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Meldonium - would this drug help ME/CFS patients ?

Messages
40
Location
Melbourne, Australia
What is Meldonium, and what does it do to your body?

http://mobile.abc.net.au/news/2016-...does-it-do-to-your-body/7228670?section=sport

Brain Performance:
  • Meldonium is associated with improved blood flow, including to the brain. At least three studies have shown mood-improving effects as well as increased learning and memory performance.
Central Nervous System:
  • At least two studies have shown enhanced activation of central nervous system (CNS) functions. One review also found it protects against stress.
Effects on Oxygen Use:
  • Meldonium has been found to improve endurance properties and aerobic capabilities of athletes.
  • It helps stop mitochondria ("powerhouses" of cells) from being overloaded by fatty acid breakdown, by stopping carnitine activites. It instead shifts focus towards the breakdown of carbohydrates, which requires less oxygen.
  • One review also found increased glycogen in the cells during exercise.
Heart Performance:
  • Meldonium has anti-ishemic properties, meaning it can prevent strokes caused by lack of blood flow. It is used clinically to treat angina, myocardial infarction and chronic heart failure.
Kidneys:
  • One review of the effects of meldonium found lower levels of lactate and urea in blood
 
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Abha

Abha
Messages
267
Location
UK
Hi sue-la-la
This is the drug that Sharapova has admitted to taking(in the news today)I have copied this from a website...Sharapova had partnered with the brand since 2004.

Meldonium is manufactured in Latvia. It is used in Lithuania and the Russian Federation but is not approved by the U.S. Food and Drug Administration. A number of athletes have tested positive for the drug since Jan. 1: Abeba Aregawi (Ethiopian-born, Swedish nationality, 1,500-meter world champion), Eduard Vorganov (Russian cyclist), EndeShaw Negesse (Ethiopian marathoner), Ekaterina Bobrova (Russian ice dancer) and Olga Abramova (Ukranian biathlete).
 

Scarecrow

Revolting Peasant
Messages
1,904
Location
Scotland
The Sharapova story got me mulling about this yesterday, too.

Interestingly, the paper that @Snow Leopard linked to hypothesises that reduced formation of carnitine palmitoyltransferase-I is responsible for the deficiency in long-chain acylcarnitines measured.

Paradoxically, this review (http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2005.tb00267.x/epdf) states that:

Tsoko et al. (66) reported that in addition to reducing carnitine concentrationinthe heart, skeletal muscles and kidneys of rats, mildronate produces a compensatory increase in acyl-CoA synthetase and carnitine palmotoyltransferase I in liver mitochondria and in peroxysomal fatty acid oxidation.
yet mildronate (meldonium) also seems to reduce long-chain acylcarnitines.

Meldonium may be worth a closer look. My metabolic knowledge is woeful and I don't have time to search further just now but this looks intriguing.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
Cartinine deficiency leads to chronic muscle weakness and muscle pain:
https://en.wikipedia.org/wiki/Systemic_primary_carnitine_deficiency

Carnitine palmitoyltransferase I deficiency leads to hypoketotic hypoglycemia.
https://en.wikipedia.org/wiki/Carnitine_palmitoyltransferase_I_deficiency
wikipedia said:
People with this disorder typically also have an enlarged liver (hepatomegaly), muscle weakness, and elevated levels of carnitine in the blood.

Carnitine palmitoyltransferase II deficiency is interesting in that the effects are transient -
https://en.wikipedia.org/wiki/Carnitine_palmitoyltransferase_II_deficiency

Wikipedia said:
Characteristic signs and symptoms include rhabdomyolysis (breakdown of muscle fibers and subsequent release of myoglobin),[5] myoglobinuria, recurrent muscle pain, and weakness. It is important to note that muscle weakness and pain typically resolves within hours to days, and patients appear clinically normal in the intervening periods between attacks.[4] Symptoms are most often exercise-induced, but fasting, a high-fat diet, exposure to cold temperature, or infection (especially febrile illness) can also provoke this metabolic myopathy.[4][5]
 

Scarecrow

Revolting Peasant
Messages
1,904
Location
Scotland

Deltrus

Senior Member
Messages
271
I'd be scared to take it because if your problem is due to b vitamins etc then your body would be struggling to metabolize energy as it is. Limitting strategies for your body to make energy might completely fuck you over. This drug lowers carnitine in cells so that your body is forced to rely on glycolysis. I believe pyruvate, the product of glycolysis, is also a fatty acid, but is very short, and it goes through different pathways. I tried to learn further today but got much too tired.

All I know for sure is that getting you b vitamins right is essential before even thinking about trying out this drug. B1 and I think a few more are extremely important for these pathways and they wont function properly at all if you are deficient.
 
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Scarecrow

Revolting Peasant
Messages
1,904
Location
Scotland
Regardless to what's is or isn't going on with carnitine and fatty acid metabolism (ok, that's a big 'regardless'), meldonium's useful mechanism of action seems to be to shift to an alternative energy pathway, particularly in conditions of hypoxia, which may be another of our problems.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
The paper you linked didn't show reduced CPT-I but proposed that it could be responsible for reduced levels of long-chain acylcarnitines, if I interpreted it correctly.


Yes, there are other possibilities to explain the paper I linked, something else effecting the carnitine levels in the cytosol for example.

There is some evidence that meldonium increases levels of CPT-I.


Yes, it is a dynamic system - if you suppress one thing, the cell tries to compensate another way. The end result of meldonium is still a suppression of fatty acid metabolism. Boosting levels of CPT-I is not desirable in itself if fatty acid metabolism is suppressed overall.

Another example:
http://cpt.sagepub.com/content/17/2/215.short

Also note that much of the literature talks about meldonium having benefits in the context of hypertension-related heart disease. The hypoxia case they are talking about is post-ischemia.

Another study:
Potential Therapeutic Role of L-Carnitine in Skeletal Muscle Oxidative Stress and Atrophy Conditions
http://www.hindawi.com/journals/omcl/2015/646171/

There are plenty more along those lines. All this suggests to me is that taking Moldronate/Meldonium is likely to harm more than help us.
 
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anciendaze

Senior Member
Messages
1,841
@Christopher

Haven't gone very deep into the subject. At the moment I'm trying to find ways of avoiding the reduced perfusion and hypoxia in the first place. Reperfusion injury is not at all trivial, and seems to have deep evolutionary roots, which implies it would not be easy to deal with. This may be a personal idiosyncrasy caused by my own serious trouble with delayed orthostatic hypotension. At the moment I'm looking more at autonomic problems. It looks easier to modify control than to directly intervene in fundamental metabolic processes.

Have to run now to make a doctor's appointment, which you will understand consumes most of my activity for the day.
 

hvac14400

fatty & acid : )
Messages
189
I'd be scared to take it because if your problem is due to b vitamins etc then your body would be struggling to metabolize energy as it is. Limitting strategies for your body to make energy might completely fuck you over. This drug lowers carnitine in cells so that your body is forced to rely on glycolysis.

taking high dose of l-carnitine (approx more than 2-3g a day) also shifts your metabolism into glycolisis - don't you know that? so what - it feels just great, don't be scared and try this - you'll not die.

mildronat helps too, in the same way, but gives less pronounced effect - i've tried them both in very high doses.
 

Deltrus

Senior Member
Messages
271
By what mechanism? Carnitine isn't used in glycolysis, it is used in the branched amino acid catabolism pathway, it should do the opposite of what meldonium does. Supplementing alcar would make your BCAA catabolism pathway more effective and add more options while meldonium removes options and makes the BCAA catabolism pathway weaker.

Here's the only study I got searching "l carnitine glycolysis": http://www.ncbi.nlm.nih.gov/pubmed/11099658

Edit this study says it increased glycolysis but only in diabetic rats which is weird. http://www.ncbi.nlm.nih.gov/pubmed/7781011

Edit apparently it boosts glycolysis through donating acetyl groups and NOT from the carnitine. http://www.ncbi.nlm.nih.gov/pubmed/1740427

At any rate alcar adds while meldonium takes away. Safety cannot be correlated.
 
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hvac14400

fatty & acid : )
Messages
189
i can't post links till 5 posts so sorry, and that article in russian anyway : )
but you need pure carnitine - not acyl one.
 

charles shepherd

Senior Member
Messages
2,239
From the discussion about this drug on the MEA Facebook page:

THE MARIA SHAROPOVA EFFECT – COULD THAT BANNED DRUG BE ANY USE TO M.E. OR POTS SUFFERERS?

Anonymous writes:

I would be interested to hear Dr Shepherd's take on the drug meldonium which has been in the press recently due to a certain tennis player.

The reason I ask is that the press reports are stating that it increases blood volume which made me wonder if it could be of some use to me / pots suffers? Has this drug ever been prescribed, tested in this manner?

Please can you make my question anonymous

Thanks

Write a comment...

Anon - We have had quite a few queries about this drug today - so I have prepared a reply that covers the main queries. This is it:

I have followed the media story you refer to today and read up the pharmacology of this drug

From the information available it appears to increase tissue oxygenation and may be of benefit in the treatment of angina and heart failure. But it does't increase blood volume.

Meldonium is made in Latvia and seems to be used in Eastern Europe and Russia

It is not used here in the UK or in the USA and does not have FDA approval in the USA

So I think there may be some doubts over the actual efficacy (and possibly safety) in relation to heart disease

And I think there are far better drugs available here in the UK for heart disease than this one

As with any heart drug that acts in this way, it may have an effect on exercise tolerance and increase excerise capacity - but there are other drugs and foods (good scientific evidence here for beetroot juice:http://www.ncbi.nlm.nih.gov/pubmed/24089377) and supplements that have similar properties

So I don't think this particular drug could be regarded as a high priority item for a clinical trial in relation to ME/CFS

Good summary of key points here:

http://www.theguardian.com/.../meldonium-maria-sharapova...

Dr Charles Shepherd
Hon Medical Adviser, MEA
 

hvac14400

fatty & acid : )
Messages
189
By what mechanism? Carnitine isn't used in glycolysis

by this one

Физиологические концентрации карнитина обладают насыщающим действием на карнитин-пальмитоил-трансферазу I, а увеличение дозы препарата не повышает транспорт ацильных групп жирных кислот в митохондрии при участии данного фермента. Однако, это приводит к активации карнитин-ацилкарнитин-транслоказы (которая не насыщается физиологическими концентрациями карнитина) и падению внутримитохондриальной концентрации ацетил-КоА, который транспортируется в цитозоль (через образование ацетилкарнитина). В цитозоле избыток ацетил-КоА подвергается воздействию ацетил-КоА-карбоксилазы с образованием малонил-КоА, который обладает свойствами непрямого ингибитора карнитин-пальмитоил-трансферазы I. Уменьшение же интрамитохондриального ацетил-КоА коррелирует с повышением уровня пируватдегидрогеназы, которая обеспечивает окисление пирувата и ограничивает продукцию лактата. Таким образом, антигипоксическое действие карнитина связано с блокадой транспорта жирных кислот в митохондрии, является дозозависимым и проявляется при назначении высоких доз препарата, в то время как низкие дозы обладают лишь специфическим витаминным действием.

terapy6_ris2.gif
 

helen1

Senior Member
Messages
1,033
Location
Canada
I found this about meldonium:

The action of the drug is to prevent accumulation of cytotoxic intermediate products of fatty acid beta-oxidation in ischemic tissues and to block this highly oxygen-consuming process. Mildronate has a beneficial effect on cerebral circulation disorders and central nervous system functions. Mildronate is prescribed for patients with decreased working efficiency.

It sounds good to me, written that way. Is anyone else apart from hvac going to try it? Has anyone tried beetroot juice as Dr Shepherd linked?

@hvac14400 Could you give us more details of the effects you had with meldonium? And how long did you use it for?