsy showed excellent integration and continuity of the collagen matrix bridge with the proximal-distal stumps in the surgical reconstruction group. In the transection-only group, the proximal-distal stumps were connected by a fibrotic, often tapered in the middle, tissue bridge. Results show that omental transposition in the surgical reconstruction group increased spinal cord blood flow by 58% when compared to transection-only animals. Fluoro-Gold was found in mesencephalic and brainstem catecholaminergic and cholinergic neurons known to send axons to the spinal cord. Immunohistochemical staining with antibodies against catecholamine synthesizing enzymes tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) showed that surgical reconstruction treated cat cords but not transection-only, developed dense bundles of dopaminergic and noradrenergic fibers which were present in the collagen matrix bridge and in the distal spinal cord. Extension of these catecholaminergic fibers in surgical reconstruction treated cats showed maximal outgrowth of 90 mm below the transection site when the neuroactive agent 4-aminopyridine was mixed into the collagen matrix. In addition, the synaptogenic marker synaptophysin (SYN) was observed on preganglionic sympathetic neurons in association with dopaminergic- and noradrenergic-containing varicosities distal to the collagen matrix bridge, an indication that neo-synaptic contacts may have been made on these previously denervated neurons. No TH, DBH or SYN was observed below the transection site in transection-only cats. These findings indicate that surgical reconstruction treated cords can develop dense supraspinal fiber outgrowth across a treated collagen matrix bridge fed by an omental blood supply and that these fibers may have made neo-synaptic contacts with appropriate distal spinal cord target tissue. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=1356594> Boston University School of Medicine, Department of Surgery, MA 02118.

    [This message was edited by Wise Young on August 27, 2001 at 05:42 PM.]

  7. #7
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    Dr. Young

    I was a text book c-5,6 Quad for two months w/ slim chances of 5-10% of recovery. W/ in two months i started to get things back a a rapid fire pace. Now, a year & 8 months later I walk quite well. My sensory is around 85% complete & motor works 100%, but kind of slow. My Gait is almost normal, yet i have many deviations when i atempt to run. When I try to do things at a faster pace, everything seems to slow down. By giving my self diagnosis, I feel that i could benifit from 4-ap. Do you know whem Acordia is going into phase 3 testing of 4-ap?

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    ?????////

  9. #9
    Angus, Acorda will be meeting with the FDA soon to negotiate and finalize the details of the phase 3 trial.

    I am really glad that you have recovered so much. I assume that you received methylprednisolone after your injury. Did you get surgical decompression as well?

    Whether you will benefit from 4-AP depend on the extent of demyelination or dysmyelination you have. The symptoms of dysmyelination probably include:

    • fatigue and reduced function with higher activity levels (due to fatigue and increased refractory period)
    • possibly tremor and increased spasticity with higher activity levels (due to reduced inhibitory activity).

    But, these symptoms also may appear for other reasons, including sparse innervation.

    Wise.

  10. #10
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    Wise,

    I was given methlprednisonlone on the scene of my car accident. Then I was in a halo w/ 35lbs of traction for a day & 1/2. Followed by a spinal fusion of C-5,6.

    Those are the symptom that i have. When i work out hard, i sometimes get light headed & require a nap. I can't seem to put my finger on what is wrong w/ me, but demyelination makes sence to me.

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