Rasagiline Ameliorates MPTP Damage To Dopaminergic Neurons.

[Bravoncius Roxford]

Rasagiline is an extremely potent inhibitor of monoamine oxidase B with pico molar affinity for the enzyme. It inhibits the enzyme irreversibly, by binding covalently to the N5 nitrogen of the flavin residue of MAO, leading to the destruction of the enzyme. It is used as a monotherapy for early Parkinson's and as an adjunct for advanced Parkinson's. Daily doses of 1 milligram of rasagiline will result in 90% irreversible inhibition of MAO-B in platelets and brain within 1 to 2 weeks. Rasagiline is also a potent MAO-A inhibitor, being 6 X more potent than tranylcypromine, but the inhibition of MAO-A is not clinically significant at the daily doses of 0.5 to 1 milligrams.

The most interesting property of rasagiline, however, is not it's potent MAOI effect, but it's ability to induce several biochemical cascades in the brain that protect and even rescue neurons, especially dopaminergic neurons, from apoptosis. The propargyl moiety of rasagiline induces CREB in the brain, and this in turns triggers several proteins responsible for neuron growth and differentiation, such as bcl-2, BDNF and tyrosine kinase. Rasagiline also boosts dopamine synthesis, since one of the genes controlled by CREB is tyrosine hydroxylase, which converts tyrosine into l-dopa, and is the rate-limiting step in the production of dopamine.

An interesting study: https://www.google.com.br/url?sa=t&.../PMC2386362/&usg=AOvVaw2LFzyiPF6SNTKUQJ2pCyYx

 

[AlphaMethylPhenyl]

I'd be interested to know if it shares some of these neuroprotective effects with selegiline (another MAO-B inhibitor with MAO-inhibition at high doses, as the latter is considered to be healthy for the brain, some people saying it can reverse aging (which I doubt, but I think there's enough evidence to suggest its status as basically brain health-food).

That said EMSAM doesn't have the pharmacodynamics that selegiline in an oral form would have at least because l-amp and l-methamp are produced in significantly lower concentrations by metabolism of the transdermal form.

What I want to know is microdose effects on these neurodegenerative diseases. I'd say mescaline /LSD at first due to their dopaminregic actions, though LSD has about a wide profile of activity as otherwise exists. If this holds true: https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide#/media/File:LSDaffinities.GIF

 

[Bravoncius Roxford]

I'd be interested to know if it shares some of these neuroprotective effects with selegiline (another MAO-B inhibitor with MAO-inhibition at high doses, as the latter is considered to be healthy for the brain, some people saying it can reverse aging (which I doubt, but I think there's enough evidence to suggest its status as basically brain health-food).

That said EMSAM doesn't have the pharmacodynamics that selegiline in an oral form would have at least because l-amp and l-methamp are produced in significantly lower concentrations by metabolism of the transdermal form.

What I want to know is microdose effects on these neurodegenerative diseases. I'd say mescaline /LSD at first due to their dopaminregic actions, though LSD has about a wide profile of activity as otherwise exists. If this holds true: https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide#/media/File:LSDaffinities.GIF

Yes, selegiline has the same neuroprotective action of rasagiline. The anti-apoptic effect comes from the propargyl moiety, and both selegiline and rasagiline have it. The problem is that selegiline upon metabolization yields levo-methamphetamine, which has the opposite effect being strongly pro-apoptic. Furthermore, both isomers of meth, both the levo-rotatory and the dextro-rotatory, are strongly pro-oxidant, which negates the positive effects of the drug. Basically, the meth that results from the metabolization of selegiline negates most of the neuroprotective effects. Rasagiline is a better option.

 

[AlphaMethylPhenyl]

Strange as deprenyl is given a lot to those with dementia--parkinson's in particular, I thought.

EMSAM doesn't produce nearly as much l-meth/l-amp as deprenyl (transdermal vs oral).

 

[Bravoncius Roxford]

Strange as deprenyl is given a lot to those with dementia--parkinson's in particular, I thought.

EMSAM doesn't produce nearly as much l-meth/l-amp as deprenyl (transdermal vs oral).

Your point is invalid. The vast majority of medical doctors, including neurologists, are not even aware that deprenyl yields levo-methamphetamine upon metabolization. And the few who do don't care anyway. Medical doctors are not taught in medical school to care about long-term consequences of drug use. They are trained strictly to make diagnosis and then treat the symptoms, and that's it. Case in point: most medical doctors still use amiodarone as a first-line treatment for arrytmia, even though it is known for 50 years that amiodarone causes pulmonary fibrosis in up to 5% of all people who take it, which is both extremely serious and incurable. Case in point 2: it took the FDA 6 years to respond to the thalidomide scandal, which resulted in literally thousands of stillborn births and deformation of children. Case in point 3: most medical doctors prescribe insulin to diabetics while still allowing them to eat whatever they want, which results in progressive deterioration as the body develops insulin resistance. They also prescribe oxymetholone for the muscle wasting of HIV, eve though it increases the odds of strokes by thickening the blood through increased erythropoietin production, and worsens the symptoms of AIDS since oxymetholone decreases white blood cell formation.

Medical doctors are not trained to treat the causes of problems, or to evaluate the body in a holistic fashion and think about the effect of what they are doing the person as how it will affect the person in 20 years. No: they are trained to identify symtoms and treat them. This way of thinking is valid in life-and-death situations, but it is terrible in every other way. For instance, if you arrive at an I.C.U with sarin poisoning, they will give you atropine. Atropine is a poison almost as bad as sarin, and you don't want to take it at any other time. But if you have sarin poisoning, atropine is the only thing that can save your life. So it is the lesser of two evils, and it's use it justified in this case. Likewise, if you are on Marplan and you just ate a pound of Gouda cheese and you are having a severe hypertensive crisis with a systolic blood pressure reading of 220+, they will give you intravenous phentolamine to lower your blood pressure. Phentolamine is lethal, and even as little as 1 mg taken intravenously can make you go into hypotensive shock. But, in that situation, phentolamine is the only thing that can save your life. If you don't take it, you will have a subarachnoid hemorrage and die.

Point is, medical doctors are trained for extreme life-and-death situations, and their way of thinking of identifying symptoms and eliminating them is a valid way of thinking for saving lives in emergencies. The problem is, it is not a good way of thinking for most patients most of the time.

In conclusion, doctors couldn't care less that selegiline yields methamphetamine in the body which could actually make the Parkinson's worse in 10 years: they care about improving the patient's motor ability now. And since selegiline does just that, that is what they care about.

 

[AlphaMethylPhenyl]

Your point is invalid. The vast majority of medical doctors, including neurologists, are not even aware that deprenyl yields levo-methamphetamine upon metabolization. And the few who do don't care anyway. Medical doctors are not taught in medical school to care about long-term consequences of drug use. They are trained strictly to make diagnosis and then treat the symptoms, and that's it. Case in point: most medical doctors still use amiodarone as a first-line treatment for arrytmia, even though it is known for 50 years that amiodarone causes pulmonary fibrosis in up to 5% of all people who take it, which is both extremely serious and incurable. Case in point 2: it took the FDA 6 years to respond to the thalidomide scandal, which resulted in literally thousands of stillborn births and deformation of children. Case in point 3: most medical doctors prescribe insulin to diabetics while still allowing them to eat whatever they want, which results in progressive deterioration as the body develops insulin resistance. They also prescribe oxymetholone for the muscle wasting of HIV, eve though it increases the odds of strokes by thickening the blood through increased erythropoietin production, and worsens the symptoms of AIDS since oxymetholone decreases white blood cell formation.

Medical doctors are not trained to treat the causes of problems, or to evaluate the body in a holistic fashion and think about the effect of what they are doing the person as how it will affect the person in 20 years. No: they are trained to identify symtoms and treat them. This way of thinking is valid in life-and-death situations, but it is terrible in every other way. For instance, if you arrive at an I.C.U with sarin poisoning, they will give you atropine. Atropine is a poison almost as bad as sarin, and you don't want to take it at any other time. But if you have sarin poisoning, atropine is the only thing that can save your life. So it is the lesser of two evils, and it's use it justified in this case. Likewise, if you are on Marplan and you just ate a pound of Gouda cheese and you are having a severe hypertensive crisis with a systolic blood pressure reading of 220+, they will give you intravenous phentolamine to lower your blood pressure. Phentolamine is lethal, and even as little as 1 mg taken intravenously can make you go into hypotensive shock. But, in that situation, phentolamine is the only thing that can save your life. If you don't take it, you will have a subarachnoid hemorrage and die.

Point is, medical doctors are trained for extreme life-and-death situations, and their way of thinking of identifying symptoms and eliminating them is a valid way of thinking for saving lives in emergencies. The problem is, it is not a good way of thinking for most patients most of the time.

In conclusion, doctors couldn't care less that selegiline yields methamphetamine in the body which could actually make the Parkinson's worse in 10 years: they care about improving the patient's motor ability now. And since selegiline does just that, that is what they care about.

No I;d say you definitely need a source that states that the l-meth/l-amp effects outweighs the selegiline neuroprotective effect. The studies suggest that it doesn't...

Yes and no. They don't just study the drugs, but the profiles and indications. Case in point against what you're saying is how, even in the US, stimulants are avoided unless for ADHD or narcolepsy legitimately, because of the effects that happen long-term, the wasting effect on mood and the liability for an addiction to sprout.

The exhaustive, contemporary system for approving drugs says enough about safety, buffered by widespread use for a long time. A few duds out of hundreds and more, I'd say they have a good track record.

No again. In Europe there is a strong holistic style of psychiatric practice, especially in the North. I've had the sam experience when I was in the states.

The dose makes it a poison or a medicien. No...they definitely are wary against long-term detrimental effects. I've been taken off a benzo explicitly because of troubles "down the line".

You're making pretty giant accusations based on your experience, not the system overall.

 

[Bravoncius Roxford]

You are completely wrong about everything you wrote. Also, reply with quotes because I have no idea what part of my answer you are replying to with your confusing style of posting.

No I;d say you definitely need a source that states that the l-meth/l-amp effects outweighs the selegiline neuroprotective effect. The studies suggest that it doesn't...

I don't need any source for anything. I gave my opinion, and didnt' make a statement of fact. Me do know for a fact, however, that methamphetamine is a neurotoxin. Saying that the "dose makes the medicine" is completely ridiculous. Bringing Paracelsus here is completely uncalled for. There isn't any dose of methamphetamine that is beneficial to the human body! Even very small doses of meth damage dopaminergic axons of neurons. Not to mention that the brains of rats and baboons exposed to methamphetamine for protracted periods of time show extensive lipid peroxidation of tissues, inflammation and white matter loss upon autopsy.

Yes and no. They don't just study the drugs, but the profiles and indications. Case in point against what you're saying is how, even in the US, stimulants are avoided unless for ADHD or narcolepsy legitimately, because of the effects that happen long-term, the wasting effect on mood and the liability for an addiction to sprout.

Actually, that methamphetamine is a neurotoxin has been known for less than 20 years now, but Desoxyn has been on the market for some 50 years. This clearly shows that doctors will use medicine without assessing long-term consequences of their use.

The exhaustive, contemporary system for approving drugs says enough about safety, buffered by widespread use for a long time. A few duds out of hundreds and more, I'd say they have a good track record.

You are missing the point completely. In fact, you are wrong on two counts. First, drugs are not tested for long-term effects. They are tested for short-term mutagenic potential, as well as acute hepatotoxicity, nephrotoxicity and cardiotoxicity. They will give repeated doses of a drug for several weeks to several months at the most, and evaluate things like liver enzyme, white blood cell profile, plasma lipoprotein profile, etc. The reason why drugs take so long to be approved is not because they evaluate the drugs for 10-15 years, but because the FDA has a limited budget and drugs have to "wait in line" for approval. It has nothing to do with drugs being evaluated for years. For instance, agomelatine and tolcapone are both "approved" drugs, and yet both are strongly hepatotoxic and have been implicated in deaths. In fact, the warning boxing label in Tasmar that it can cause irreversible liver damage was included after the drug was released due to post-marketing reports of serious liver injury.

No again. In Europe there is a strong holistic style of psychiatric practice, especially in the North. I've had the sam experience when I was in the states.

No, the vast majority of psychiatrists in both the U.S and Europe work only with drugs. I know this for a fact because I actually have gone to several psychiatrists.

The dose makes it a poison or a medicien.

No, the dose making the poison is relevant only when it comes to desired effects VS acute toxicity. Drugs are all poisons to the body anyway at any dose for 99% of the effects they have in the body. We only call them "medicines" because they have a desired effect. But, ideally, medicine or poisons are not needed for the functioning of the human body, unlike air, food and water, and there is no long-term benefit from their consumption. Save people with very rare genetic disorders, 99% of human beings are healthier when their bodies are allowed to work with their own homeostatic balance. We did not evolve to need any drugs. We evolved to need Oxygen, food and water. Even in Western Medicine, all doctors will tell you that you are much better off in terms of health from not taking anything than from taking any type of drugs. I really don't understand why you are quoting Paracelsus here, since "the dose makes the medicine" only has relevance when it comes to a desired effect of a drug VS the drug's acute toxicity and has no relevance to long-term effects to the body. Drugs are all poisons at ANY amount to the body in the long-term for 995 of all people. The exception, again, are people with chronic intractable diseases, usually of genetic origin, that would be dead without drugs. But, in the long-run, ALL drugs are poison to almost everyone.

No...they definitely are wary against long-term detrimental effects. I've been taken off a benzo explicitly because of troubles "down the line".

And yet, there are millions of people addicted to benzos(and opiates), exactly because doctors don't care much about the long-term consequences of drug use. Just look at the opiate crisis. Millions of people addicted because doctors thought it was a good solution to give opiates for people who had pain for more than several weeks, when it takes only a few days for the body to develop tolerance to opiates. They simply don't care. If they cared, knowing the pain would last for at least several weeks, tey would have given strong NSAIDs instead of opiates. Patch, fix and treat.

You're making pretty giant accusations based on your experience, not the system overall.

No, I am basing my argument on the millions of people who take drugs prescribed by doctors for years or decades, and get progressively worse. All you have to do is look at the statistics for people that have diabetes and arteriosclerosis, and are treated with things like insulin and statins, and yet their chronic diseases progress anyway. While a simple change in diet gives much better long-term results with much less toxicity, but doctors simply don't care.[/QUOTE][/QUOTE]

 

[S.J.B.]

And yet, there are millions of people addicted to benzos(and opiates), exactly because doctors don't care much about the long-term consequences of drug use. Just look at the opiate crisis. Millions of people addicted because doctors thought it was a good solution to give opiates for people who had pain for more than several weeks, when it takes only a few days for the body to develop tolerance to opiates. They simply don't care. If they cared, knowing the pain would last for at least several weeks, tey would have given strong NSAIDs instead of opiates. Patch, fix and treat.

Iatrogenic addiction to opioids is fairly rare and the vast majority of those cases occur with people who are already recreational drug users and/or have drug addictions. Doctors are right to continue to prescribe opioids to treat pain instead of refraining to do so for the sake of the 0.2% of drug-naive patients who will "abuse" them or become addicted.

 

[vecktor]

Rasagiline Ameliorates MPTP Damage To Dopaminergic Neurons.....so does cocaine, so what???

I am clearly missing some link here that gives this statement some greater importance so help me out here.
Unless of course you are eating MPTP and want to avoid frying your neurons, but the better solution to that is not to consume MPTP in the first place.

Selegiline is often used in Parkinson's to rescue the declining effect of Carbidopa Levodopa treatment, once Parkinson's patients are at that point then neurotoxicity if it exists from single digit mg l-methamphetamine per day which I doubt, is totally irrelevant.

cocaine protection MPTP
www.ncbi.nlm.nih.gov/pubmed/3875884

 

[AlphaMethylPhenyl]

You are completely wrong about everything you wrote. Also, reply with quotes because I have no idea what part of my answer you are replying to with your confusing style of posting.

Firstly, you bolding words does nothing more than make you sound annoying.

Lol how about some evidence?

I don't need any source for anything. I gave my opinion, and didnt' make a statement of fact. Me do know for a fact, however, that methamphetamine is a neurotoxin. Saying that the "dose makes the medicine" is completely ridiculous. Bringing Paracelsus here is completely uncalled for. There isn't any dose of methamphetamine that is beneficial to the human body! Even very small doses of meth damage dopaminergic axons of neurons. Not to mention that the brains of rats and baboons exposed to methamphetamine for protracted periods of time show extensive lipid peroxidation of tissues, inflammation and white matter loss upon autopsy.

No you definitely betrayed it as fact. Regardless, your opinion has nothing behind it, study-wise.

And yes, sometimes the dose is 0mg. Just fyi, pharma meth in 25mg or less is not neurotoxic, by the opinion of people in the industry.

Actually, that methamphetamine is a neurotoxin has been known for less than 20 years now, but Desoxyn has been on the market for some 50 years. This clearly shows that doctors will use medicine without assessing long-term consequences of their use.

No, as stated succinctly, above, you are clearly in the wrong.

You are missing the point completely. In fact, you are wrong on two counts. First, drugs are not tested for long-term effects. They are tested for short-term mutagenic potential, as well as acute hepatotoxicity, nephrotoxicity and cardiotoxicity. They will give repeated doses of a drug for several weeks to several months at the most, and evaluate things like liver enzyme, white blood cell profile, plasma lipoprotein profile, etc. The reason why drugs take so long to be approved is not because they evaluate the drugs for 10-15 years, but because the FDA has a limited budget and drugs have to "wait in line" for approval. It has nothing to do with drugs being evaluated for years. For instance, agomelatine and tolcapone are both "approved" drugs, and yet both are strongly hepatotoxic and have been implicated in deaths. In fact, the warning boxing label in Tasmar that it can cause irreversible liver damage was included after the drug was released due to post-marketing reports of serious liver injury.

Ten years of trials isn't long enough? Scientists know how to account for time beyond that. But these days new drugs are building on substances that have been on the market for a while.

The FDA doesn't pay for the drugs in trials. That was a bizarre thing to say. It's the corporation that owns it that pays for trials.

You're trying to sensationalize a rare occurrence in the industry.

No, the vast majority of psychiatrists in both the U.S and Europe work only with drugs. I know this for a fact because I actually have gone to several psychiatrists.

So have I. So, you're wrong. Again, you're making blanket statements off of your experience and god knows what else.

No, the dose making the poison is relevant only when it comes to desired effects VS acute toxicity. Drugs are all poisons to the body anyway at any dose for 99% of the effects they have in the body. We only call them "medicines" because they have a desired effect. But, ideally, medicine or poisons are not needed for the functioning of the human body, unlike air, food and water, and there is no long-term benefit from their consumption. Save people with very rare genetic disorders, 99% of human beings are healthier when their bodies are allowed to work with their own homeostatic balance. We did not evolve to need any drugs. We evolved to need Oxygen, food and water. Even in Western Medicine, all doctors will tell you that you are much better off in terms of health from not taking anything than from taking any type of drugs. I really don't understand why you are quoting Paracelsus here, since "the dose makes the medicine" only has relevance when it comes to a desired effect of a drug VS the drug's acute toxicity and has no relevance to long-term effects to the body. Drugs are all poisons at ANY amount to the body in the long-term for 995 of all people. The exception, again, are people with chronic intractable diseases, usually of genetic origin, that would be dead without drugs. But, in the long-run, ALL drugs are poison to almost everyone.

This does not merit response. Same thing as above.

And yet, there are millions of people addicted to benzos(and opiates), exactly because doctors don't care much about the long-term consequences of drug use. Just look at the opiate crisis. Millions of people addicted because doctors thought it was a good solution to give opiates for people who had pain for more than several weeks, when it takes only a few days for the body to develop tolerance to opiates. They simply don't care. If they cared, knowing the pain would last for at least several weeks, tey would have given strong NSAIDs instead of opiates. Patch, fix and treat.

FYI, dependence and addiction are different. That's a start for your learning. For pain, they work for longer. Did pharma overextend its bounds in this case? Yes. No debate here, except that we wouldn't use opioids if they weren't so good at pain management. You can't just sub out for an NSAID...

No, I am basing my argument on the millions of people who take drugs prescribed by doctors for years or decades, and get progressively worse. All you have to do is look at the statistics for people that have diabetes and arteriosclerosis, and are treated with things like insulin and statins, and yet their chronic diseases progress anyway. While a simple change in diet gives much better long-term results with much less toxicity, but doctors simply don't care.

And yet you can't even offer a link to your supposed treasure trove of righteous statistics

 

[Bravoncius Roxford]

Iatrogenic addiction to opioids is fairly rare and the vast majority of those cases occur with people who are already recreational drug users and/or have drug addictions. Doctors are right to continue to prescribe opioids to treat pain instead of refraining to do so for the sake of the 0.2% of drug-naive patients who will "abuse" them or become addicted.

Completely incorrect, as there currently is an opioid addiction crisis, with at least several hundred deaths. If you want, I can link to newspaper articles discussing the opioid crisis.

 

[S.J.B.]

This thread has run its course.