1565 replies to this topic

[Isochroma]

Just found this thread today.

An admin should merge this thread with the other one here: Sunifiram.

Until then I'll be dupliposting in both.

Sunifiram is now listed in the Racetam Prices list along with Unifiram which as of late now has a supplier!

An affordable Coluracetam supplier has also appeared.

One final comment on Sunifiram and Unifiram: As per the papers so far published - see the other Sunifiram thread for the PDFs - these compounds have strong n-shaped dose-response curves.

Overdosing the test animals resulted in zero effect.

No such result has been shown for any racetam - but these molecules are not racetams - they are Racerams - a totally different family of drugs.

Edited by Isochroma-Reborn, 26 March 2013 - 02:53 AM.

[peakplasma]

No such result has been shown for any racetam - but these molecules are not racetams - they are Racerams - a totally different family of drugs.

Raceram? Do you have some more info on the family/structure?

[Isochroma]

Their names were suffixed with RAM because they are so different from the TAMs.

SunifRAM and UnifiRAM.

My main concern is that neither will work to restore mitochondrial energy generation like the TAMs do - even if they had that inherent ability their extreme receptor potency (the other effect) and n-shaped dose-response curve means that the concentration which works for receptor sensitization is orders of magnitude below that which restores mitochondrial function.

Receptors are highly sensitive because they're evolved as signal-transducers (think of them as phone lines) vs. energy generation/transmission systems (mitochondria as powerlines). The voltage difference is orders of magnitude, and in the brain case the concentration needed to evoke response is thus also different by such amounts due to the much higher sensitivity of signal-systems vs. power systems.

For example, Piracetam restores mitochondrial energy generation by migrating en-mass into the lipid bilayers of mitochondria and functioning as a kind of soapy surfactant which makes them run more efficiently. But the amount needed for such a task is 10-1000x more than needed for receptor sensitization. Luckily though, Piracetam has no n-shaped dose-response curve so a large dose can be taken to cover both function areas. Not so with Sunifiram because of its n-shaped dose-response curve - taking enough (presuming it has the ability) to repotentiate mitochondria would thoroughly abolish its receptor effects.

Taking the right amount for receptor effects would be completely inadequate for mitochondrial repotentialization.

I have good reason to believe that Noopept might also restore mitochondrial function - but just like the RAMs its extreme receptor potency means that dosing would have to be in the 300mg+ per dose area to see mitochondrial effects. I tested it myself and found that at normal 'receptor' doses it has no mitochondrial effect. I suffer from severe mitochondrial damage causing brain fatigue.

Noopept at large enough doses to even test its mitochondrial effects would be both prohibitively expensive and have disastrous side-effects.

These are my darkest yet most realistic fears after all the papers I've read and experience testing virtually all of the TAMs and Noopept against that monster which haunts me.

The papers are linked in the other thread.

It's unfortunate that at least Sunifiram has such a sharp n-curve, because it means that it will be a unimodal therapeutic - that is, it will only be usable within a narrow dosage range for conditions that are affected by its physiological concentration within that narrow range - unlike the less-potent but far more broad-spectrum therapeutic actions of most racetams.

What I'm saying is that due to their sharp n-shaped dose-response curves, the two most popular racerams are therapeutically unimodal in their action of restoration of concentration-dependant conditions in different brain subsystems.

Most tellingly, I sent an email last year to the lead discoverer of Sunifiram and Unifiram asking why he did not test the other main therapeutic area addressed by racetams - the restoration and protection of damaged mitochondrial energy generation which is crucial to refunctionalizing dying brains - and he never replied.

I find these scientists tend to drill down into tiny little pixels of investigation while neglecting the whole.

If they aren't slapped in the face often then they wander off into abstract and/or useless tangents while the people supporting them with their tax dollars suffer.

A final note: most natural herbs work multimodally and that is why they are so effective. Look even at the worst of the worst: cocaine. The natural Coca leaf has been chewed for thousands of years without the detrimental effects of purified cocaine or crack - due to the leaf's natural mix of therapeutic alkaloids, rich vitamins and minerals.

Though the racetams are indeed chemically pure they are nonetheless each multimodal.

Edited by Isochroma-Reborn, 26 March 2013 - 03:37 AM.

[HenryHH]

Has anyone taken Sunifiram or Unifiram? If so, how would you describe their effects in regards to memory improvement? I'll be looking forward to reading about everyone's experiences...

[therein]

Really interesting post, Isochroma. Would you mind telling us how you got severe mitochondrial damage and what it feels like?

[Isochroma]

I wish I knew how it happened but I was exposed to a lot of toxic lead for about a decade as a kid, and in late teens took DXM, and have several bad preexisting conditions as well.

What it feels like is brain is stuck in mud, no mental energy, no memory, constant mental fatigue, slept 12 hours daily and still end up falling asleep at keyboard a few hours after getting up, poor coordination (loss of balance/stability control which is like always being dizzy). Along with general mental decline: no creativity or interest in anything needing brain activity, loss of visual colour satuation (black-and-white shaded vision) and dynamic range.

No amount of vitamins, blue light, activity, etc. worked to fix it but Piracetam made it go away in a matter of days when I started taking it Summer 2008 - after all those years of it getting worse it finally cleared up.

If you want to understand how bad it was for me, look at the size of the Racetam Prices list.

That list was my personal weapon against Cerebral Health's cranking up Piracetam price to $100/kg with shipping.

I saw my chances at existing normally dying as it became unaffordable and then I became very very angry.

When I say angry I mean like someone stabbing me in the brain.

So I decided that to keep living a livable life, due to my very low income I would have to guarantee myself a lifelong supply of affordable Racetam medicine or I would decay again into dysfunction, consequent depression and the inevitable suicide which happens when life becomes unlivable.

So the size of that list is your answer to how bad my suffering was - and will be - if I cannot obtain Racetam medicine affordably.

And I won - I found cheap suppliers and even better racetams - first Aniracetam which elevates mitochondrial energy generation more than Piracetam can, and then when that was only 80% good enough I moved up to Oxiracetam which cleared it up by 90%, and now up to Pramiracetam + Piracetam (PIR for some of its other effects) which clears it up 95%.

But as I age the old monster keeps pushing harder at the door trying to get back in and brutalize me again. So I have to keep finding strong racetams or even better molecules than them.

Which led me to Sunifiram and Unifiram and Coluracetam.

Edited by Isochroma-Reborn, 26 March 2013 - 03:50 AM.

[therein]

I wish I knew how it happened but I was exposed to a lot of toxic lead for about a decade as a kid, and in late teens took DXM, and have several bad preexisting conditions as well.

What it feels like is brain is stuck in mud, no mental energy, no memory, constant mental fatigue, slept 12 hours daily and still end up falling asleep at keyboard a few hours after getting up, poor coordination (loss of balance/stability control which is like always being dizzy). Along with general mental decline: no creativity or interest in anything needing brain activity, loss of visual colour satuation (black-and-white shaded vision) and dynamic range.

No amount of vitamins, blue light, activity, etc. worked to fix it but Piracetam made it go away in a matter of days when I started taking it Summer 2008 - after all those years of it getting worse it finally cleared up.

Great to hear that Piracetam worked so well for you. I'm sure you've but have you tried stimulants (amphetamines, methylphenidate etc) and Pyrroloquinoline Quinone at try?

[Isochroma]

Stimulants are depleters.

They do not repair or protect brain systems but instead deplete them by signalling for the engines to run faster.

They are the equivalent of pumping a well faster to yield the same flowrate - causing even faster depletion of the already substandard water-table.

Racetams restore actual energy generation in the generators and also repotentiate receptors without toxifying and depleting - which is the last thing a sick person needs.

As for PQQ - I didn't know, so thanks!

I have opened a new folder on it in my Nootropics folder for further investigation.

However, so far I have noted that there is no replacement for the refluidization capacity of racetams.

Edited by Isochroma-Reborn, 26 March 2013 - 03:54 AM.

[therein]

Stimulants are depleters.

They do not repair or protect brain systems but instead deplete them by signalling for the engines to run faster.

They are the equivalent of pumping a well faster to yield the same flowrate - causing even faster depletion of the already substandard water-table.

Racetams restore actual energy generation in the generators and also repotentiate receptors without toxifying and depleting - which is the last thing a sick person needs.

I agree but I think stimulants are still useful for providing motivation and promoting wakefulness. Methylphenidate isn't toxic and Amphetamines aren't that toxic after all.

I feel bad hijacking the thread so here is my last question. How much Piracetam are you taking daily?

[Isochroma]

Ultimately I'm racing against Time itself to find the Cure.

The Cure is something that makes me cry at night before bed - it is the water of life and I am the dehydrating man walking an infinite sea of sand dunes with the blazing Sun overhead burning my eyes and frying my mind.

Every so often I find a puddle to drink from: the first was Piracetam, then Aniracetam, next Oxiracetam, now Pramiracetam.

Will I ever find the Lake or the River or will I be stuck drinking from the ever-warming always evaporating water puddles that are only partial solutions?

And how many others - if this happened to me then it must have happened to many others - are also stuck - often with brutish stimulants which further worsen their condition, not knowing or affording to find the Cure?

Edited by Isochroma-Reborn, 26 March 2013 - 04:05 AM.

[Isochroma]

First, MPH and AMPH are both neurotoxic (proven, and in small doses like those used to treat ADHD - I have the papers) and also cause loss of brain mass - also proven.

Worse, even if they did not - it's the equivalent to revving an already half-broken engine to get its original output - it's EXPONENTIALLY MORE DAMAGING TO AN ENGINE to do so when it is already damaged or worn-out.

The body has auto-throttle systems and the brain does too - that is why the signalling system throttles down brain activity as it auto-senses loss of energy conversion capacity in the mitochondria and also auto-senses other degenerative changes and compensates by lowering brain activity in order to prolong life. Natural selection found over the course of hundreads of thousands of years the best average optimal wear-rate to gross expenditure rate ratio - it's an imperfect compromise, and in some rare cases the auto-signalling system itself may be dysfunctional.

However, the precautionary principle dictates that one should assume that 100,000 years of evolution is more likely to be right than a person's few decades of life experience.

A simple example is the need to sleep - which is the diurnal regenerative phase for both brain and body.

The tiredness is a signal in the short-term - it can be overridden - but at high price in the not-distanct future. Psychosis and shortly afterwards death are the result of ignoring or overriding that signal and for the given reason.

The candle that burns twice as bright burns less than half as long, since biosystems lose efficieny at higher expenditure rates and damaged systems do so at an even steeper loss of efficiency to expenditure rate curve.

The reason is that oxidatively or otherwise damaged biosystems - just like a car engine - self-damage as they operate at a higher rate than undamaged systems.

Self-damage or autowear is a property of all entropic systems and especially energy-conversion systems.

Aging causes brain and body auto-throttling too.

Stimulants override the natural signal. Worse, the brain is inherently incapable of distinguishing between a false signal and true wear/tiredness - until the later consequences appear or by previous experience or outside information - intellectual learning as from reading this text. Which is why so many are so fooled for so long by stimulants and keep using them, with visible results.

Even the children who are hooked early on Caffeine by drug dispensers in the schools and free availability, not to mention the horrrific ADHD drugs.

The proof is the crash after their use (short-term) and the longer-term degenerative (de-generative: to destroy the ability to generate energy) changes they induce which are easily visible.

They are only on the market because of Big Pharma interests otherwise the FDA and other agencies would have banned them long ago.

Edited by Isochroma-Reborn, 26 March 2013 - 04:23 AM.

[therein]

First, MPH and AMPH are both neurotoxic (proven, and in small doses like those used to treat ADHD - I have the papers) and also cause loss of brain mass - also proven.

Worse, even if they did not - it's the equivalent to revving an already half-broken engine to get its original output - it's EXPONENTIALLY MORE DAMAGING TO AN ENGINE to do so when it is already damaged or worn-out.

The body has auto-throttle systems and the brain does too - that is why the signalling system throttles down brain activity as it auto-senses loss of energy conversion capacity in the mitochondria and also auto-senses other degenerative changes and compensates by lowering brian activity in order to prolong life.

A simple example is the need to sleep - which is the diurnal regenerative phase for both brain and body.

The tiredness is a signal in the short-term - it can be overridden - but at high price in the not-distanct future. Psychosis and shortly afterwards death are the result of ignoring or overriding that signal and for the given reason.

The candle that burns twice as bright burns less than half as long, since biosystems lose efficieny at higher expenditure rates and damaged systems do so at an even steeper loss of efficiency to expenditure rate curve.

The reason is that oxidatively or otherwise damaged biosystems - just like a car engine - self-damage as they operate at a higher rate than undamaged systems.

Self-damage or autowear is a property of all entropic systems and especially energy-conversion systems.

Aging causes brain and body auto-throttling too.

Stimulants override the natural signal. Worse, the brain is inherently incapable of distinguishing between a false signal and true wear/tiredness - until the later consequences appear or by previous experience or outside information - intellectual learning as from reading this text. Which is why so many are so fooled for so long by stimulants and keep using them, with visible results.

Even the children who are hooked early on Caffeine by drug dispensers in the schools and free availability, not to mention the horrrific ADHD drugs.

The proof is the crash after their use (short-term) and the longer-term degenerative (de-generative: to destroy the ability to generate energy) changes they induce which are easily visible.

They are only on the market because of Big Pharma interests otherwise the FDA and other agencies would have banned them long ago.

You're right, big pharmaceutical companies are pushing stimulants to general public and even to kids to maximize their profits and the use of stimulants is pretty much analogous to "the candle that burns twice as bright burns less than half as long" but I still think there is a way to use stimulants responsibly by getting adequate amount of sleep, eating healthy, staying hydrated and obviously not taking too much of it.

I would be interested in seeing that article you mentioned about Methylphenidate neurotoxicity.

ALSO, back to the topic.

I just got an email from NSN, telling that my package is shipped.

Edited by therein, 26 March 2013 - 04:37 AM.

[peakplasma]

And I won - I found cheap suppliers and even better racetams - first Aniracetam which elevates mitochondrial energy generation more than Piracetam can, and then when that was only 80% good enough I moved up to Oxiracetam which cleared it up by 90%, and now up to Pramiracetam + Piracetam (PIR for some of its other effects) which clears it up 95%.

How about Coluracetam? It's rather potent... does this mean it is not effective for mitochondrial energy generation?

[Isochroma]

Nice!

Early methylphenidate administration to young rats causes a persistent reduction in the density of striatal dopamine transporters

"Methylphenidate is widely and effectively used for the treatment of attention deficit hyperactivity disorder during early childhood and adolescence, but until now possible effects of this treatment on brain development and the maturation of monoaminergic systems have not been investigated systematically. This experimental animal study describes the effects of methylphenidate administration (2 mg/kg/day) for 2 weeks to very young (prepubertal) and somewhat older (postpubertal) rats on the densities of dopamine, serotonin, and norepinephrine transporters in the striatum and in the midbrain. As shown by ligand-binding-assays, the K(D) values of all three transporters were unaffected by this treatment. No alterations were found for the Bmax values of [3H]-paroxetine and [3H]-nisoxetine binding, but the density of dopamine transporters (Bmax values of [3H]-GBR binding) in the striatum (but not in the midbrain) was significantly reduced after early methylphenidate administration (by 25% at day 45), and this decline reached almost 50% at adulthood (day 70), that is, long after termination of the treatment. This is the first empirical demonstration of long-lasting changes in the development of the central dopaminergic system caused by the administration of methylphenidate during early juvenile life."

The Effects of Long-term Ritalin (Methylphenidate) Use [Full PDF available for free at link]

Abstract

Ritalin, or methylphenidate, is often used to treat attention deficit hyperactivity
disorder (ADHD) and attention deficit disorder (ADD). Some of the many long-term
effects of Ritalin use are reduced cerebral blood flow, increased energy consumption in
many areas of the brain, permanent loss of brain tissue, life-long increased sensitivity to
cocaine, and life-long increased rates of depression and anxiety.

Amphetamine treatment similar to that used in the treatment of adult ADHD damages dopaminergic nerve endings in the striatum of adult non-human primates [Full PDF available for free at link]

ABSTRACT

Pharmacotherapy with amphetamine is effective in the man-
agement of attention-deficit/hyperactivity disorder (ADHD),
now recognized in adults as well as in children and adoles-
cents. Here we demonstrate that amphetamine treatment, sim-
ilar to that used clinically for adult ADHD, damages dopaminer-
gic nerve endings in the striatum of adult nonhuman primates.
Furthermore, plasma concentrations of amphetamine associ-
ated with dopaminergic neurotoxicity in nonhuman primates
are on the order of those reported in young patients receiving
amphetamine for the management of ADHD. These findings
may have implications for the pathophysiology and treatment of
ADHD. Further preclinical and clinical studies are needed to
evaluate the dopaminergic neurotoxic potential of therapeutic
doses of amphetamine in children as well as adults.

Confirming the Hazards of Stimulant Drug Treatment

Low-Dose Amphetamine Neurotoxicity

Abstract

Pharmacotherapy with amphetamine is effective in the management of attention-deficit/
hyperactivity disorder (ADHD), now recognized in adults, as well as in children and adolescents.
Here we demonstrate that amphetamine treatment, similar to that used clinically for adult
ADHD, damages dopaminergic nerve endings in the striatum of adult non-human primates.
Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity
in non- human primates are on the order of those reported in young patients receiving
amphetamine for the management of ADHD. These findings may have implications for the
pathophysiology and treatment of ADHD. Further preclinical and clinical studies are needed to
evaluate the dopaminergic neurotoxic potential of therapeutic doses of amphetamine, in children
as well as adults.

Edited by Isochroma-Reborn, 26 March 2013 - 04:42 AM.

[Isochroma]

As for Coluracetam, I tested it in a month where I was under severe mental and physical stress - sick and living in a homeless shelter among psychos, drug-addicts and criminals.

I took it with saturation doses of Piracetam (5g x 6/day) and Pramiracetam (300mg x 6/day) to maximize the absolute therapeutic effect so as to offset the horrific conditions - so I cannot tell.

I will have to test it alone in the future.

Edited by Isochroma-Reborn, 26 March 2013 - 04:45 AM.

[Dashwolf]

Anyone who ordered Sunifiram from NSN, did you guys get an email back from them about tracking information or anything about your item being shipped? I didn't get anything.

Just got an email from NSN,

"We have prepared your package and have either already shipped it or will be doing so within a few hours."

They also included a tracking number for it. That was surprisingly fast, since I placed the order earlier today. So it should be here in about 3 days!

[emckai]

Anyone who ordered Sunifiram from NSN, did you guys get an email back from them about tracking information or anything about your item being shipped? I didn't get anything.

Just got an email from NSN,

"We have prepared your package and have either already shipped it or will be doing so within a few hours."

They also included a tracking number for it. That was surprisingly fast, since I placed the order earlier today. So it should be here in about 3 days!

I didn't get any type of email at all. I sent my order in on Saturday and it's only 1g of Noopept....

[therein]

Nice!

Early methylphenidate administration to young rats causes a persistent reduction in the density of striatal dopamine transporters

"Methylphenidate is widely and effectively used for the treatment of attention deficit hyperactivity disorder during early childhood and adolescence, but until now possible effects of this treatment on brain development and the maturation of monoaminergic systems have not been investigated systematically. This experimental animal study describes the effects of methylphenidate administration (2 mg/kg/day) for 2 weeks to very young (prepubertal) and somewhat older (postpubertal) rats on the densities of dopamine, serotonin, and norepinephrine transporters in the striatum and in the midbrain. As shown by ligand-binding-assays, the K(D) values of all three transporters were unaffected by this treatment. No alterations were found for the Bmax values of [3H]-paroxetine and [3H]-nisoxetine binding, but the density of dopamine transporters (Bmax values of [3H]-GBR binding) in the striatum (but not in the midbrain) was significantly reduced after early methylphenidate administration (by 25% at day 45), and this decline reached almost 50% at adulthood (day 70), that is, long after termination of the treatment. This is the first empirical demonstration of long-lasting changes in the development of the central dopaminergic system caused by the administration of methylphenidate during early juvenile life."

The Effects of Long-term Ritalin (Methylphenidate) Use [Full PDF available for free at link]

Abstract

Ritalin, or methylphenidate, is often used to treat attention deficit hyperactivity
disorder (ADHD) and attention deficit disorder (ADD). Some of the many long-term
effects of Ritalin use are reduced cerebral blood flow, increased energy consumption in
many areas of the brain, permanent loss of brain tissue, life-long increased sensitivity to
cocaine, and life-long increased rates of depression and anxiety.

Amphetamine treatment similar to that used in the treatment of adult ADHD damages dopaminergic nerve endings in the striatum of adult non-human primates [Full PDF available for free at link]

ABSTRACT

Pharmacotherapy with amphetamine is effective in the man-
agement of attention-deficit/hyperactivity disorder (ADHD),
now recognized in adults as well as in children and adoles-
cents. Here we demonstrate that amphetamine treatment, sim-
ilar to that used clinically for adult ADHD, damages dopaminer-
gic nerve endings in the striatum of adult nonhuman primates.
Furthermore, plasma concentrations of amphetamine associ-
ated with dopaminergic neurotoxicity in nonhuman primates
are on the order of those reported in young patients receiving
amphetamine for the management of ADHD. These findings
may have implications for the pathophysiology and treatment of
ADHD. Further preclinical and clinical studies are needed to
evaluate the dopaminergic neurotoxic potential of therapeutic
doses of amphetamine in children as well as adults.

Confirming the Hazards of Stimulant Drug Treatment

Low-Dose Amphetamine Neurotoxicity

Abstract

Pharmacotherapy with amphetamine is effective in the management of attention-deficit/
hyperactivity disorder (ADHD), now recognized in adults, as well as in children and adolescents.
Here we demonstrate that amphetamine treatment, similar to that used clinically for adult
ADHD, damages dopaminergic nerve endings in the striatum of adult non-human primates.
Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity
in non- human primates are on the order of those reported in young patients receiving
amphetamine for the management of ADHD. These findings may have implications for the
pathophysiology and treatment of ADHD. Further preclinical and clinical studies are needed to
evaluate the dopaminergic neurotoxic potential of therapeutic doses of amphetamine, in children
as well as adults.

I have nothing to say on Amphetamine neurotoxicity but when it comes to Methylphenidate;

I don't consider Krystle A Cole a reputable source. Her abstract and conclusions in the article are over-simplified and hasty at best. She is just jumping to conclusions. Having said that, she has a really interesting past but no experience in the field. She was just exposed to a lot of drugs with no training in the field at all. If you haven't, you should watch this: https://www.youtube....h?v=r7qliVpGEk0

Increased sensitivity to cocaine and higher addiction rate to stimulants are expected. While interesting, I don't think that reduction in the density of dopamine transporters mean a lot.

Edited by therein, 26 March 2013 - 05:25 AM.

[Isochroma]

I could dig up more studies but it isn't worth the effort.

MPH is degeneratory to health as are the other stimulants, AMPH and its analogs especially.

They work great to make already broken biologics further damaged - that's their specialty which is why they are so profitable and addictive.

They are not net therapeutic.

They do not fix the problems of energy generation in mitochondria but increase them by increasing the 'burn rate' without ameliorating the underlying problems.

They do not resensitize receptors that need more sensitivity but instead cause desensitization and eventual loss of both receptors and whole neurons - thus loss of brain mass.

The truth is shinging bright as the tiger in the night and the magnificent Sun whose light is fun but even its rays cannot penetrate closed eyes.

Edited by Isochroma-Reborn, 26 March 2013 - 05:19 AM.

[therein]

I don't expect them to fix mitochondrial function. They are good for motivation and drive. I am not really looking for high ATP turnout. Receptor downregulation is a problem but can be ameliorated by not overdoing them.

[Isochroma]

Dose-related immunohistochemical and ultrastructural changes after oral methylphenidate administration in cerebrum and cerebellum of the rat

Abstract

Methylphenidate is a piperidine derivative and is the drug most often used to treat attention deficit/hyperactivity disorder of children and young adults. Our aim is to investigate dose-dependent dopamine-2 receptor and glial fibrillary acidic protein expression and ultrastructural changes of the rat brain, to demonstrate possible toxicity of the long-term and high dose use of the methylphenidate. In this study, 27 female prepubertal Wistar albino rats, divided into three different dose groups (5, 10 and 20 mg/kg) were treated orally with methylphenidate dissolved in saline solution for 5 days per week during 3 months. At the end of the third month, tissues were removed and sections were collected for immunohistochemical and ultrastructural studies. We believe that methylphenidate causes dose-related activation of the dopaminergic system in several brain regions especially in ventral tegmental area and also causing neuronal degeneration and capillary wall structural changes such as basal membrane thickness and augmentation of the pinostatic vesicle in the endothelial cells. Also, increased dose of Ritalin is inducing astrocytes hypertrophy especially astrogliosis in pia-glial membrane and this is the result of the degenerative changes in prefrontal cortex region due to high dose methylphenidate administration. The dose-related accumulation of the astrocytes in capillary wall might well be a consequence of the need for nutrition of the neuronal tissue, due to transport mechanism deficiency related to neuronal and vascular degeneration. Thus, we believe that the therapeutic dose of methylphenidate must be kept in minimum level to prevent ultrastructural changes.

Hepatopathy and Reno-cardiopathy Induced by Ritalin in Rats

Abstract

The aim of the present investigation was to illustrate the pathological oxidative toxic effects
of ritalin induced tissue damage on different organs of rats. Animals were divided into two groups; G1:
normal control (not received any drug), G2: Ritalin treated group. Ritalin administered orally using a
single dose of 1 mg/ 100gm body weight. The pathological toxic effects of this drug on different tissue
organs (liver, kidney and heart) were studied after three different experimental periods (after 10, 20 and
30 days) just after drug administration. The results showed that ingestion of Ritalin induced significant
increase in the activity of xanthin oxidase (XO, free radical producing enzyme), coupled with elevated
level of nitric oxide (NO) in liver, kidney and heart of Ritalin-treated rats versus normal animals,
indicating oxidative tissue damage. The deterioration of these biomarkers was in line with induction of
malondialdehyde (MDA, index of lipid peroxidation) in kidney, and decreased in adenosine triphosphatase
(ATPase) and lactate dehdrogenase (LDH) activities in cardiac tissue. [Isochroma-Reborn note: loss of energy conversion capacity]

The tissue injury induced in liver of rats under the effect of Ritalin was documented by a depletion in the activity of liver sorbitol
dehydrogenase (SD) with elevation in liver serum marker enzymes, aspartate aminotransferase (AST),
alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT). In addition, the pronounced
increased levels of serum biomarkers of kidney function, creatinine and uric acid as well as in serum
index enzyme of heart, creatine phosphokinase (CPK) in Ritalin treated rats in relation to normal animals,
indicating the adverse toxic effects of the used drug on kidney and heart tissues. The current investigation
also demonstrates that ingestion of Ritalin to rats led to a decrease in level of hemoglobin (Hb) compared
with normal animals. The toxic effect of the tested drug on the histomorphology of the studied organs was
also conducted. The degenerative necrotic alterations observed in biochemical parameters and reflected by
histopathological pictures were severe in the three studied periods.

There's tons more but I have to go to bed.

Edited by Isochroma-Reborn, 26 March 2013 - 05:34 AM.

[therein]

I hate being this guy but those dosages are ridiculously high. I weigh around 100kg and I usually take 5mg Methylphenidate, 10mg at most. Nobody is prescribed more than 90mg per day, and if you were to follow those rat studies, we would have to take 975mg, 5 days per week for 3 months. I am not even accounting for the rat->human conversion. It would be easily more than 1g.

But if your point is that it has an LD50 and toxicity, yes, I totally agree. It is not comprable to racetams in that sense.

Edited by therein, 26 March 2013 - 05:40 AM.

[peakplasma]

I hate being this guy but those dosages are ridiculously high. I weigh around 100kg and I usually take 5mg Methylphenidate, 10mg at most. Nobody is prescribed more than 90mg per day, and if you were to follow those rat studies, we would have to take 975mg, 5 days per week for 3 months. I am not even accounting for the rat->human conversion. It would be easily more than 1g.

I hate being that guy but you have no idea what you're talking about... you really think rat->human doses mg/kg are converted upward?

MPH rat doses are much greater due to differences in metabolism + adjustments for body surface area and therefore, are by no means representative of human equivalent doses. 2mg/kg is a threshold dose so 5-20mg/kg is high but reasonable oral dosage for a rat.

Edited by peakplasma, 26 March 2013 - 07:05 AM.

[therein]

I guess I was wrong about that. So are those dosages on the rat studies reasonable dosages for therapeutic results in humans?

Edited by therein, 26 March 2013 - 07:26 AM.

[synaptiq]

Anyone who ordered Sunifiram from NSN, did you guys get an email back from them about tracking information or anything about your item being shipped? I didn't get anything.

Just got an email from NSN,

"We have prepared your package and have either already shipped it or will be doing so within a few hours."

They also included a tracking number for it. That was surprisingly fast, since I placed the order earlier today. So it should be here in about 3 days!

I got that same email last night. I'm glad they're burning the midnight oil (literally - mine came at 12:15am EDT) to get all the orders out.

Edited by synaptiq, 26 March 2013 - 10:43 AM.

[Isochroma]

Good news!

I got a reply this morning from Fulvio Gualtieri <fulvio.gualtieri@unifi.it>, the discoverer of Sunifiram and Unifiram and the team's lead researcher!

First, below is the email I sent him yesterday, then the reply:

Your dream has now come true.

As of today Sunifiram is available to buy in the USA or anywhere in the world consumer market online:

New Star Nootropics [located in the state of Arizona, USA] has just put it up for sale in small quantities affordable to anyone for personal use - and they ship internationally by Mail or Express Mail.

They also have HNMR and HPLC results to show the purity of their product.

And I have also found a Chinese manufacturer - Trust&We Group - who now has Sunifiram in stock in large quantities for sale directly to anyone for low prices!

To see all the details check my Racetam Prices list - Sunifiram is near the bottom of the list in the yellow table.

Soon people will start reporting their results with Sunifiram, so check these discussions on the Longecity Forum for new reports:

Longecity Forum: Ampakines!?

Longecity Forum: Sunifiram

Also, Trust&We Group will have Unifiram for sale mid-April of this year - in only half a month's time!

Check my Racetam Prices list for their pricing.

Yours,

Jason Lalancette

Then today's reply:

Dear Jason,

thank you for your mail. I am delighted to know that so many persons are interested to our compounds but not surprised: I always thought that they have very good pharmacodynamic and pharmacokinetic properties. Unfortunately our budged did not allow further development of the most promising molecules. As I told you, I am retired, so I forwarded your message to Prof. Maria Novella Romanelli who is now the responsible of this research. She is continuing to study structure activity relationships with very good results but at present her budget is quite reduced because of the Italian financial problems and the research is progressing very slowly. Do you know if some of the companies interested would like to make a research agreement to give financial support the this research?

Best regards, Fulvio Gualtieri

PS- I did not understand what use the buyers make of sunifiram. Personal use, research, clinical trials ? Can you please inform us about? In any case I continue to discourage personal use until the drug is proved to be safe.

Fulvio Gualtieri,

Professor Emeritus of Medicinal Chemistry

Department of Neurosciences, Psychology,

Drug Research and Child Health (NEUROFARBA)

Section of Pharmaceutical and Nutraceutical Sciences

University of Florence,

Via Ugo Schiff 6

50019 Sesto Fiorentino (Fi) Italy

Tel. ++39 055 4573694

Fax ++39 055 4573671

So I replied thus:

Thanks for your reply!

The buyers are for personal use, they will test it for Nootropic activity and report their perceptions on the forum links I sent you.

Most are experienced with other Nootropics like Piracetam so they will also be able to offer comparison of the effects.

Yes, maybe you can get a discount from these two companies if you tell them who you are!

I think they would be very happy to hear from you, the discoverer of these amazing new products.

Yours,

Jason Lalancette

Edited by Isochroma-Reborn, 26 March 2013 - 03:05 PM.

[peakplasma]

It's awesome that he even forwarded you to Prof. Maria Novella Romanelli... although, it's unfortunate that the lingering financial crisis is a limit on their research.

It's not surprising that he would discourage personal use but I hope this gives them some ammunition to fundraise.

[Isochroma]

Another big question is the half-life of Sunifiram - what if it only works for an hour?

I should re-read the papers to see if they tested it but I'm sure they did not.

[brendan1]

Take it hourly? Just kidding... would be good to know

[synaptiq]

There's really no substitute for human pharmacokinetic studies, since enzymes vary so widely between species. I guess we'll have to settle for informal bioassays.