4AP
4AP Article - Posted by Goodshape - April 5, 2001
4-AP: All You Need to Know, Part One
By Wise Young, M.D., Ph.D.
4-aminopyridine, or 4-AP, is a drug that improves the function of surviving nerve fibers in your spinal cord. Most people with spinal cord injury still have some connections, but many have lost their myelin (an insulating material) and cannot conduct signals well. 4-AP allows these demyelinated axons to send signals.
The drug, not approved by the Food and Drug Administration, is available in compounding pharmacies with a doctor's prescription. A compounding pharmacy makes drugs from ingredients that doctors prescribe. The FDA allows such drugs to be made even though they have not been formally approved. A list of compounding pharmacies can be obtained from the Internet by doing a search for "compounding pharmacies."
4-AP works only while it is taken, and the effect goes away within hours after you stop. It is not an innocuous or miraculous drug. Indeed, it is a powerful substance with beneficial effects on spinal cord injury but with complex effects on the body; it also has interactions with many drugs.
An estimated 10,000 people in the United States with multiple sclerosis or spinal cord injury are taking 4-AP, yet more studies are needed to establish its safety and efficacy.
What are the effects of 4-AP?
4-AP's effects can range from reduced spasticity and pain, increases in strength and in some, walking. The worst effect is seizures, but the risk is low when dosage is kept lower than 40 milligrams per day.
Several clinical trials have reported beneficial effects of the drug in multiple sclerosis and spinal cord injury. Over 100 people with spinal cord injury have received various formulations of 4-AP in clinical trials.
It appears that about a third of people with spinal cord injury have clinically detectable improvement in spasticity or sensory, bladder, bowel or motor function. Most of these people are more than a year after injury.
Many studies have documented the effects of 4-AP on motor function in animals and humans after spinal cord injury. In 1993, Hansebout and colleagues reported that 4-AP significantly improved motor and sensory function in eight patients with chronic spinal cord injury. The drug was given intravenously over two hours. Three patients showed no effect, but the remainder had increased motor control and sensibility below the injury site, with reduction of chronic pain and spasticity. The sensory effects outlasted the motor effects by as long as 48 hours after drug infusion.
When can I expect to start feeling the effects of 4-AP?
The beneficial effects of 4-AP depend on the symptoms and the injury. Sensory improvement should be fairly rapid (within hours), while motor function may take days or weeks to appear. Spasticity changes should be fast, but bowel and bladder improvements frequently occur within days. For some people, 40 milligrams per day may not be sufficient, but if you are not seeing any beneficial effects within four weeks at 40 milligrams per day, I suggest discontinuing the drug until the sustained-release formulation is available.
Does 4-AP have side effects?
At doses of up to 40 milligrams per day, oral immediate-release formulations of 4-AP appear to have few side effects. Sustained-release formulations may allow higher doses with fewer side effects.
At high doses, 4-AP may cause hyperexcitability, dystonic movements, seizures, cardiac arrythmias, blood pressure changes and other problems that can be treated with anti-convulsants, adrenergic antagonists and parasympathetic drugs.
Almost all cases of seizures have been reported in people with multiple sclerosis; seizures have not been reported in anyone with a spinal injury. People with multiple sclerosis have a higher risk of seizures because the disease also affects the brain. People with a history of seizures, epilepsy and head injury should take 4-AP with caution.
Other side effects include restlessness, parasthesias and increased frequency of bowel movements. Most of these side effects can be avoided by ramping up the dose of 4-AP over several weeks.
What are the long-term effects of 4-AP?
The long-term effects of 4-AP have not been systematically studied. Some people, particularly in the multiple sclerosis community, have taken the drug for many years. The drug does not have carcinogenic activity in animal studies, and there has been no report of long-term deleterious consequences of the drug on the heart, liver or kidney.
How does 4-AP work?
First, it improves conduction in demyelinated and dysmyelinated (abnormally myelinated) axons. It does so by blocking the fast voltage-sensitive potassium channels in cells, including neurons, muscle and other excitable tissues. This increases both the speed and reliability of conduction, including the amount of neurotransmitter released per action potential.
What are the dangerous interactions 4-AP has with other drugs?
4-AP is not an innocuous drug. It has powerful effects on the nervous system and interacts with many drugs, including alcohol. I recommend not drinking alcohol while taking 4-AP. Ethanol depresses neuronal excitability. 4-AP may antagonize many of the effects of ethanol and vice versa. Depending on the dose, 4-AP may mask alcohol so that you do not feel the effects of alcohol as much.
Likewise, alcohol may oppose the effects of 4-AP and reduce its efficacy. Ethanol withdrawal (the hangover stage), moreover, may be associated with irritability and hyperexcitability of the brain and spinal cord, which may increase the risk of 4-AP-induced seizures. Ethanol may also change the balance of excitability and inhibitory systems that have accommodated to 4-AP.
Many other drugs may interact with 4-AP, as it antagonizes most drugs that depress the neural activity. These include tetrahydrocannabinol, anesthetic agents, neuromuscular blockers, baclofen-induced anti-nociception, and sympathetic and parasympathetic drugs that are used to treat bladder plasticity, intestinal motility, blood pressure and other conditions. Unfortunately, most of these effects of 4-AP and interactions with drugs have not been systematically studied.
How do I get 4-AP?
The drug has not yet been approved by the FDA but nonetheless can be prescribed by doctors. It is dispensed by compounding pharmacies. Note that the FDA is attempting to regulate the compounding pharmacies, and 4-AP may be one of the first drugs that the FDA may withdraw from the compounding formulary because of concerns over variable formulation.
Because many doctors have not heard of 4-aminopyridine or do not know the drug well, they are often reluctant to prescribe it. It is important that you find a doctor who is willing to read some of the literature on the drug, learn about its use and limitations, and prescribe it for you. 4-AP must be taken under a doctor's supervision.
I do not personally know doctors who are prescribing the drug in each region of the country. I am sure, however, that there are people on the interactive SpineWire forum who know doctors in each region who are experienced with 4-AP treatment.
How much does 4-AP cost?
The cost of 4-AP will depend on the amount of the drug that is taken. The prices range from $50 to $150 per month for the immediate-release formulation.
Do I need to take 4-AP under a doctor's supervision?
Many people are now experimenting with 4-AP without adequate medical supervision. More important, the information is not sufficient for many doctors to supervise the use of 4-AP. The main reason why doctors should and must be involved is that they can take care of complications if they should arise.
Is 4-AP for me?
The drug does not work for everybody. In clinical trials to date, the drug appears to improve the function of 30 to 40 percent of people with spinal cord injury. People with some preserved function below the injury tend to benefit more.
How much should I take?
The effective dose of 4-AP varies substantially from person to person, with the recommended dose at 40 milligrams per day in divided doses for safety reasons. Many factors influence a drug's effect. The compounded drug is variable in potency, and because it has a short half-life, it tends to have lower potency, especially when it is kept on the shelves for a long time.
Different people absorb different amounts of the drug when it is ingested, and its penetration into the nervous system is probably quite variable. The drugs that people are taking for spasticity and pain also affect 4-AP. Hence, the dose of the drug therefore must be carefully and individually titrated.
Some people have gone up to 60 milligrams per day, while others have success with 20. Again, 4-AP must be taken under medical supervision. Please don't keep pushing the dose higher if you get any significant side effect of the drug.
One of the reasons 4-AP is still going through clinical trials is to find out more about the optimal dose, including whether the dose should be related to body weight and if it needs to be different for men and women.
With the immediate-release formulation, 10 milligrams taken three to four times a day is the currently recommended approach. Some people are taking more, such as 15 milligrams four times per day. I do not recommend higher doses until more is known.
What are the chances that 4-AP will have any effect on me?
About a third of people with spinal cord injury show neurologically measurable beneficial effects from 4-AP. Although 4-AP is believed to have more effects on people with "incomplete" spinal cord injury, I think that it may have some effects on people with so-called "complete" spinal cord injury for the following reasons.
1. Most people have some preserved motor and sensory function below the injury site even though they have complete spinal cord injury. 4-AP should improve such function.
2. Demyelination may be the major reason why some people with spinal cord injury have functional loss. Many people with multiple sclerosis are paralyzed and have sensory loss from demyelination.
3. 4-AP does more than improve the function of demyelinated axons. It increases the amount of neurotransmitters released by axonal activity.
4. It should increase reflexes in the spinal cord. Despite this, 4-AP has beneficial effects on spasticity.
What formulations of 4-AP are available, and what effects does each have?
4-AP is available in two kinds of formulations: immediate release and timed release.
Most compounding pharmacies provide the immediate-release version, which is just the chemical 4-aminopyridine mixed with some filler material in gel caps. 4-AP reacts with many different kinds of fillers, leading to a shortened shelf life and lower potency.
For example, some formulations of 4-AP may lose as much as 10 to 20 percent of their potency per week. It is likely that many of the 4-AP pills out there do not have the potency that they are said to have.
In addition, the immediate-release formulation results in a peak plasma dose within 30 minutes. Plasma levels fall by about one-half within three to four hours. Immediate-release formulations therefore tend to produce higher peak levels and greater variations in plasma levels. Peak levels determine side effects -- one of the reasons why a sustained or timed-release formulation of the drug is desirable. In fact, with sustained-release formulations where the drug is released slowly over time, it may be possible to give two times higher doses of 4-AP with fewer side effects.
A company called Acorda Therapeutics (Note: I am a founder and a member of the scientific advisory board and board of directors of Acorda Therapeutics. Please take this into consideration when you read what I say about Acorda Therapeutics and its drugs.) is developing a time-release version of the drug.
This formulation has not yet been approved by the FDA and therefore is not available. That version of the drug is currently undergoing phase 2 clinical trials. Click here for more information.
It may take two years, depending on the current trial, for the FDA to approve Acorda’s drug. And once these trials are completed, there will be a lot of data associated with the drug to enable researchers to determine how to reduce side effects while improving efficacy.
The FDA has not, to my knowledge, decided whether it will withdraw the compounded version and replace it with the time-release version. It is difficult to predict because there is no precedent for this situation.
4-AP: All You Need to Know, Part Two
By Wise Young, M.D., Ph.D.
Is 4-AP for any certain injury level?
4-AP should work for any level of spinal cord injury, ranging from cervical to lumbar. For example, 4-AP may help somebody with a C2 injury recover respiratory function (C3), somebody with a C5 injury recover triceps and wrist extension (C6/7) or somebody with a T12 injury get bowel, bladder and sexual function. These improvements would be worthwhile.
What is ramping, and should I ramp my 4-AP dosing?
Ramping is a way to allow the body to get used to a dose, which typically takes two weeks. The goal is to reach 40 milligrams per day in four 10-milligram doses, spread four to five hours apart. I have been reluctant to give direct recommendations of dosing on a Web site, since you should work with your doctors. However, I will suggest a ramp-up schedule for the immediate-release formulation:
· 5 mg. t.i.d. (3 times a day; every 5-6 hours while awake) for 4 days = 15 mg./day
· 5 mg. q.i.d. (4 times a day; every 4-5 hours while awake) for 5 days = 20 mg./day
· 10 mg. t.i.d. (3 times a day; every 5-6 hours while awake) for 6 days = 30 mg./day
· 10 mg. q.i.d. (4 times a day; every 4-5 hours while awake) = 40 mg./day
Such an approach will get you to the 40-milligrams-per-kilogram dose in about two weeks. The approach assumes that the person does not have any side effects such as tingling, nervousness, insomnia and dizziness at any stage along the way. If there are side effects, wait until they subside before going up to the next step. It is probably a good idea for doctors prescribing 4-AP to initially order 5-milligram capsules for the ramping-up phase.
What is the most effective way to take 4-AP?
Ways to take your dose can vary. For example, I have a friend with MS who takes a 10-milligram capsule in the morning when he wakes up. He then takes one capsule just before lunch. He takes one before dinner. Depending on how late he stays up, he takes one at 10 p.m.
When are side effects most likely to occur?
The side effects should come mostly at the peak of plasma levels, which should occur within an hour of ingesting a capsule. The half-life of the drug is about three hours (the plasma drug levels fall by one-half every three to four hours). Therefore, within three hours, the effect should be waning. If you take the drug every six hours, there will be some waxing and waning of its levels. If you take it every four hours, it should maintain the plasma levels and perhaps even build up a bit during the day.
Please note that 4-AP from compounding pharmacies has a short shelf life. The drug may lose as much as 20 percent or more potency per month after it has been mixed with standard filler materials.
I find I am having trouble sleeping since I've started taking 4-AP. What can I do?
Sleeping problems are a common complaint of first-time 4-AP users. You might escape this side effect by avoiding 4-AP before sleep. Since the immediate-release version of 4-AP probably has a plasma half-life of about three hours, you should avoid taking 4-AP at least three hours before intending to sleep.
What happens if I stop taking 4-AP?
Most people who have stopped the drug show increased spasticity and pain (if they have pain). Ramp down in the same way as the ramp up. People should taper the dose over a period of a week or more to reduce the chance of effects. Interestingly, improvement in function can be subtle and difficult to appreciate until you go off the drug.
When will the FDA approve 4-AP?
It still needs to undergo pivotal trials, which may require one to two years to complete. It is not a cure, but it may help some people regain some function.
My friend lives in Russia, and he wants 4-AP. Can I buy it in the United States for him?
I believe that several compounding pharmacies will send 4-AP overseas if they get a physician's prescription for the drug. Call the compounding pharmacies and see whether or not they send overseas.
I had my injury eight months ago. Is it OK for me to take 4-AP?
There is very little experience with 4-AP in people who are less than a year after injury. In the clinical trial setting, to ensure that whatever improvements happen are due to 4-AP, most investigators have recommended waiting. I don't know of any evidence of deleterious effects of 4-AP started at eight months after injury.
Can 4-AP prevent re-myelination of the spinal cord if I undergo a re-myelination therapy?
To my knowledge, 4-AP should not prevent re-myelination of the spinal cord. However, this is something that could be tested in animal studies.
What are other uses for 4-AP?
The Russian army has been using 4-aminopyridine since the 1980s as an antidote against botulinum toxin and possibly other nerve gases. It was part of their battle kits. In fact, after 4-AP was first tested in clinical trials in Europe during the mid-1980s, when word spread in the United States that it might be beneficial in multiple sclerosis, there was no source of pharmacological grade 4-AP. I heard rumors that people were using ampules of 4-AP from Russian army kits brought in through the Czechoslovakian embassy.
You should also know that 4-AP is also the main active ingredient of poison that they use to kill pigeons in New York City.
I am noticing increased spasticity after taking 4-AP. What could this be?
4-AP has two known mechanisms of action on neural activity. First, it improves conduction in demyelinated and dysmyelinated (abnormally myelinated) axons. It does so by blocking the fast voltage-sensitive potassium channel, which normally limits the duration of action potentials that propagate in axons. This increases both the speed and reliability of conduction.
Second, it increases the duration of action potentials that reach the end of the axons. This causes more neurotransmitter release per action potential. The effects of 4-AP therefore depend on which axons are demyelinated and what remaining connections you have. If you have imbalance of excitatory and inhibitory connections to your legs, for example, 4-AP may enhance spasms.
Some drugs interact with 4-AP to produce more spasticity. If you are taking baclofen, tizanidine, clonidine and other anti-spasticity drugs, 4-AP may interact with these drugs to produce more spasticity. Interaction information is not sufficient to predict these effects. Also, individual reactions may differ.
How does 4-AP affect motor function?
Many studies have documented the effects of 4-AP on motor function in animals and humans after spinal cord injury. Besides Hansebout's trials, several other small trials have documented effects of 4-AP on motor function in spinal cord injury in humans; none has reported an increase in extensor spasms, although several subjects have reported reduced plasticity.
Qiao and colleagues, in 1997, studied the effects of 4-AP on motor-evoked potentials of subjects with chronic spinal cord injury. He showed a significant reduction in conduction latency (the time it took for the signal to go from the brain to the leg) but little change in the spinal reflex amplitudes. They concluded that the primary effect of the dose of 4-AP they used was on the conduction of signals from the brain to the spinal cord, as opposed to increased neurotransmitter release (which should be reflected in the reflex changes). Note that the doses of 4-AP used in this study were relatively low.
Dubuc and colleagues, in a 1986 study, showed that 4-AP increased rhythmic discharges from the spinal cord of cats below complete transection sites. This strongly suggests that 4-AP synchronizes the discharges of neuronal activity in the spinal cord, an effect that can override other spontaneous activity that may be occurring in the spinal cord. This may lead to spasms at rest.
Hatch and colleagues had an interesting observation that is potentially relevant. They showed that 4-AP and other excitatory drugs can reverse anesthesia in dogs. What was most fascinating was the fact that they observed opisthotonus, or extensor rigidity, in several dogs that were given combinations of excitatory drugs and were also receiving atropine.
In an early study, we found that 4-AP increases extracellular potassium levels and sensory conduction in rats that are genetically myelin deficient. Direct application of high doses of 4-AP to the rat spinal cord can cause tremors or shaking of the legs (personal observation). Very high doses (millimolar concentrations -- hundreds of times greater than therapeutic dose) can cause conduction failure in the spinal cord. So, the effects of 4-AP are very dose dependent.
4AP Article - Posted by Goodshape - April 5, 2001
4-AP: All You Need to Know, Part One
By Wise Young, M.D., Ph.D.
4-aminopyridine, or 4-AP, is a drug that improves the function of surviving nerve fibers in your spinal cord. Most people with spinal cord injury still have some connections, but many have lost their myelin (an insulating material) and cannot conduct signals well. 4-AP allows these demyelinated axons to send signals.
The drug, not approved by the Food and Drug Administration, is available in compounding pharmacies with a doctor's prescription. A compounding pharmacy makes drugs from ingredients that doctors prescribe. The FDA allows such drugs to be made even though they have not been formally approved. A list of compounding pharmacies can be obtained from the Internet by doing a search for "compounding pharmacies."
4-AP works only while it is taken, and the effect goes away within hours after you stop. It is not an innocuous or miraculous drug. Indeed, it is a powerful substance with beneficial effects on spinal cord injury but with complex effects on the body; it also has interactions with many drugs.
An estimated 10,000 people in the United States with multiple sclerosis or spinal cord injury are taking 4-AP, yet more studies are needed to establish its safety and efficacy.
What are the effects of 4-AP?
4-AP's effects can range from reduced spasticity and pain, increases in strength and in some, walking. The worst effect is seizures, but the risk is low when dosage is kept lower than 40 milligrams per day.
Several clinical trials have reported beneficial effects of the drug in multiple sclerosis and spinal cord injury. Over 100 people with spinal cord injury have received various formulations of 4-AP in clinical trials.
It appears that about a third of people with spinal cord injury have clinically detectable improvement in spasticity or sensory, bladder, bowel or motor function. Most of these people are more than a year after injury.
Many studies have documented the effects of 4-AP on motor function in animals and humans after spinal cord injury. In 1993, Hansebout and colleagues reported that 4-AP significantly improved motor and sensory function in eight patients with chronic spinal cord injury. The drug was given intravenously over two hours. Three patients showed no effect, but the remainder had increased motor control and sensibility below the injury site, with reduction of chronic pain and spasticity. The sensory effects outlasted the motor effects by as long as 48 hours after drug infusion.
When can I expect to start feeling the effects of 4-AP?
The beneficial effects of 4-AP depend on the symptoms and the injury. Sensory improvement should be fairly rapid (within hours), while motor function may take days or weeks to appear. Spasticity changes should be fast, but bowel and bladder improvements frequently occur within days. For some people, 40 milligrams per day may not be sufficient, but if you are not seeing any beneficial effects within four weeks at 40 milligrams per day, I suggest discontinuing the drug until the sustained-release formulation is available.
Does 4-AP have side effects?
At doses of up to 40 milligrams per day, oral immediate-release formulations of 4-AP appear to have few side effects. Sustained-release formulations may allow higher doses with fewer side effects.
At high doses, 4-AP may cause hyperexcitability, dystonic movements, seizures, cardiac arrythmias, blood pressure changes and other problems that can be treated with anti-convulsants, adrenergic antagonists and parasympathetic drugs.
Almost all cases of seizures have been reported in people with multiple sclerosis; seizures have not been reported in anyone with a spinal injury. People with multiple sclerosis have a higher risk of seizures because the disease also affects the brain. People with a history of seizures, epilepsy and head injury should take 4-AP with caution.
Other side effects include restlessness, parasthesias and increased frequency of bowel movements. Most of these side effects can be avoided by ramping up the dose of 4-AP over several weeks.
What are the long-term effects of 4-AP?
The long-term effects of 4-AP have not been systematically studied. Some people, particularly in the multiple sclerosis community, have taken the drug for many years. The drug does not have carcinogenic activity in animal studies, and there has been no report of long-term deleterious consequences of the drug on the heart, liver or kidney.
How does 4-AP work?
First, it improves conduction in demyelinated and dysmyelinated (abnormally myelinated) axons. It does so by blocking the fast voltage-sensitive potassium channels in cells, including neurons, muscle and other excitable tissues. This increases both the speed and reliability of conduction, including the amount of neurotransmitter released per action potential.
What are the dangerous interactions 4-AP has with other drugs?
4-AP is not an innocuous drug. It has powerful effects on the nervous system and interacts with many drugs, including alcohol. I recommend not drinking alcohol while taking 4-AP. Ethanol depresses neuronal excitability. 4-AP may antagonize many of the effects of ethanol and vice versa. Depending on the dose, 4-AP may mask alcohol so that you do not feel the effects of alcohol as much.
Likewise, alcohol may oppose the effects of 4-AP and reduce its efficacy. Ethanol withdrawal (the hangover stage), moreover, may be associated with irritability and hyperexcitability of the brain and spinal cord, which may increase the risk of 4-AP-induced seizures. Ethanol may also change the balance of excitability and inhibitory systems that have accommodated to 4-AP.
Many other drugs may interact with 4-AP, as it antagonizes most drugs that depress the neural activity. These include tetrahydrocannabinol, anesthetic agents, neuromuscular blockers, baclofen-induced anti-nociception, and sympathetic and parasympathetic drugs that are used to treat bladder plasticity, intestinal motility, blood pressure and other conditions. Unfortunately, most of these effects of 4-AP and interactions with drugs have not been systematically studied.
How do I get 4-AP?
The drug has not yet been approved by the FDA but nonetheless can be prescribed by doctors. It is dispensed by compounding pharmacies. Note that the FDA is attempting to regulate the compounding pharmacies, and 4-AP may be one of the first drugs that the FDA may withdraw from the compounding formulary because of concerns over variable formulation.
Because many doctors have not heard of 4-aminopyridine or do not know the drug well, they are often reluctant to prescribe it. It is important that you find a doctor who is willing to read some of the literature on the drug, learn about its use and limitations, and prescribe it for you. 4-AP must be taken under a doctor's supervision.
I do not personally know doctors who are prescribing the drug in each region of the country. I am sure, however, that there are people on the interactive SpineWire forum who know doctors in each region who are experienced with 4-AP treatment.
How much does 4-AP cost?
The cost of 4-AP will depend on the amount of the drug that is taken. The prices range from $50 to $150 per month for the immediate-release formulation.
Do I need to take 4-AP under a doctor's supervision?
Many people are now experimenting with 4-AP without adequate medical supervision. More important, the information is not sufficient for many doctors to supervise the use of 4-AP. The main reason why doctors should and must be involved is that they can take care of complications if they should arise.
Is 4-AP for me?
The drug does not work for everybody. In clinical trials to date, the drug appears to improve the function of 30 to 40 percent of people with spinal cord injury. People with some preserved function below the injury tend to benefit more.
How much should I take?
The effective dose of 4-AP varies substantially from person to person, with the recommended dose at 40 milligrams per day in divided doses for safety reasons. Many factors influence a drug's effect. The compounded drug is variable in potency, and because it has a short half-life, it tends to have lower potency, especially when it is kept on the shelves for a long time.
Different people absorb different amounts of the drug when it is ingested, and its penetration into the nervous system is probably quite variable. The drugs that people are taking for spasticity and pain also affect 4-AP. Hence, the dose of the drug therefore must be carefully and individually titrated.
Some people have gone up to 60 milligrams per day, while others have success with 20. Again, 4-AP must be taken under medical supervision. Please don't keep pushing the dose higher if you get any significant side effect of the drug.
One of the reasons 4-AP is still going through clinical trials is to find out more about the optimal dose, including whether the dose should be related to body weight and if it needs to be different for men and women.
With the immediate-release formulation, 10 milligrams taken three to four times a day is the currently recommended approach. Some people are taking more, such as 15 milligrams four times per day. I do not recommend higher doses until more is known.
What are the chances that 4-AP will have any effect on me?
About a third of people with spinal cord injury show neurologically measurable beneficial effects from 4-AP. Although 4-AP is believed to have more effects on people with "incomplete" spinal cord injury, I think that it may have some effects on people with so-called "complete" spinal cord injury for the following reasons.
1. Most people have some preserved motor and sensory function below the injury site even though they have complete spinal cord injury. 4-AP should improve such function.
2. Demyelination may be the major reason why some people with spinal cord injury have functional loss. Many people with multiple sclerosis are paralyzed and have sensory loss from demyelination.
3. 4-AP does more than improve the function of demyelinated axons. It increases the amount of neurotransmitters released by axonal activity.
4. It should increase reflexes in the spinal cord. Despite this, 4-AP has beneficial effects on spasticity.
What formulations of 4-AP are available, and what effects does each have?
4-AP is available in two kinds of formulations: immediate release and timed release.
Most compounding pharmacies provide the immediate-release version, which is just the chemical 4-aminopyridine mixed with some filler material in gel caps. 4-AP reacts with many different kinds of fillers, leading to a shortened shelf life and lower potency.
For example, some formulations of 4-AP may lose as much as 10 to 20 percent of their potency per week. It is likely that many of the 4-AP pills out there do not have the potency that they are said to have.
In addition, the immediate-release formulation results in a peak plasma dose within 30 minutes. Plasma levels fall by about one-half within three to four hours. Immediate-release formulations therefore tend to produce higher peak levels and greater variations in plasma levels. Peak levels determine side effects -- one of the reasons why a sustained or timed-release formulation of the drug is desirable. In fact, with sustained-release formulations where the drug is released slowly over time, it may be possible to give two times higher doses of 4-AP with fewer side effects.
A company called Acorda Therapeutics (Note: I am a founder and a member of the scientific advisory board and board of directors of Acorda Therapeutics. Please take this into consideration when you read what I say about Acorda Therapeutics and its drugs.) is developing a time-release version of the drug.
This formulation has not yet been approved by the FDA and therefore is not available. That version of the drug is currently undergoing phase 2 clinical trials. Click here for more information.
It may take two years, depending on the current trial, for the FDA to approve Acorda’s drug. And once these trials are completed, there will be a lot of data associated with the drug to enable researchers to determine how to reduce side effects while improving efficacy.
The FDA has not, to my knowledge, decided whether it will withdraw the compounded version and replace it with the time-release version. It is difficult to predict because there is no precedent for this situation.
4-AP: All You Need to Know, Part Two
By Wise Young, M.D., Ph.D.
Is 4-AP for any certain injury level?
4-AP should work for any level of spinal cord injury, ranging from cervical to lumbar. For example, 4-AP may help somebody with a C2 injury recover respiratory function (C3), somebody with a C5 injury recover triceps and wrist extension (C6/7) or somebody with a T12 injury get bowel, bladder and sexual function. These improvements would be worthwhile.
What is ramping, and should I ramp my 4-AP dosing?
Ramping is a way to allow the body to get used to a dose, which typically takes two weeks. The goal is to reach 40 milligrams per day in four 10-milligram doses, spread four to five hours apart. I have been reluctant to give direct recommendations of dosing on a Web site, since you should work with your doctors. However, I will suggest a ramp-up schedule for the immediate-release formulation:
· 5 mg. t.i.d. (3 times a day; every 5-6 hours while awake) for 4 days = 15 mg./day
· 5 mg. q.i.d. (4 times a day; every 4-5 hours while awake) for 5 days = 20 mg./day
· 10 mg. t.i.d. (3 times a day; every 5-6 hours while awake) for 6 days = 30 mg./day
· 10 mg. q.i.d. (4 times a day; every 4-5 hours while awake) = 40 mg./day
Such an approach will get you to the 40-milligrams-per-kilogram dose in about two weeks. The approach assumes that the person does not have any side effects such as tingling, nervousness, insomnia and dizziness at any stage along the way. If there are side effects, wait until they subside before going up to the next step. It is probably a good idea for doctors prescribing 4-AP to initially order 5-milligram capsules for the ramping-up phase.
What is the most effective way to take 4-AP?
Ways to take your dose can vary. For example, I have a friend with MS who takes a 10-milligram capsule in the morning when he wakes up. He then takes one capsule just before lunch. He takes one before dinner. Depending on how late he stays up, he takes one at 10 p.m.
When are side effects most likely to occur?
The side effects should come mostly at the peak of plasma levels, which should occur within an hour of ingesting a capsule. The half-life of the drug is about three hours (the plasma drug levels fall by one-half every three to four hours). Therefore, within three hours, the effect should be waning. If you take the drug every six hours, there will be some waxing and waning of its levels. If you take it every four hours, it should maintain the plasma levels and perhaps even build up a bit during the day.
Please note that 4-AP from compounding pharmacies has a short shelf life. The drug may lose as much as 20 percent or more potency per month after it has been mixed with standard filler materials.
I find I am having trouble sleeping since I've started taking 4-AP. What can I do?
Sleeping problems are a common complaint of first-time 4-AP users. You might escape this side effect by avoiding 4-AP before sleep. Since the immediate-release version of 4-AP probably has a plasma half-life of about three hours, you should avoid taking 4-AP at least three hours before intending to sleep.
What happens if I stop taking 4-AP?
Most people who have stopped the drug show increased spasticity and pain (if they have pain). Ramp down in the same way as the ramp up. People should taper the dose over a period of a week or more to reduce the chance of effects. Interestingly, improvement in function can be subtle and difficult to appreciate until you go off the drug.
When will the FDA approve 4-AP?
It still needs to undergo pivotal trials, which may require one to two years to complete. It is not a cure, but it may help some people regain some function.
My friend lives in Russia, and he wants 4-AP. Can I buy it in the United States for him?
I believe that several compounding pharmacies will send 4-AP overseas if they get a physician's prescription for the drug. Call the compounding pharmacies and see whether or not they send overseas.
I had my injury eight months ago. Is it OK for me to take 4-AP?
There is very little experience with 4-AP in people who are less than a year after injury. In the clinical trial setting, to ensure that whatever improvements happen are due to 4-AP, most investigators have recommended waiting. I don't know of any evidence of deleterious effects of 4-AP started at eight months after injury.
Can 4-AP prevent re-myelination of the spinal cord if I undergo a re-myelination therapy?
To my knowledge, 4-AP should not prevent re-myelination of the spinal cord. However, this is something that could be tested in animal studies.
What are other uses for 4-AP?
The Russian army has been using 4-aminopyridine since the 1980s as an antidote against botulinum toxin and possibly other nerve gases. It was part of their battle kits. In fact, after 4-AP was first tested in clinical trials in Europe during the mid-1980s, when word spread in the United States that it might be beneficial in multiple sclerosis, there was no source of pharmacological grade 4-AP. I heard rumors that people were using ampules of 4-AP from Russian army kits brought in through the Czechoslovakian embassy.
You should also know that 4-AP is also the main active ingredient of poison that they use to kill pigeons in New York City.
I am noticing increased spasticity after taking 4-AP. What could this be?
4-AP has two known mechanisms of action on neural activity. First, it improves conduction in demyelinated and dysmyelinated (abnormally myelinated) axons. It does so by blocking the fast voltage-sensitive potassium channel, which normally limits the duration of action potentials that propagate in axons. This increases both the speed and reliability of conduction.
Second, it increases the duration of action potentials that reach the end of the axons. This causes more neurotransmitter release per action potential. The effects of 4-AP therefore depend on which axons are demyelinated and what remaining connections you have. If you have imbalance of excitatory and inhibitory connections to your legs, for example, 4-AP may enhance spasms.
Some drugs interact with 4-AP to produce more spasticity. If you are taking baclofen, tizanidine, clonidine and other anti-spasticity drugs, 4-AP may interact with these drugs to produce more spasticity. Interaction information is not sufficient to predict these effects. Also, individual reactions may differ.
How does 4-AP affect motor function?
Many studies have documented the effects of 4-AP on motor function in animals and humans after spinal cord injury. Besides Hansebout's trials, several other small trials have documented effects of 4-AP on motor function in spinal cord injury in humans; none has reported an increase in extensor spasms, although several subjects have reported reduced plasticity.
Qiao and colleagues, in 1997, studied the effects of 4-AP on motor-evoked potentials of subjects with chronic spinal cord injury. He showed a significant reduction in conduction latency (the time it took for the signal to go from the brain to the leg) but little change in the spinal reflex amplitudes. They concluded that the primary effect of the dose of 4-AP they used was on the conduction of signals from the brain to the spinal cord, as opposed to increased neurotransmitter release (which should be reflected in the reflex changes). Note that the doses of 4-AP used in this study were relatively low.
Dubuc and colleagues, in a 1986 study, showed that 4-AP increased rhythmic discharges from the spinal cord of cats below complete transection sites. This strongly suggests that 4-AP synchronizes the discharges of neuronal activity in the spinal cord, an effect that can override other spontaneous activity that may be occurring in the spinal cord. This may lead to spasms at rest.
Hatch and colleagues had an interesting observation that is potentially relevant. They showed that 4-AP and other excitatory drugs can reverse anesthesia in dogs. What was most fascinating was the fact that they observed opisthotonus, or extensor rigidity, in several dogs that were given combinations of excitatory drugs and were also receiving atropine.
In an early study, we found that 4-AP increases extracellular potassium levels and sensory conduction in rats that are genetically myelin deficient. Direct application of high doses of 4-AP to the rat spinal cord can cause tremors or shaking of the legs (personal observation). Very high doses (millimolar concentrations -- hundreds of times greater than therapeutic dose) can cause conduction failure in the spinal cord. So, the effects of 4-AP are very dose dependent.
No comments:
Post a Comment