Combatting RU58841 side effects

[Swooping]

Swooping, would you happen to know the life time of fin in the system? How long after one quits would it leave the system completely. I reckon it would take a week or half for Ru.

We will speak about approximations again but generally the half life of finasteride is ~4.7 to ~7.1 hours, this may accumulate over time though. A single dosage of finasteride may suppress serum DHT for up to 4 days. So I would guess finasteride would take some days to completely leave your system, especially after prolonged usage.

Finasteride undergoes extensive hepatic metabolism to essentially inactive metabolites, which are eliminated through the bile and urine. The terminal elimination half-life (t1/2z) is 4.7 to 7.1 hours; but despite this, slow accumulation occurs with multiple doses. Values of t1/2z are higher in elderly men, but no dosage adjustments are necessary. Likewise, no dosage adjustments are necessary for patients with renal dysfunction, since the metabolites which accumulate are relatively inactive and well tolerated, and because greater faecal excretion of the metabolites occurs in these patients. The effect of hepatic dysfunction on the metabolism of finasteride is unknown. Therapeutic doses of finasteride produce a rapid and pronounced effect in reducing both plasma and prostate tissue levels of DHT. Doses below 0.5 mg/day do not produce much suppression of DHT levels, and doses above 5 mg/day have little additional benefit. A single dose of finasteride suppresses serum DHT levels for up to 4 days, longer than would be expected from the serum terminal elimination half-life (t1/2z) of the drug: this is probably due to the high affinity that finasteride has for the 5 alpha-reductase enzyme.

[lilpauly]

[QUOTE=goldnt;193435]

no not all . I have gyno and flares up .[/QUOTE

Alright and what what that german website for kb solution again lilpauly? Im going to switch to that right away.

http://www.medizinfuchs.de/preisverg...zn-946384.html. U must add a little ethanol I believe , to make a 5% sokution

[goldnt]

[QUOTE=lilpauly;193434]no not all . I have gyno and flares up .[/QUOTE

Alright and what what that german website for kb solution again lilpauly? Im going to switch to that right away.

[lilpauly]

Once gyno develops only surgery can remove it right?

no not all . I have gyno and flares up .

[goldnt]

Once gyno develops only surgery can remove it right?

[goldnt]

gyno and exercise don't really relate. i was working out regularly too but it didn't prevent me from developing gyno.

Your absolutely right. It helps a bit but not really effective. Im starting to dose down on the ru to help stop these effects. Ive been on the ru for about a year now and these effects came out of no where.

[inbrugge]

Swooping, would you happen to know the life time of fin in the system? How long after one quits would it leave the system completely. I reckon it would take a week or half for Ru.

[inbrugge]

Yeah I am affraid you're right. It's a shame though, I saw RU as my last resort but now even my last resort seems kind of a bad option. I guess it's no different from you.

How bad is your gyno? Is it on both sides? I only have gyno in my right nipple, something that really baffles me tbh. My androgen receptors must be way more sensitive in my right nipple or something weird like that

My gyno is on both sides. However, it seems to be stronger on the left side. It seems like it will deflate for a few days here and there and then flare back up. I hope it goes away in a couple of months, this is really holding me back from going on Ru again.

Thanks for the answer, Swooping. I will be reading that.

[Swooping]

But what I don't get is the following: If the half life is that short and if it's being metabolized to an inactive metabolite immediately when going systematic, then why are some people experiencing side effects? Or let me put this more clear, why are some people experiencing side effects throughout the whole day and not just the first few hours (when most of the RU is still in our bodies)?

Good question. Biology isn't math. Pharmacokinetics (http://en.wikipedia.org/wiki/Pharmacokinetics) studies the moment from when a drug is administered to the point it is eliminated from the body with rough models. Note how I say "rough". Thing is everybody is different. Such models give only an approximation. The real actual half life can differ between different people. Enzymes of a person for instances are involved often in metabolism of various drugs/compounds. The quantity of these enzymes varies according your genetics. So the fact that RU58841 calculated half life is 1 hour doesn't mean that it applies to your body, it may be longer, may be shorter. Same with other many drugs including finasteride.

Then we don't even get to the point of how people can react differently to drugs as you know. People vary greatly too in response to drugs in terms of side effects. We all just have different genetics.

[Swooping]

So how does it accomplish anything if the half life is only 1 hour? Or does that apply only to the Ru that goes systematic. How long does the ones attaching to the receptors stay active?

A compound for instance can have a half life of 3 hours but only stay bound to a receptor for a few minutes. Read this article it will let you understand more of it; http://www.pharmaceutical-journal.co...065576.article.

Studying how long a drug stays bound to a receptor can help scientists develop more effective medicines.

One of the best-selling antihypertensive drugs candesartan lowers blood pressure more effectively than any other drug in its class. One possible reason for this effectiveness is its binding kinetics: the active agent spends several hours bound to its target receptor, the angiotensin II receptor, compared with just a few minutes for losartan — another drug in its class.

“It has been postulated that for this reason candesartan is advantageous because it produces more prolonged blood pressure lowering, meaning that it has greater efficacy at lower doses and retains efficacy in the event of a missed dose,” explains Mike Waring, principal scientist at AstraZeneca, which markets the drug as Atacand.

Over the past five years, scientists have increasingly been studying drugs’ binding kinetics, which determine how fast a drug and its receptor associate (K on ) and dissociate (K off ). There is mounting evidence to suggest that the ‘residence time’ — a term introduced by Robert Copeland and colleagues at GlaxoSmithKline in 2006 to describe the time a drug remains bound to its target — has a strong influence on a drug’s clinical success.

Only 10% of drug candidates that enter phase I trials end up being approved by the US Food and Drug Administration[1] . To try to reduce this attrition, pharmaceutical companies have started studying binding kinetics in drug discovery programmes, but this is not yet being systematically applied because of a lack of experience and uncertainty about its importance.

“Until recently, binding kinetics has been ignored — the least we can do is pay more attention to it,” says Ad IJzerman, a medicinal chemist at the University of Leiden in the Netherlands. “We want to convince the research community you can’t live without it.”

Molecular basis

The concept of binding kinetics dates back to work in the early 1960s by William Paton, one of the pioneers of pharmacology [2[9]] [3] . In one paper, Paton postulated a rate theory, which uses the interaction of a drug with its receptor to explain drug action, potency and speed of offset3 .

Several important advances have since led to the current interest. In 1984, Motulsky and Mahan laid the theoretical foundations for binding kinetics and outlined the equations used to measure it[4] . And in 2004, David Swinney highlighted the importance of the biochemical mechanism of drug action in drug efficacy and safety[5] .He described the potential discovery and development risks associated with the binding mechanism of drugs and proposed simple rules to minimise them.

However, researchers have tended to focus on the strength of the binding between a drug candidate and its target (the affinity), rather than on how long the drug remains bound to the target (the residence time). The affinity of a drug is the concentration at which 50% of the target receptors are occupied. This is the ratio of K off to K on but says nothing about the binding kinetics.

“Initially, researchers believed that if a drug has good affinity, it would have a good effect. But this is not the case,” says IJzerman. “You can have a good website, but if you don’t stick to its pages long enough, you probably won’t have learnt that much.”

He explains that two drugs can have the same affinity to a receptor but have different binding kinetics, and these may affect the drug’s efficacy. “If you focus on affinity alone, you’d have difficulty in selecting promising drug candidates,” he says.

Four key factors are thought to play a part in controlling drug–receptor binding kinetics at a molecular level: molecular size, hydrophobic effects, electrostatic interactions, and conformational fluctuations[6] .

“It has been observed that as you increase the hydrophobicity of a drug, it creates a higher energy barrier; in other words, it makes it harder for the drug to dissociate from its receptor,” says Waring. “The hydrophobic parts of a drug are shielding the hydrogen bond from the water.” He adds that the conformational flexibility of a drug is also being studied to see how it affects the binding kinetics. In general, more flexible compounds tend to have longer residence times at the target receptor.

[Illusion]

Illusion, thanks for the response. it answers a lot of questions. I agree SJW seems to be to good to be true as a problem-free way to get rid of potential Anti-Androgen sides.

Also, your DHT theory sounds good on paper, but we have no idea if that will work. It definitely would be counter-productive for finasteride, though. However, I don't think it's a good idea to be messing with the hormone balance that much. One medicine is already risky enough, I wouldn't try to counter Ru sides by adding another factor which we have no idea about the side effects. However, if one was willing to try it I'd be interested in the results. But honestly, I'd be so hard the gauge what was going on. You'd have to be 100% certain about previous Ru sides, and again be 100% certain that it was the external DHT that took them away. There are cases when sides reside by themselves through time as the body adjusts.

I think the best route for A-A is just to be ready for the sides. If my gyno from topica fin gets better, I will try Ru again at a very very low dosage like 15 mg.

Yeah I am affraid you're right. It's a shame though, I saw RU as my last resort but now even my last resort seems kind of a bad option. I guess it's no different from you.

How bad is your gyno? Is it on both sides? I only have gyno in my right nipple, something that really baffles me tbh. My androgen receptors must be way more sensitive in my right nipple or something weird like that

[Illusion]

Jup. Thing is RU58841 half life is extremely short, 1 hour. When you apply it to your skin RU58841 is already being metabolized immediately to an inactive metabolite which has a way weaker affinity to the androgen receptor. Btw it will never touch your hormones, just targets the androgen receptor. It won't mess with your production of hormones.

Well, there goes my theory about increasing DHT production. If you say it doesn't touch our hormone production, it doesn't matter how much we produce anyway. It also means that we shouldn't be looking into the "change your hormone level" route to combat RU sides, which by the way isn't a very desirable route to go down in the first place.

But what I don't get is the following: If the half life is that short and if it's being metabolized to an inactive metabolite immediately when going systematic, then why are some people experiencing side effects? Or let me put this more clear, why are some people experiencing side effects throughout the whole day and not just the first few hours (when most of the RU is still in our bodies)?

[inbrugge]

Jup. Thing is RU58841 half life is extremely short, 1 hour. When you apply it to your skin RU58841 is already being metabolized immediately to an inactive metabolite which has a way weaker affinity to the androgen receptor. Btw it will never touch your hormones, just targets the androgen receptor. It won't mess with your production of hormones.

So how does it accomplish anything if the half life is only 1 hour? Or does that apply only to the Ru that goes systematic. How long does the ones attaching to the receptors stay active?

[inbrugge]

Illusion, thanks for the response. it answers a lot of questions. I agree SJW seems to be to good to be true as a problem-free way to get rid of potential Anti-Androgen sides.

Also, your DHT theory sounds good on paper, but we have no idea if that will work. It definitely would be counter-productive for finasteride, though. However, I don't think it's a good idea to be messing with the hormone balance that much. One medicine is already risky enough, I wouldn't try to counter Ru sides by adding another factor which we have no idea about the side effects. However, if one was willing to try it I'd be interested in the results. But honestly, I'd be so hard the gauge what was going on. You'd have to be 100% certain about previous Ru sides, and again be 100% certain that it was the external DHT that took them away. There are cases when sides reside by themselves through time as the body adjusts.

I think the best route for A-A is just to be ready for the sides. If my gyno from topica fin gets better, I will try Ru again at a very very low dosage like 15 mg.

[Swooping]

Another thought popped in...

RU is stopping a certain %age of T and DHT from binding to the hair follicle right?

So if RU will go systematic, does that mean that it will both reduce your T and DHT?

Jup. Thing is RU58841 half life is extremely short, 1 hour. When you apply it to your skin RU58841 is already being metabolized immediately to an inactive metabolite which has a way weaker affinity to the androgen receptor. Btw it will never touch your hormones, just targets the androgen receptor. It won't mess with your production of hormones.