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Thread: 4ap

  1. #1
    Member chris t4's Avatar
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    4ap

    do you think 4ap restricts the healing process of the spinal cord if it is already healing or does it contribute to it???

  2. #2
    Kris,

    There is very little empirical experience with using 4-AP in people during the first year after injury and therefore there is no data with which to answer your question. In the 1980's, there were two reports that 4-AP may be a growth factor for axons and claims that it may improve healing. However, to my knowledge, these claims were not substantiated by others in the field and the mechanisms of any early effect on healing are not well understood.

    On the other hand, there is substantial experience now in multiple animal studies and clinical trials that indicate significant beneficial effects of 4-AP on the functioning of injured axons:
    1. <LI> Improving conduction of demyelinated axons. 4-AP blocks fast voltage sensitive potassium channels on axons that are partly responsible for depressing axonal excitability. When these channels are blocked, action potentials generate more current (longer duration) and partly demyelinated or remyelinated axons can conduct signals more reliably. If a person has many demyelinated or partly remyelinated axons crossing the injury site, 4-AP should improve the ability of these axons to conduct signals. Axons should be able to conduct signals more reliably and also sustain higher frequency bursts, therefore transmitting more information. This should improve both motor and sensory function in people who have demyelinated axons crossing the injury site.

      <LI> Increasing neurotransmitter release. Increased duration of action potentials (the signals that axons conduct) also will increase the amount of neurotransmitter released by the axons if it does conduct a signal. This means that an axon has more influence on the neurons. This applies not only to axons that cross the injury site but also axons that are above and below the injury site. Above the injury site, this gives rise to some of the side-effects of 4-AP. Some people complain of nervousness, insomnia, tremor, and tingling sensations, etc. when they take the drug but these usually subside after a while. Note that it may also affect the sympathetic nervous system, including those of the bowel and bladder, and sexual function.


    Several clinical trials of 4-AP have been carried out and the results suggest that a third to half of the people show objective improvements of motor or sensory function, reduced spasticity, and even reduced neuropathic pain. On the other hand, it may "unmask" pain that may be suppressed by sensory loss. Two of the most consistent reports from previous trials are reduced spasticity and improved bowel frequency and regularity, occurring in as many as half of patients. Note that 4-AP has also been reported to improve motor and sensory function in a higher proportion of people with multiple sclerosis, which is a primary demyelinating disease.

    Sorry for all the technical terms but please ask questions about anything that might not be clear and I will try to explain further.

    Wise.

  3. #3
    Member beelady's Avatar
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    I am almost embarrassed to ask but is there a place to go to that gives the definitions of certain words that a person should know who is dealing with SCI? For instance, demyelinated, axsons, neurotransmitter, etc. I usually just skim over articles without totally understanding many terms but now I need to know. BTW, Dr. Young, Jesse is going to start 4AP as soon as he receives it. He is going to be having a phone conversation on Monday afternoon with someone. He made the contact through a Doc. he is seeing in Carlsbad. Anyway, Jess said he would be starting with immediate release, not time release. What is your opinion on the two. Sorry if this is a repeat question but he just told me Friday night that he was going to start it so now I need to read up on it.

  4. #4
    Member chris t4's Avatar
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    Dr.Wise,
    We spoke about this sometime ago,I am doing biofeedback and it shows that I have signals passing the injury site(T4)down to my hip flexors and a bit in the quads.I can remember you saying something about axons passing the injury site now,does this mean that 4AP will be of great help to me? Also, which do you think is more effective immediate release or time release and what do you think it should be compounded with?

  5. #5
    Beelady (Jesse's Mom),

    I spoke to Jesse in the chatroom. I wrote a Carecure Glossary some time ago that degines many of the terms that I used. If you lose track of this topic, the link is on the front of the cure forum as well. Let me try to define some of the terms here:
    • Action potential. These are the signals that nerve fibers conduct. These are electrical signals that are mediated by sodium and potassium ions moving across membranes.
    • Axon. These are individual nerve fibers that communicate signals from the brain to the spinal cord (motor) and from the spinal cord to the brain (sensory).
    • Conduction. This word indicates when signals travel in axons. Each axon comes from a single nerve cell situated in the brain, spinal cord, or dorsal root ganglion outside the cord.
    • Excitability. In order to conduct action potentials, axons must be "excited". This can be done either by the neuron receiving signals or by electrical stimulation of the axon.
    • Demyelinated. Injury damage oligodendroglial cells which myelinate axons. When these cells are damaged in spinal cord injury or multiple sclerosis, the axons become demyelinated.
    • Neuron. These an individual nerve cells. Each neuron receives information from numerous axons but sends an axon that may contact multiple neurons.
    • Myelin. Most long axons are myelinated, i.e. covered with layers of membrane that help insulate the axon and allow it to conduct more efficiently and rapidly.
    • Neurotransmitter. Axons communicate with neurons by releasing chemicals called neurotransmitters.
    • Potassium. This is an ion that is present in higher concentration inside the cells. Axons have potassium channels that open and allow the potassium ions out.
    • Sodium. This is an ion that is present in higher concentration outside of the cells. Axons have sodium channels that open and allow sodium channels in.
    • Sympathetic nervous system. This is the part of the nervous system that controls bowel, bladder, heart, blood vessels, and other organs.

    Not very much is known about the so-called time-release formulation from compounding pharmacies, so I can't comment.

    The immediate-release (IR) formulation is just the drug 4-aminopyridine mixed with some filler material in a capsule. When taken by mouth, it is rapidly absorbed and should reach a peak level within 30 minutes has a plasma half-life (declines to half of its peak value) in about 4 hours. Therefore, it is taken every 4-6 hours. Because the drug is immediately absorbed, it frequently goes to high peak levels and there may be some side-effects when the levels are high. The current recommended maximum dose is 10 mg four times a day. Some people push it to higher levels but this must be carefully done under supervision of an experienced physician. Because the side-effects decrease over time, it is useful to go up on the dose in steps. One approach is to take take initially one 5-mg capsule. If there is no side-effects, go to a two 5-mg capsule per day (i.e. every 12 hours), then three 5-mg capsules, and then four 5-mg capsule. If there is still no side-effects, replace one of the 5-mg capsules with a 10-mg capsule. On consecutive days, he can replace one more of the 5-mg capsules with a 10-mg capsule until he is taking 10-mg capsules every 6 hours. The timing might be adjusted a little, i.e. taking the capsules every 4 hours during the day.

    The sustained release formulation (SR) is in clinical trial right now by Acorda Therapeutics. This drug is designed to release the drug over a longer period and one needs to take only two capsules per day. Because Fampridine SR absorbs slower and over a longer period, blood levels are stable and do not reach high peaks. For that reason, higher doses can be taken with less side effects. Thus, in one of the clinical trials, people are taking 50 mg per day, i.e. two 25-mg capsules 12-hours apart. In another clinical trial, they are taking as much as 80 mg per day. Note that side-effects are more common but not inevitable at these higher doses. I am expecting the results of the Phase 3 trial of Fampridine SR to be announced by March to June. If the trial results are positive, it will hopefully to be approved by the FDA by first quarter of 2005. I am not sure what will happen during the intervening 8-9 months. It is possible that Acorda Therapeutics may enroll more patients into an open label trial.

    If the drug is ineffective or has intolerable side effects that limits the use of the drug, Jesse may have to wait until Fampridine SR becaomes available. Note that he should ramp down off the drug rather than go cold-turkey off the drug, even if the drug does not appear to be effective. If he stops the drug suddenly, he may experienced increased spasticity or spasms. In summary, if Jesse takes the immediate release formulation, he will end up taking four capsules per day after a ramp-up period of perhaps 8 days, aiming for a dose of about 40 mg per day.

    Wise.

  6. #6
    I live in southern illinois &lt;bluford> ,i cant find a doctor willing to prescribe 4-ap.Has anyone near this area found a doctor to prescribe it?

  7. #7
    Dr. Young, do serum potassium or sodium levels have any effect on the conduction potential of axons in those with some white matter preservation? In other words, could the effects of 4-AP be enhanced by lowering blood potassium levels.

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