Tag Archive for SARMs

AICAR, GW1516 Are An Exercise In A Pill

AICAR, GW1516 Are An Exercise In A Pill

AICAR and GW1516 experiments suggest that these two drugs, also called exercise in a pill, might protect against gaining weight on a high-fat diet, which might make it useful for treating obesity.

Researchers have identified two drugs, AICAR and GW1516, that mimic many of the physiological effects of exercise. The drugs increase the ability of cells to burn fat and are the first compounds that have been shown to enhance exercise endurance.

Both AICAR and GW1516 can be given orally and work by genetically reprogramming muscle fibers so they use energy better and contract repeatedly without fatigue. In laboratory experiments, mice taking the drugs ran faster and longer than normal mice on treadmill tests. Animals that were given AICAR, one of the two drugs, ran 44 percent longer than untreated animals. The second compound, GW1516, had a more dramatic impact on endurance, but only when combined with exercise.

Ronald M. Evans, the Howard Hughes Medical Institute investigator who led the study, said drugs that mimic exercise could offer potent protection against obesity and related metabolic disorders. They could also help counter the effects of devastating muscle-wasting diseases like muscular dystrophy. Evans and his colleagues, who are at the Salk Institute for Biological Studies, published their findings on July 31, 2008, in an advance online publication in the journal Cell.

Concerned about the potential for abuse of the two performance-enhancing drugs AICAR and GW1516, Evans has also developed a test to detect the substances in the blood and urine of athletes who may be looking for way to gain an edge on the competition.

In 2004, Evans and his colleagues genetically engineered mice that had altered muscle composition and enough physical endurance to run twice as far as normal mice. These “marathon mice” had an innate resistance to weight gain, even when fed a high-fat diet. “We made these mice and they had low blood sugar, they resisted weight gain, they had low fats in their blood. They were much healthier animals,” Evans said. “And when we put them on a treadmill, the engineered mice ran twice as far than normal mice – they transformed into remarkable runners.”

The scientists achieved these effects by modifying a gene called PPAR-delta, a master regulator of numerous genes. Evans and his colleagues showed that by enhancing PPAR-delta’s activity, they had shifted the genetic network in muscle cells to favor burning fat over sugar as their energy source. But the effects seen in the marathon mice were caused by a genetic manipulation that was present in their bodies as their muscles were developing. Evans’s group began to wonder whether they could duplicate these effects by turning on PPAR-delta in adult mice.

“We had shown that we could pre-program muscle using genetic engineering. If you express this gene while the muscle is being formed, you can increase the amount of non-fatiguing muscle fibers,” Evans says. “But what about reprogramming in an adult? When all the muscles are in place, can you give a drug that washes over the muscle for a few hours at a time and reprograms existing muscle fibers? That’s a very different question.”

PPAR-delta has long been an attractive drug target because of its central role in metabolism, so Evans and his colleagues had no shortage of chemical compounds available to test. They began by testing a compound called GW1516. They treated young adult mice with the drug for five weeks. “We measured gene changes and the muscles looked like they were responding, so we knew the drug was working.”

Thus, while fully expecting the drug to dramatically increase endurance – Evans says, “There was no change at all in running performance. Nothing — not even a percent.”

Surprised by this spectacular failure, Evans and his colleagues decided to try a different approach, based on real-life experience. “If you’re out of shape – and most of us are – and you want to change, you have to do some exercise. The way we reprogram muscle in adults is by training.”

So the scientists subjected two groups of mice — one that received the drug and one that did not — to interval training. The mice ran for 30 minutes on a slow treadmill five days a week for a total of four weeks. At the end of the training period, all of the mice – regardless of whether they had received GW1516 – had improved their performance. Those that had received GW1516, however, ran 68 percent longer than those that had only done the exercise training. “The dramatic effect of the drug was stunning,” Evans said.

The scientists were intrigued by this synergistic interaction and wanted to know how exercise allowed the drug to work. One possibility was an enzyme called AMP kinase (AMPK). During exercise, cells burn ATP as their primary source of energy. In the process, they create a by-product called AMP. When cells sense the presence of AMP, they activate AMPK. Activation of AMPK creates more ATP for the cell to burn. AMPK also triggers changes that lower blood sugar, sensitize cells to insulin, enable cells to burn more fat, suppress inflammation, and otherwise influence metabolic pathways. This is one reason that exercise is so beneficial.

Evans’s team found that in addition to replenishing the cell’s energy stores, AMPK also assists PPAR-delta in activating its gene targets. “It hops onto PPAR-delta in the nucleus and turbo-charges its transcriptional activity,” Evans explained. “We think AMPK activity is the secret to allowing PPAR-delta drugs to work.”

The critical question was whether chemical activation of AMPK is sufficient to trick the muscle into thinking it has been exercised. The second drug, called AICAR, enabled them to answer that question. AICAR mimics AMP, Evans said, “so muscle thinks it’s burning fat.” The researchers were encouraged when they found that when they gave the drug to mice, they activated many of the genes in muscle that are turned on by exercise.

After four weeks of treatment with AICAR, Evans and his colleagues once again challenged sedentary mice to run on the treadmill. They found that mice that had received AICAR were able to run 44 percent longer than untreated mice. “This is a drug that is like pharmacological exercise,” Evans says. “After four weeks of receiving the drug, the mice were behaving as if they’d been exercised.” In fact, he says, those that got the drug actually ran longer and further than animals that received exercise training.

The animals receiving AICAR improved their running performance and their ability to burn fat. None of these effects, however, were as strong as they were in the animals that received both exercise and activation of PPAR-delta via GW1516.

Evans said this indicates that the benefits are likely due to collaboration between cells’ AMPK and PPAR-delta signaling pathways. The team’s genetic analyses supported this hypothesis; they found that AICAR and GW1516 alone activated a subset of exercise-induced genes, but activating both pathways (by combining GW1516 with exercise) activated a larger group of genes. Many of those genes regulate metabolism and muscle remodeling. Evans and his colleagues called this the “endurance gene signature.”

Like exercise, AICAR and GW1516 trigger a variety of changes that contribute to muscles cells’ improved endurance and ability to burn fat. These changes include an increase in mitochondria, the structures responsible for producing energy; a shift in metabolism that takes advantage of lipids as an energy source; and an increase in blood flow, which enables the steady delivery of fat to burn. While the scientists only examined the drugs’ effects on muscle cells in this study, Evans says it is likely that they confer benefits on other systems impacted by exercise, such as the heart and lungs.

Based on his group’s findings, Evans is optimistic about using small molecules that mimic exercise to treat and prevent a variety of common conditions. For example, the way in which AICAR and GW1516 transformed the muscle fibers of mice suggests they might help reverse the muscle frailty associated with aging or diseases like muscular dystrophy. “We have now created the potential for a really simple intervention in an area of major health problems for which there is no intervention,” he says.

More broadly, AICAR and GW1516 could offer the benefits of exercise to people who do not get enough. “Almost no one gets the recommended 40 minutes to an hour per day of exercise,” he says. “For this group of people, if there was a way to mimic exercise, it would make the quality of exercise that they do much more efficient. This might be enough to move people out of the `danger zone’ toward a lower risk, healthier set point. By intervening early, you may forestall the emergence of more serious problems.”

Evans expects these types of drugs will be attractive to a variety of individuals. “If you like exercise, you like the idea of getting more bang for your buck,” he says of GW1516. “If you don’t like exercise, you love the idea of getting the benefits from a pill,” as with AICAR. So, while Evans sees tremendous opportunities for health benefits from drugs that mimic exercise, he also sees serious potential for abuse.

“Drugs that improve health are not only going to be used by people who have medical problems. They may also be used by people who are healthy – or by athletes who want an edge,” said Evans. He noted that the sports world has long been aware of his lab’s work demonstrating a link between PPAR-delta and endurance. What’s more, GW1516 has a relatively simple chemical structure and can be synthesized easily. Evans anticipates that athletes will seek their own sources of the drug – if they haven’t already.

Concerned about the potential for abuse, Evans thought it was important to develop a test that could detect whether the drug was being used as a performance-enhancing substance. With HHMI support, his group has created a highly sensitive test that uses mass spectrometry to detect the two drugs and their metabolic by-products in the blood or urine. While the test is very reliable in mice, Evans says that further analyses are needed to ensure that it is accurate in humans. Evans, HHMI and the World Anti-Doping Agency are now working to certify the detection system and make it available in time to retroactively test athletes who compete in the 2008 Olympics

Submitted by Armen Hareyan

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How to get rid of gyno using Letrozole in Bodybuilders

How to get rid of gyno using Letrozole in Bodybuilders

I am posting this Gyno Article to help answer all of the questions regarding gyno prevention and reversal, the use of letrozole and other anti-e’s. I will go over everything in very simple easy to understand language. Also we are talking about estrogen gyno here, not progesterone (but using letro will stop progesterone related problems as well since it inhibits all estrogen anyways). Progesterone gyno will be enlargement of your nipple area, the actual aereola, not a lump under it.

To first understand why you are doing what you are doing I am going to go over a few things and a few definitions:

SERM – Selective estrogen receptor modulator. These drugs work by binding to the estrogen receptors and flooding them in a sense, making it difficult (but not impossible by any means) for estrogen to bind to the receptors and thus prevent the onset of estrogen related side effects.
Most common forms:
Tamoxifen (Nolvadex),
Clomiphene (Clomid)

AI – Aromatase Inhibitor. These drugs work by inhibiting the aromatization of estrogen. This means that in effect AI’s prevent androgens from converting to estrogen, again, making it difficult (but not impossible) for estrogen to reach receptor sites.
Most common forms:
Anastrozole (l-dex, a-dex),
Exemestane (aromasin),
Femera (letrozole).
For our purpose of reversing gyno we are interested in Letro.

Letro and your sex drive:
Letrozole will suppress your sex drive. This is another reason why it is so important to act on preventing gyno as soon as possible. Since we all know that Test should be run in every cycle this will cancel out the effect of sex drive suppression.

Running letrozole to prevent gyno:
If you decide to run estrogen protection while on cycle (and I suggest you do unless you are aware that you do not require it), you can run either a SERM or an AI. Letro will be the most powerful AI you can use, it will inhibit 98+% of estrogen using a dose as low as .25mg and even lower. This is why I suggest you do not use a dose higher than .50mg while on cycle just trying to prevent estrogen related side effects.

You will want to start running the letro approximately 2 weeks before you begin your cycle to allow it to fully stabilize in your blood. I have often heard the argument that letro takes up to 60 days to stabilize, I don’t know if I buy into this for the reason that I have reversed gyno after using letro for only 1 week. Still to be safe I recommend starting it before your cycle as stated above.

If you do decide to run letro there is absolutely no need to run another AI or SERM. Do not make the mistake of thinking more is better. Think of it this way; if letro is preventing the conversion of androgens to estrogen than there is no estrogen, what would the purpose of a SERM be when there is no estrogen to bind to the receptors? Nolva will only take away from the effectiveness of letro.

It is very important that you begin taking letrozole immediately, the longer your wait the more risk you take in not being able to reverse it.

How do I know if I have gyno?
If you have developed gyno you will have a lump behind your nipple. It will be fairly hard, and it will be tender to touch.

Running letro to reverse gyno:
I am going to go over the three different scenarios which people could fit into. Remember regardless of what scenario you are in it is important that you begin taking the letro ASAP.

1. Already using an anti-e aside from letrozole.

2. Already using letro @ a dose of .25mg or .50mg ED.

3. Not running any estrogen protection.

1.
Day 1: .25mg Letro + anti-e*
Day 2: .50mg Letro
Day 3: 1.0mg Letro
Day 4: 1.5mg Letro
Day 5: 2.0mg Letro
Day 6: 2.5mg Letro **

2.
Day 1: .50mg Letro
Day 2: 1.0mg Letro
Day 3: 1.5mg Letro
Day 4: 2.0mg Letro
Day 5: 2.5mg Letro **

3.
Day 1: .50mg Letro
Day 2: 1.0mg Letro
Day 3: 1.5mg Letro
Day 4: 2.0mg Letro
Day 5: 2.5mg Letro **

*Regardless of the anti-e you are using it is important to still use it for the first day you begin letro as the letro will not have taken any effect and you by no means want your body to be without any protection when gyno is already prevalent.

** You will remain at this dose until gyno symptoms subside. Once you believe your gyno is gone it is important to stay at this dose for another 4-7 days to ensure all traces are gone. I recommend people with a bf% over 15 stay on for a week as it may be harder to judge completely whether the lump is completely gone. Once this period is over it will be important to taper letro down slowly rather than coming off it completely. Regardless of which manner you tapered up your dose you will all taper down in the same fashion.

Day 1: 2.0mg
Day 2: 1.5mg
Day 3: 1.0mg
Day 4: .50mg***
Day 5: .25mg
***You can remain at this dose or go down further to .25mg. It is really up to you at this point. They are both very common maintenance doses as an anti-e while on cycle. Personally I have stayed with .25mg and never had a problem.

Letro and the estrogen rebound:
With your estrogen being completely inhibited there is a definite estrogen rebound as your body tries to re-stabilize the testosterone/estrogen balance. We can prevent this rebound effect by supplementing further with another AI or SERM. So, I suggest that when you are coming to the end of your cycle you will more than likely be using Nolva in your PCT so just make sure that you begin taking nolva the last day you are going to take your letro and then continue on as you would with regular PCT.

This now leads us into the question of reversing gyno while not on cycle. There are a few things to remember here. You have already waited longer than you should have, and your sex drive will be shot. You can use Tribulus 1000mg or another natural Testosterone Booster to help you in this scenario but I can’t guarantee the effectiveness. Just follow gyno reversal protocols 2 or 3. When coming off again you must taper and begin using nolvadex to prevent any rebound effect that may occur.

How much nolvadex should you use if you are not going into PCT and running this off cycle? I suggest starting at 20mg ED for a week and then lowering it to 10mg for another week and then coming off completely.
written by C_Bino

Click here to save you 25% on your next purchase of Letrozole, Nolvadex, Arimidex or Clomid

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