ULTRA HOTTER (Is methylated ATD safe for pct?)
- Thread starter enimity
- Start date
CyberMuscle
Member
Im curious as well.
natedogg
Well-known member
New Ingredients in Ultra Hotter(directly from the ALRI webpage):Yagman said:
ALRI Proprietary blend includes: 135mg
Avena Sativa Extract 20:1,
Agaricus bisporus extract.,
6-acetoxy-3-hydroxy-17-keto-etioallocholane,
17a-methyl-17b-hydroxyl-3-keto-delta 1,4,6-etioallocholtriene,
Condensed Agaricus bisporus extract.
bigpetefox
Board Sponsor
Why is it that whenever anyone sees "Methyl.." they automatically think the liver is in danger? :think:
What about products with betaine(trimethylglycine) or DMG (dimethylglycine) or even creatine monohydrate (N-Methyl-N-Guanylglycine)? See how silly it is?
What about products with betaine(trimethylglycine) or DMG (dimethylglycine) or even creatine monohydrate (N-Methyl-N-Guanylglycine)? See how silly it is?
natedogg
Well-known member
17a-methyl-17b-hydroxyl-3-keto-delta 1,4,6-etioallocholtriene: is another new and highly effective aromatase inhibiting compound. The reason is rather simple in that it binds to aromatase more tightly than any other available product due to a unique high affinity. Yes, it is an interesting analog of ATD.
So all this is is a methylated analog of ATD? How much more effective are we talking here?
So all this is is a methylated analog of ATD? How much more effective are we talking here?
natedogg
Well-known member
3,17-dioxo-etiochol-1,4,6-triene is also a site-specific (like the hypothalamus) androgen receptor agonist. Based upon some studies the unique structure of this compound allows for an 80-90% reduction in androgen receptor activity of the hypothalamus, yet only a very small 10% decrease in the rest of the body. So all of that extra testosterone you are now making really works in all the right places!
17a-methyl-17b-hydroxyl-3-keto-delta 1,4,6-etioallocholtriene is also most likely the most powerful site-specific (like the hypothalamus) androgen receptor agonist. Based upon some animal studies the unique structure of this compound allows for an 80-90% reduction in androgen receptor activity of the hypothalamus, yet only a very small decrease in the rest of the body.
The descriptions are almost identical. Does the methylated version just allow for less to be used while still being just as/more effective? Is there more to it than meets the eye?
17a-methyl-17b-hydroxyl-3-keto-delta 1,4,6-etioallocholtriene is also most likely the most powerful site-specific (like the hypothalamus) androgen receptor agonist. Based upon some animal studies the unique structure of this compound allows for an 80-90% reduction in androgen receptor activity of the hypothalamus, yet only a very small decrease in the rest of the body.
The descriptions are almost identical. Does the methylated version just allow for less to be used while still being just as/more effective? Is there more to it than meets the eye?
THE GREATEST
I'm Hungry
I'm liking the sound of this
bigpetefox
Board Sponsor
True, for androgens maybe.. These newer products are NOT androgens, not like M1T or others banned before them..Enigma76 said:
shootmeagain
Registered User
I could be wrong (it's been known to happen):
While the word METHYL may itself not warrant any undue attention (as in the examples cited above and many others), when we are talking about a [size=-1]17 alpha-alkylated [/size][size=-1]substance, i.e. - a chemically methylated substance for the purpose of increased oral bioavailabilty (by avoiding breakdown and excretion), doesn't that warrant at least a question concerning potential hepatoxicity?
Or, as perhaps in this case, IF a person HAS been using a methylated oral (for say 4-6 weeks) would it not be prudent to question the use of such a substance (as that contained in Ultra H.O.T.ter) during PCT?
[/size]
While the word METHYL may itself not warrant any undue attention (as in the examples cited above and many others), when we are talking about a [size=-1]17 alpha-alkylated [/size][size=-1]substance, i.e. - a chemically methylated substance for the purpose of increased oral bioavailabilty (by avoiding breakdown and excretion), doesn't that warrant at least a question concerning potential hepatoxicity?
Or, as perhaps in this case, IF a person HAS been using a methylated oral (for say 4-6 weeks) would it not be prudent to question the use of such a substance (as that contained in Ultra H.O.T.ter) during PCT?
[/size]
N4cer
Banned
Well, the thing with these liver dangers is that while YES, they raise liver enzyme levels, I've not yet seen a case of anyone developing a liver disorder from them. Just increased enzyme values.
How did this first poster get the kidneys involved in methylated substances? Kidneys are taxed by the higher blood pressure that androgens bring, if I'm not mistaken.
How did this first poster get the kidneys involved in methylated substances? Kidneys are taxed by the higher blood pressure that androgens bring, if I'm not mistaken.
Enigma76
Active member
Increased enzyme values indicates liver damage; while not permanent (the liver regenerates) and while I havent seen any liver problems arise from 17aa use (such as cirrosis sp?) I personally would rather damage my liver as little as possible. Not saying that it really matters for me, seeing as I dont use AAS (especially 17aa).N4cer said:
sMd2001
Banned
They think it because.....
Not everyone is a chemist, or understands the inner working of methylated substances. Why don't we cut some slack to those of us that aren't ''in the know'' about all those methylated compunds, and see what we get for an answer. Most know methylated products to carry heavier warnings of liver toxicity(by word of mouth), and those that don't have enough experience in this arena just assume that ANY methyl will be bad. Can you really blame them for trying to err on the side of caution? I would hope not.
Same way most people who don't know lots about computers think that ANYTHING that slows down their computer is a virus. Most people will never see a true virus - but they always hear about how much damage they cause, so any indication of a problem is automatically assumed to be ''virus'' infection (when it could be trojans, mail worms, etc )
bigpetefox said:Why is it that whenever anyone sees "Methyl.." they automatically think the liver is in danger? :think:
What about products with betaine(trimethylglycine) or DMG (dimethylglycine) or even creatine monohydrate (N-Methyl-N-Guanylglycine)? See how silly it is?
Not everyone is a chemist, or understands the inner working of methylated substances. Why don't we cut some slack to those of us that aren't ''in the know'' about all those methylated compunds, and see what we get for an answer. Most know methylated products to carry heavier warnings of liver toxicity(by word of mouth), and those that don't have enough experience in this arena just assume that ANY methyl will be bad. Can you really blame them for trying to err on the side of caution? I would hope not.
Same way most people who don't know lots about computers think that ANYTHING that slows down their computer is a virus. Most people will never see a true virus - but they always hear about how much damage they cause, so any indication of a problem is automatically assumed to be ''virus'' infection (when it could be trojans, mail worms, etc )
Dwight Schrute
I am faster than 80% of all snakes
Enigma76 said:
No it doens't. Increased enzyme count means its just wokring harder than normal.
Dwight Schrute
I am faster than 80% of all snakes
N4cer said:
If jaundice counts, I've seen it twice.
bigpetefox
Board Sponsor
Indeed, but my statement was that not all methylated products are toxic.. So far, the only true toxicity concerns have been with androgens and not with anything from nature.. The only way to provide a valid argument is if someone took a non AAS product which was methylated, and had their liver values checked.. As Bobo said, elevated levels are an indication of work, not trauma..sMd2001 said:Not everyone is a chemist, or understands the inner working of methylated substances. Why don't we cut some slack to those of us that aren't ''in the know'' about all those methylated compunds, and see what we get for an answer. Most know methylated products to carry heavier warnings of liver toxicity(by word of mouth), and those that don't have enough experience in this arena just assume that ANY methyl will be bad. Can you really blame them for trying to err on the side of caution? I would hope not.
Same way most people who don't know lots about computers think that ANYTHING that slows down their computer is a virus. Most people will never see a true virus - but they always hear about how much damage they cause, so any indication of a problem is automatically assumed to be ''virus'' infection (when it could be trojans, mail worms, etc )
GrossSizeRocks
New member
Never Hurt Me
I am having all I can do here to refrain from posting some smartass crap about smoking methylated cigarettes and never having any liver trouble.
I am having all I can do here to refrain from posting some smartass crap about smoking methylated cigarettes and never having any liver trouble.
Enigma76
Active member
Invalid Link RemovedBobo said:
"Liver function tests are blood tests that include alkaline phosphatase, prothrombin time (PT, a measure of blood clotting), serum bilirubin and serum albumin. The most commonly used indicators of liver damage are the alanine aminotransferase (ALT) and aspartate aminotransferase (AST), formally referred to as SPGT and SGOT. These are enzymes normally found in liver cells that leak out of these cells and make their way to the blood when liver cells are injured. The ALT is felt to be a more specific indicator of liver inflammation, as AST is also found in other organs, such as the heart and skeletal muscle.
In acute injury to the liver, as in viral Invalid Link Removed, the level of the ALT and AST may be used as a general measure of the degree of liver inflammation or damage."
Invalid Link Removed
...The liver associated enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl peptidyl transferase (GGT) are indirect measures of liver homeostasis (well being). While they have a relatively high concentration in the cells of the liver, they are also present in other tissues of the body. If the liver is damaged or the normal flow of blood or bile is obstructed, the cellular contents leak or are secreted into the blood that bathes the organ.... Any agent that damages the liver may cause elevations of the liver enzymes.
Not trying to be a jerk, just thought I would point the above out and try to clarify.
Dwight Schrute
I am faster than 80% of all snakes
Evaluation of aminotransferase elevations in a bodybuilder using anabolic steroids: hepatitis or rhabdomyolysis?
Pertusi R, Dickerman RD, McConathy WJ.
Department of Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107-2699, USA.
The use of anabolic steroids among competitive athletes, particularly bodybuilders, is widespread. Numerous reports have noted "hepatic" dysfunction secondary to anabolic steroid use based on elevated serum aminotransferase levels. The authors' objective was to assess whether primary care physicians accurately distinguish between anabolic steroid-induced hepatotoxicity and serum aminotransferase elevations that are secondary to acute rhabdomyolysis resulting from intense resistance training. Surveys were sent to physicians listed as practicing family medicine or sports medicine in the yellow pages of seven metropolitan areas. Physicians were asked to provide a differential diagnosis for a 28-year-old, anabolic steroid-using male bodybuilder with an abnormal serum chemistry profile. The blood chemistries showed elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) levels, and normal gamma-glutamyltransferase (GGT) levels. In the physician survey (n = 84 responses), 56% failed to mention muscle damage or muscle disease as a potential diagnosis, despite the markedly elevated CK level of the patient. Sixty-three percent indicated liver disease as their primary diagnosis despite normal GGT levels. Prior reports of anabolic steroid-induced hepatotoxicity that were based on aminotransferase elevations may have overstated the role of anabolic steroids. Correspondingly, the medical community may have been led to emphasize anabolic steroid-induced hepatotoxicity and disregard muscle damage when interpreting elevated aminotransferase levels. Therefore, when evaluating enzyme elevations in patients who use anabolic steroids, physicians should consider the CK and GGT levels as essential elements in distinguishing muscle damage from liver damage.
As they say, its an indirect measure and tru liver damage is found by ultrasonography and computed tomography.
"The liver associated enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl peptidyl transferase (GGT) are indirect measures of liver homeostasis (well being)."
You can easily have elevated AST or ALT with no damage whatsoever.
Pertusi R, Dickerman RD, McConathy WJ.
Department of Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107-2699, USA.
The use of anabolic steroids among competitive athletes, particularly bodybuilders, is widespread. Numerous reports have noted "hepatic" dysfunction secondary to anabolic steroid use based on elevated serum aminotransferase levels. The authors' objective was to assess whether primary care physicians accurately distinguish between anabolic steroid-induced hepatotoxicity and serum aminotransferase elevations that are secondary to acute rhabdomyolysis resulting from intense resistance training. Surveys were sent to physicians listed as practicing family medicine or sports medicine in the yellow pages of seven metropolitan areas. Physicians were asked to provide a differential diagnosis for a 28-year-old, anabolic steroid-using male bodybuilder with an abnormal serum chemistry profile. The blood chemistries showed elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) levels, and normal gamma-glutamyltransferase (GGT) levels. In the physician survey (n = 84 responses), 56% failed to mention muscle damage or muscle disease as a potential diagnosis, despite the markedly elevated CK level of the patient. Sixty-three percent indicated liver disease as their primary diagnosis despite normal GGT levels. Prior reports of anabolic steroid-induced hepatotoxicity that were based on aminotransferase elevations may have overstated the role of anabolic steroids. Correspondingly, the medical community may have been led to emphasize anabolic steroid-induced hepatotoxicity and disregard muscle damage when interpreting elevated aminotransferase levels. Therefore, when evaluating enzyme elevations in patients who use anabolic steroids, physicians should consider the CK and GGT levels as essential elements in distinguishing muscle damage from liver damage.
As they say, its an indirect measure and tru liver damage is found by ultrasonography and computed tomography.
"The liver associated enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl peptidyl transferase (GGT) are indirect measures of liver homeostasis (well being)."
You can easily have elevated AST or ALT with no damage whatsoever.
GrossSizeRocks
New member
3 Weeks?
Under "Suggested Use," it says do not use continuously for more than 3 weeks.
That's stricter than the warnings on most of the stuff we talk about at AM, isn't it?
What are we to infer from this?
Under "Suggested Use," it says do not use continuously for more than 3 weeks.
That's stricter than the warnings on most of the stuff we talk about at AM, isn't it?
What are we to infer from this?
Anarchy939
Member
Hey, suppkings still has the original formula in stock... I just stocked up on a few bottles.. I don't know about this "new" formulation and it's overall safeness, especially if used after running methylated orals..
Anarchy939
Member
hmm... must've changed since the weekend... I placed my order saturday for the original formula, and got confirmation this morning.. Hopefully it comes in as the orginal formula..milwood said:
Anarchy939
Member
ah well, I just hope it works the same as HOT did for me.jonny21 said:
GrossSizeRocks
New member
Gotta Get Rid of These Eyes
****.
Used to be a character on the original cast Saturday Night Live named Emily Latella. She would screw up like I did and reply "Ohhh, well that's DIFFERENT then."
My liver's fine, but the damn Methyl groups are fogging up my eyes. Glad it's 8 weeks and not 3.
Did I understand you right that you ordered what you thought was the old UH and received the new UH instead? That is kinda crappy of Sup King, I specifically ordered from them so I could stash a few old bottles, knowing I can get the new version anywhere from now on. That was a coupla days ago, and they did have UHot displayed, not UHottER. Got nothing against the new one, just wanted both versions to compare.
****.
Used to be a character on the original cast Saturday Night Live named Emily Latella. She would screw up like I did and reply "Ohhh, well that's DIFFERENT then."
My liver's fine, but the damn Methyl groups are fogging up my eyes. Glad it's 8 weeks and not 3.
Did I understand you right that you ordered what you thought was the old UH and received the new UH instead? That is kinda crappy of Sup King, I specifically ordered from them so I could stash a few old bottles, knowing I can get the new version anywhere from now on. That was a coupla days ago, and they did have UHot displayed, not UHottER. Got nothing against the new one, just wanted both versions to compare.
jonny21 said:
jonny21
Registered User
Nope. they were on point. They sent an e-mail re: xt delay and that they would have UHotter available on Friday. They were actually better than usual, I ordered on Friday had it today.GrossSizeRocks said:
ALR proudly touts Hotter's efficacy, who am I to doubt.
Last edited:
Cheezefacta
New member
I know I pimp Suppkings alot...but a notice was given out to everyone giving them a heads up on Ultra HOTTER. The guy over there has been awesome with every order I ever made and responds to emails in less than 5 minutes everytime. I wouldnt take credit away from that site because he always gives heads up, has really fast service, and replies to customers lightning fast. I was confused when I saw that he was "shady", when he has been the complete opposite for me.
Dwight Schrute
I am faster than 80% of all snakes
coofoostu said:
No its not.
Dwight Schrute
I am faster than 80% of all snakes
Sure. You post your studies on it being a carnicogen then I will explain to you how to interpret that study.
Then I will discuss how women have taken it for 20+ years on end.
Then I will discuss how women have taken it for 20+ years on end.
Dwight Schrute
I am faster than 80% of all snakes
They say that about Tylenol. Most OTC drugs will stress the liver as well but they are not liver toxic. Drugs, hell even massive doses of viatmines will raise liver enzymes. It doens't mean they are toxic.
About Toxicity:
ABSTRACT: Toxicity of Antiestrogens
The object of this article is to review briefly the preclinical and clinical safety of some antiestrogens.
Tamoxifen, toremifene, droloxifene, and idoxifene are polyphenylethylene antiestrogens, whereas the pure antiestrogen, ICI 182,780 or faslodex, as well as raloxifene, is of a different structure.
Tamoxifen has been shown to be genotoxic in several studies. It induces unscheduled DNA synthesis in rat hepatocytes and micronuclei in MCL-5^a cells in vitro. Tamoxifen also induces aneuploidy in rat liver in vivo and chromosome aberrations and micronuclei in mouse bone marrow.
Toremifene has also shown to be genotoxic, but to a far lower extent, by inducing micronuclei in MCL-5^a cells in vitro and by inducing aneuploidy in rat liver in vivo.
Tamoxifen has been shown to be hepatocarcinogenic in the rat in at least four independent long-term studies. The initiation of tumors in the rat is the result of metabolic activation by cytochrome P450 isoenzymes to an electrophile(s) that binds irreversibly to DNA.
The other antiestrogens have not been shown to be carcinogenic in rodents. In several independent clinical studies, the risk of endometrial cancer has increased among tamoxifen-treated women.
After reviewing the available data, the International Agency for Research on Cancer concluded that there was sufficient evidence to show that tamoxifen is a class I human carcinogen.
The increased risk for endometrial cancer occurs predominantly among women who are 50 years old or older and who have been treated with tamoxifen. It is not yet clear whether the uterine tumor formation is a result of genetic mechanisms, analogous to those seen in the rat liver or due to the estrogen agonist action of tamoxifen.
However, the other antiestrogens with a more or less similar intrinsic estrogenic potential have not been shown to be carcinogenic in humans.
Andrew James Parker
Dept. Biomedical Science,
University of Sheffield,
Sheffield, England
Updated May 25, 2000
Generic Name : Tamoxifen
USA Brand Name: Nolvadex (Zeneca Pharmaceuticals)
Other Proprietary Names: Dignatomoxi, Emblon, Fentamox, Istubol, Kessar, Mamofen, Noltam, Novofen, Oestrifen, Tamaxin, Tamifen, Tamoplex, Tamoxen, Valodex, Zitazonium
Classification: Antineoplastic; Antiestrogen
BT Dosage: 200mg/day (f) 240mg/day (m) [Adult] 60 -100mg/day [Children] Dosage depends on weight, tolerance and toxicity and varies according to individual circumstances. Always take in consultation with a physician.
Delivery: Oral tablet
Potential Side Effects: Hot flushes; Vaginal bleeding; Early onset menopause; GI distress; Vomiting; cataracts; Visual disturbances; Dizziness; thrombosis
Availability: This drug is routinely prescribed, inexpensive and should be readily available.
Abstract: The drug tamoxifen is most commonly associated with chemotherapy of breast cancer but has been used recently to treat other cancers including brain tumors. The mechanism of its action is complex involving several sites in and on cells. Current opinion suggests that its key role in malignant glioma is to inhibit a cell signaling enzyme called protein kinase C. It does this in a dose-dependent manner and consequently is administered at a much higher dose for brain tumor sufferers than is given to breast cancer patients. It has a low toxicity and its side effects are minimal. There is evidence to suggest that it should not be used in conjunction with the anti-epileptic (anticonvulsant) phenytoin. It has been used on its own and in conjunction with other drugs (adjuvant chemotherapy). Although tamoxifen does not improve all instances of brain tumor, there is considerable evidence that it is of benefit to many.A new non-invasive procedure may be able to detect those patients who will respond to tamoxifen.
TAMOXIFEN MINIREVIEW
The drug tamoxifen was synthesised in 1962 by scientists at ICI working on a contraceptive pill. Since it blocks the natural hormone estrogen (a steroid), it was classified as a nonsteroidal estrogen antagonist (8) . It has been used in the treatment of breast cancer for over 20 years (16) , although its efficacy has often been controversial (63) . Articles in the Lancet in the spring (3) and summer (61, 79) of 1998 respectively supported then refuted the value of tamoxifen with breast cancer. Later that year, the FDA approved tamoxifen citrate for reducing the incidence of breast cancer in women at high risk for developing the disease. In May 2000, an extensive study reported by Professor Sir Richard Peto has found convincingly in favor of tamoxifen, with the death rate falling by a third over ten years (54) . In addition to breast cancer, tamoxifen has been used to treat other cancers such as melanoma (30, 65) , hepatocellular carcinoma (73) , ovarian cancer (81) and prostate cancer (10) . This short review considers its application to cancer of the brain.
The action of tamoxifen is now known to operate at several sites in the cell (e.g. as a channel blocker : 2, 36, 74) and to affect numerous genes (40) but early studies concentrated on its action as an antihormone, specifically an antiestrogen (33, 67, 83) . Antiestrogenic mechanisms have been studied for around 40 years 83) but are still not fully understood. One known mechanism is that the tamoxifen molecule competes with the natural female hormone (estrogen) for binding sites on the surface of cells (46) . Estrogens are known to promote the growth of breast cancer cells, so if an antiestrogen such as tamoxifen blocks those sites, the effect of estrogen is diminished. Experiments have shown that tamoxifen blocks the effect of estradiol in cultures of astrocytes (31) , but are related to the type of estrogen receptor (ER) present (41) . Although tamoxifen has been found to be effective in decreasing brain tumor proliferation, whether this is mediated via the ER remains controversial, despite evidence of such mechanisms with a glioblastoma cell line (43) and in meningiomas (25) . Other studies have shown a specific cell cycle action of tamoxifen, mediated by mechanisms other than estrogen inhibition (66). There is also an important interaction between the ER and an enzyme called protein kinase C (35) .
Protein kinase C (PKC) denotes a group of enzymes that regulate functions such as cell growth and differentiation. It is known to be involved in a process called signal transduction. This is a messenger system, which transfers a signal arriving at the cell surface (e.g. hormone or neurotransmitter) into a cellular response. Protein kinase C has been implicated in glioma invasion (18, 77) and its role in malignant glioma growth and proliferation has been reviewed (5, 12, 27, 60) . Tamoxifen has been shown to block cell growth in brain tumor cell lines (26, 49, 68) and inhibits PKC (10, 47) . Proliferative signal transduction in glioma cells has been shown to occur through a predominantly PKC-dependent pathway (6, 7) . One isoform of PKC (isoform A) may be of particular importance (6, 18) . In addition to tamoxifen's action against PKC in adult high-grade gliomas, it has been shown to inhibit proliferation of cell lines derived from both low- and high-grade pediatric glial tumor (56) . A model cell system has been constructed for the screening and identification of PKC inhibitors potentially active against astrocytoma cells in culture (69, 70) .
As well as tamoxifen, a number of other PKC inhibitors have been shown to be effective in glioma inhibition. These include calphostin C (38, 59) and UCN-01 (57) .Another PKC inhibitor, hypericin (derived from the herb St John's Wort) has been used with tamoxifen for adjuvant chemotherapy of malignant glioma. In a study of seven human malignant glioma cell lines it was found that hypericin and tamoxifen induce apoptosis in a concentration and time-dependent manner (80) . In one patient, hypericin was able to replace tamoxifen's growth inhibition after loss of sensitivity to tamoxifen after a 22-month period (34, 55, 85) . One study on the action of tamoxifen on PKC activity in glioblastoma tissue found the inhibitory effect arrested the cell in the G (1) phase of the cell cycle. However, this action was observed to occur in a dose-dependent manner (22) and it is apparent that to be effective against gliomas tamoxifen has to be administered in a high dose.
The dose of tamoxifen used in the treatment of breast cancer is in the range 20-40 mg/day. However, since it has been shown that tamoxifen inhibits PKC in a dose dependent manner (22, 39, 80) , investigators have used higher doses to treat brain tumors. A key worker in this area is William Couldwell who, in a pioneering study (21) , first gave tamoxifen in antiestrogen doses (40mg/day) to monitor possible side effects in a cohort of malignant glioma patients. Provided no adverse reactions were observed dosage was then increased to 160mg (female) and 200mg/day (male). A positive response was obtained with a minority of patients (3 out of 11). A later study using the same dosage also found a subgroup of patients responding or stabilizing with high-dose tamoxifen. (23) .
In a study using doses graded between 40, 80 and 120mg/day, it was found that the patients receiving the higher doses demonstrated a longer median survival (51) . One study using 240mg/m (2) observed a variation in tamoxifen metabolic profile (29) . If there is a variation in how individuals metabolize this drug this may partially explain the variation in response to tamoxifen. However at that same dosage [240mg/m (2) ] another group found that symptoms of neurotoxicity occurred when tamoxifen was given in conjunction with interferon alpha-2a (17) .
In childhood glioma (45) , tamoxifen has been shown to produce tumor reduction and halting of tumor progression (9) . Pollack et al (58) found stabilization in 4 of 14 patients previously exhibiting progressive disease. One group had received 60mg/m (2) and a second group 100mg/m (2) daily. This study concluded that tamoxifen's low toxicity and easy administration; its proven effectiveness with some patients merited further study. Furthermore it was suggested that in patients with malignant gliomas, tamoxifen could potentate the effects of conventional chemothrapeutic agents.
A drug is said to have a synergistic effect when its action in combination with another drug is greater than the action of the two drugs administered separately - a "gestalt" pharmacology. There is considerable support for this effect with tamoxifen. Experiments on a human glioblastoma cell line (39) found that tamoxifen or tumor necrosis factor alpha could each inhibit proliferation in a dose-dependent manner. However, when given together the inhibitory action was greater than either agent alone. It has also been shown to improve quality of life when used in conjunction with procarbazine (11) and hypericin (86) . Similarly, the antiestrogenic action of tamoxifen is potentiated by bepridil - a sodium-calcium exchange blocker - in experiments on human astrocytoma and neuroblastoma cells (42) . Synergism has also been reported with radiotherapy (13, 26, 28, 50) .
Not all of tamoxifen's interactions are beneficial. There is evidence to support an adverse reaction with phenytoin (32, 64) and care should be exercised if tamoxifen is being considered for patients receiving this anti-convulsant. One report suggests that it may protect glioma cells from the action of cytotoxins (72) . A study reporting risk of thrombosis with tamoxifen (71) requires examination. Out of 4095 patients, 21 incidences of thrombosis were observed (0.5%), only one of these cases occurred with a brain cancer sufferer. The age range was 29 - 75 years and no evidence is presented as to whether the reported incidence exceeds that of a normal population not receiving chemotherapy.
Tamoxifen is generally considered to be of low toxicity (14, 82) but some workers have expressed doubts as to whether tamoxifen may be carcinogenic (4, 75) . However, such evidence is less substantial than that for its beneficial effects and indeed many malignant brain tumor sufferers would consider a "long term " risk in a positive way. In terms of proven carcinogenicity, tamoxifen is considerably less harmful than many other chemothrapeutic agents (15) .
As the number of trials and treatments of brain tumors with tamoxifen increases, so do the analyses and statistical analyses of such protocols (20, 37, 48, 84) . A review of treatment of high-grade astrocytomas by all treatments (37) found in favor of the nitrosoureas and platinums in the treatment of this type of tumor but also highlights the many problems associated with such group comparisons. How are patients selected for treatment and inclusion in the study? Do they receive the same dose - for the same period, and are they stratified by histology? Because these surveys are derived from individual patients and each patient will have received the physician's best treatment it is impossible to determine a standard treatment, only overall trends. If there is a subset of patients who are particularly susceptible to one chemotherapy, their positive response may be diluted by many that are not. The laws of statistics forbid a researcher from subjective selection of sample.
Long term survival with tamoxifen has been reported with a woman who developed a solitary brain metastasis following cancer of the breast. Following surgery and radiotherapy, this patient received tamoxifen and is generally well 10 years after brain metastases (53) . A positive response to tamoxifen has been observed with other metastatic brain tumors (44, 78) . Indeed the point is made that tamoxifen offers the benefit of treating both the primary (extracranial) and secondary (intracranial) tumors (44) . A detailed report of long term survival with primary brain tumor and tamoxifen awaits collation and analysis (52)
In summary, the evidence for tamoxifen in chemotherapy of brain tumor, although by no means proven, is more than encouraging. As with many experimental chemotherapies, there is often more promise shown with in vitro tissue culture studies than are delivered in clinical trials. There are many reasons for such a difference in response (76) . It would seem that this drug is effective with a minority of malignant glioma sufferers (21, 23) . The reason for this may be attributable to individual variations in tamoxifen metabolism (29) or it may point to variations in brain tumor pathology or metabolism yet to be clarified. Use of screening assays to predict the action of tamoxifen (1, 69, 70) may give insights into variations amongst gliomas and their susceptibility to this agent. Even more promising is the use of proton magnetic resonance spectroscopic imaging to predict how malignant gliomas will react to tamoxifen chemotherapy (62) . This paper suggests that it is possible to accurately predict the response of the tumor to tamoxifen on the basis of noninvasively acquired in vivo biochemical information. Certainly tamoxifen's low toxicity (71, 82) and minimal side effects coupled with its ready availability and low cost, present strong arguments for its application. It may be given alone (53, 69) or in combination with other agents (39, 42, 80) which enhances its action. It has also shown promise in conjunction with other techniques such as stereotactic radiosurgery (24) and radiotherapy (26, 28)
The potential benefits of tamoxifen clearly outweigh possible deleterious effects in brain tumor patients. It may only achieve a positive effect in a minority of patients but that fortunate group should not be denied the benefit simply because the drug does not improve survival for all brain tumor sufferers. The very fact that its action may take a considerable time to be manifest (19) will be good news to many. Indeed, the reasons underlying tamoxifen's variability may well indicate further avenues of research and treatment and broaden our understanding of this pernicious disease.
Considering the doses and time use we are talking about, I think the toxicity issue is a bit overblown.
About Toxicity:
ABSTRACT: Toxicity of Antiestrogens
The object of this article is to review briefly the preclinical and clinical safety of some antiestrogens.
Tamoxifen, toremifene, droloxifene, and idoxifene are polyphenylethylene antiestrogens, whereas the pure antiestrogen, ICI 182,780 or faslodex, as well as raloxifene, is of a different structure.
Tamoxifen has been shown to be genotoxic in several studies. It induces unscheduled DNA synthesis in rat hepatocytes and micronuclei in MCL-5^a cells in vitro. Tamoxifen also induces aneuploidy in rat liver in vivo and chromosome aberrations and micronuclei in mouse bone marrow.
Toremifene has also shown to be genotoxic, but to a far lower extent, by inducing micronuclei in MCL-5^a cells in vitro and by inducing aneuploidy in rat liver in vivo.
Tamoxifen has been shown to be hepatocarcinogenic in the rat in at least four independent long-term studies. The initiation of tumors in the rat is the result of metabolic activation by cytochrome P450 isoenzymes to an electrophile(s) that binds irreversibly to DNA.
The other antiestrogens have not been shown to be carcinogenic in rodents. In several independent clinical studies, the risk of endometrial cancer has increased among tamoxifen-treated women.
After reviewing the available data, the International Agency for Research on Cancer concluded that there was sufficient evidence to show that tamoxifen is a class I human carcinogen.
The increased risk for endometrial cancer occurs predominantly among women who are 50 years old or older and who have been treated with tamoxifen. It is not yet clear whether the uterine tumor formation is a result of genetic mechanisms, analogous to those seen in the rat liver or due to the estrogen agonist action of tamoxifen.
However, the other antiestrogens with a more or less similar intrinsic estrogenic potential have not been shown to be carcinogenic in humans.
Andrew James Parker
Dept. Biomedical Science,
University of Sheffield,
Sheffield, England
Updated May 25, 2000
Generic Name : Tamoxifen
USA Brand Name: Nolvadex (Zeneca Pharmaceuticals)
Other Proprietary Names: Dignatomoxi, Emblon, Fentamox, Istubol, Kessar, Mamofen, Noltam, Novofen, Oestrifen, Tamaxin, Tamifen, Tamoplex, Tamoxen, Valodex, Zitazonium
Classification: Antineoplastic; Antiestrogen
BT Dosage: 200mg/day (f) 240mg/day (m) [Adult] 60 -100mg/day [Children] Dosage depends on weight, tolerance and toxicity and varies according to individual circumstances. Always take in consultation with a physician.
Delivery: Oral tablet
Potential Side Effects: Hot flushes; Vaginal bleeding; Early onset menopause; GI distress; Vomiting; cataracts; Visual disturbances; Dizziness; thrombosis
Availability: This drug is routinely prescribed, inexpensive and should be readily available.
Abstract: The drug tamoxifen is most commonly associated with chemotherapy of breast cancer but has been used recently to treat other cancers including brain tumors. The mechanism of its action is complex involving several sites in and on cells. Current opinion suggests that its key role in malignant glioma is to inhibit a cell signaling enzyme called protein kinase C. It does this in a dose-dependent manner and consequently is administered at a much higher dose for brain tumor sufferers than is given to breast cancer patients. It has a low toxicity and its side effects are minimal. There is evidence to suggest that it should not be used in conjunction with the anti-epileptic (anticonvulsant) phenytoin. It has been used on its own and in conjunction with other drugs (adjuvant chemotherapy). Although tamoxifen does not improve all instances of brain tumor, there is considerable evidence that it is of benefit to many.A new non-invasive procedure may be able to detect those patients who will respond to tamoxifen.
TAMOXIFEN MINIREVIEW
The drug tamoxifen was synthesised in 1962 by scientists at ICI working on a contraceptive pill. Since it blocks the natural hormone estrogen (a steroid), it was classified as a nonsteroidal estrogen antagonist (8) . It has been used in the treatment of breast cancer for over 20 years (16) , although its efficacy has often been controversial (63) . Articles in the Lancet in the spring (3) and summer (61, 79) of 1998 respectively supported then refuted the value of tamoxifen with breast cancer. Later that year, the FDA approved tamoxifen citrate for reducing the incidence of breast cancer in women at high risk for developing the disease. In May 2000, an extensive study reported by Professor Sir Richard Peto has found convincingly in favor of tamoxifen, with the death rate falling by a third over ten years (54) . In addition to breast cancer, tamoxifen has been used to treat other cancers such as melanoma (30, 65) , hepatocellular carcinoma (73) , ovarian cancer (81) and prostate cancer (10) . This short review considers its application to cancer of the brain.
The action of tamoxifen is now known to operate at several sites in the cell (e.g. as a channel blocker : 2, 36, 74) and to affect numerous genes (40) but early studies concentrated on its action as an antihormone, specifically an antiestrogen (33, 67, 83) . Antiestrogenic mechanisms have been studied for around 40 years 83) but are still not fully understood. One known mechanism is that the tamoxifen molecule competes with the natural female hormone (estrogen) for binding sites on the surface of cells (46) . Estrogens are known to promote the growth of breast cancer cells, so if an antiestrogen such as tamoxifen blocks those sites, the effect of estrogen is diminished. Experiments have shown that tamoxifen blocks the effect of estradiol in cultures of astrocytes (31) , but are related to the type of estrogen receptor (ER) present (41) . Although tamoxifen has been found to be effective in decreasing brain tumor proliferation, whether this is mediated via the ER remains controversial, despite evidence of such mechanisms with a glioblastoma cell line (43) and in meningiomas (25) . Other studies have shown a specific cell cycle action of tamoxifen, mediated by mechanisms other than estrogen inhibition (66). There is also an important interaction between the ER and an enzyme called protein kinase C (35) .
Protein kinase C (PKC) denotes a group of enzymes that regulate functions such as cell growth and differentiation. It is known to be involved in a process called signal transduction. This is a messenger system, which transfers a signal arriving at the cell surface (e.g. hormone or neurotransmitter) into a cellular response. Protein kinase C has been implicated in glioma invasion (18, 77) and its role in malignant glioma growth and proliferation has been reviewed (5, 12, 27, 60) . Tamoxifen has been shown to block cell growth in brain tumor cell lines (26, 49, 68) and inhibits PKC (10, 47) . Proliferative signal transduction in glioma cells has been shown to occur through a predominantly PKC-dependent pathway (6, 7) . One isoform of PKC (isoform A) may be of particular importance (6, 18) . In addition to tamoxifen's action against PKC in adult high-grade gliomas, it has been shown to inhibit proliferation of cell lines derived from both low- and high-grade pediatric glial tumor (56) . A model cell system has been constructed for the screening and identification of PKC inhibitors potentially active against astrocytoma cells in culture (69, 70) .
As well as tamoxifen, a number of other PKC inhibitors have been shown to be effective in glioma inhibition. These include calphostin C (38, 59) and UCN-01 (57) .Another PKC inhibitor, hypericin (derived from the herb St John's Wort) has been used with tamoxifen for adjuvant chemotherapy of malignant glioma. In a study of seven human malignant glioma cell lines it was found that hypericin and tamoxifen induce apoptosis in a concentration and time-dependent manner (80) . In one patient, hypericin was able to replace tamoxifen's growth inhibition after loss of sensitivity to tamoxifen after a 22-month period (34, 55, 85) . One study on the action of tamoxifen on PKC activity in glioblastoma tissue found the inhibitory effect arrested the cell in the G (1) phase of the cell cycle. However, this action was observed to occur in a dose-dependent manner (22) and it is apparent that to be effective against gliomas tamoxifen has to be administered in a high dose.
The dose of tamoxifen used in the treatment of breast cancer is in the range 20-40 mg/day. However, since it has been shown that tamoxifen inhibits PKC in a dose dependent manner (22, 39, 80) , investigators have used higher doses to treat brain tumors. A key worker in this area is William Couldwell who, in a pioneering study (21) , first gave tamoxifen in antiestrogen doses (40mg/day) to monitor possible side effects in a cohort of malignant glioma patients. Provided no adverse reactions were observed dosage was then increased to 160mg (female) and 200mg/day (male). A positive response was obtained with a minority of patients (3 out of 11). A later study using the same dosage also found a subgroup of patients responding or stabilizing with high-dose tamoxifen. (23) .
In a study using doses graded between 40, 80 and 120mg/day, it was found that the patients receiving the higher doses demonstrated a longer median survival (51) . One study using 240mg/m (2) observed a variation in tamoxifen metabolic profile (29) . If there is a variation in how individuals metabolize this drug this may partially explain the variation in response to tamoxifen. However at that same dosage [240mg/m (2) ] another group found that symptoms of neurotoxicity occurred when tamoxifen was given in conjunction with interferon alpha-2a (17) .
In childhood glioma (45) , tamoxifen has been shown to produce tumor reduction and halting of tumor progression (9) . Pollack et al (58) found stabilization in 4 of 14 patients previously exhibiting progressive disease. One group had received 60mg/m (2) and a second group 100mg/m (2) daily. This study concluded that tamoxifen's low toxicity and easy administration; its proven effectiveness with some patients merited further study. Furthermore it was suggested that in patients with malignant gliomas, tamoxifen could potentate the effects of conventional chemothrapeutic agents.
A drug is said to have a synergistic effect when its action in combination with another drug is greater than the action of the two drugs administered separately - a "gestalt" pharmacology. There is considerable support for this effect with tamoxifen. Experiments on a human glioblastoma cell line (39) found that tamoxifen or tumor necrosis factor alpha could each inhibit proliferation in a dose-dependent manner. However, when given together the inhibitory action was greater than either agent alone. It has also been shown to improve quality of life when used in conjunction with procarbazine (11) and hypericin (86) . Similarly, the antiestrogenic action of tamoxifen is potentiated by bepridil - a sodium-calcium exchange blocker - in experiments on human astrocytoma and neuroblastoma cells (42) . Synergism has also been reported with radiotherapy (13, 26, 28, 50) .
Not all of tamoxifen's interactions are beneficial. There is evidence to support an adverse reaction with phenytoin (32, 64) and care should be exercised if tamoxifen is being considered for patients receiving this anti-convulsant. One report suggests that it may protect glioma cells from the action of cytotoxins (72) . A study reporting risk of thrombosis with tamoxifen (71) requires examination. Out of 4095 patients, 21 incidences of thrombosis were observed (0.5%), only one of these cases occurred with a brain cancer sufferer. The age range was 29 - 75 years and no evidence is presented as to whether the reported incidence exceeds that of a normal population not receiving chemotherapy.
Tamoxifen is generally considered to be of low toxicity (14, 82) but some workers have expressed doubts as to whether tamoxifen may be carcinogenic (4, 75) . However, such evidence is less substantial than that for its beneficial effects and indeed many malignant brain tumor sufferers would consider a "long term " risk in a positive way. In terms of proven carcinogenicity, tamoxifen is considerably less harmful than many other chemothrapeutic agents (15) .
As the number of trials and treatments of brain tumors with tamoxifen increases, so do the analyses and statistical analyses of such protocols (20, 37, 48, 84) . A review of treatment of high-grade astrocytomas by all treatments (37) found in favor of the nitrosoureas and platinums in the treatment of this type of tumor but also highlights the many problems associated with such group comparisons. How are patients selected for treatment and inclusion in the study? Do they receive the same dose - for the same period, and are they stratified by histology? Because these surveys are derived from individual patients and each patient will have received the physician's best treatment it is impossible to determine a standard treatment, only overall trends. If there is a subset of patients who are particularly susceptible to one chemotherapy, their positive response may be diluted by many that are not. The laws of statistics forbid a researcher from subjective selection of sample.
Long term survival with tamoxifen has been reported with a woman who developed a solitary brain metastasis following cancer of the breast. Following surgery and radiotherapy, this patient received tamoxifen and is generally well 10 years after brain metastases (53) . A positive response to tamoxifen has been observed with other metastatic brain tumors (44, 78) . Indeed the point is made that tamoxifen offers the benefit of treating both the primary (extracranial) and secondary (intracranial) tumors (44) . A detailed report of long term survival with primary brain tumor and tamoxifen awaits collation and analysis (52)
In summary, the evidence for tamoxifen in chemotherapy of brain tumor, although by no means proven, is more than encouraging. As with many experimental chemotherapies, there is often more promise shown with in vitro tissue culture studies than are delivered in clinical trials. There are many reasons for such a difference in response (76) . It would seem that this drug is effective with a minority of malignant glioma sufferers (21, 23) . The reason for this may be attributable to individual variations in tamoxifen metabolism (29) or it may point to variations in brain tumor pathology or metabolism yet to be clarified. Use of screening assays to predict the action of tamoxifen (1, 69, 70) may give insights into variations amongst gliomas and their susceptibility to this agent. Even more promising is the use of proton magnetic resonance spectroscopic imaging to predict how malignant gliomas will react to tamoxifen chemotherapy (62) . This paper suggests that it is possible to accurately predict the response of the tumor to tamoxifen on the basis of noninvasively acquired in vivo biochemical information. Certainly tamoxifen's low toxicity (71, 82) and minimal side effects coupled with its ready availability and low cost, present strong arguments for its application. It may be given alone (53, 69) or in combination with other agents (39, 42, 80) which enhances its action. It has also shown promise in conjunction with other techniques such as stereotactic radiosurgery (24) and radiotherapy (26, 28)
The potential benefits of tamoxifen clearly outweigh possible deleterious effects in brain tumor patients. It may only achieve a positive effect in a minority of patients but that fortunate group should not be denied the benefit simply because the drug does not improve survival for all brain tumor sufferers. The very fact that its action may take a considerable time to be manifest (19) will be good news to many. Indeed, the reasons underlying tamoxifen's variability may well indicate further avenues of research and treatment and broaden our understanding of this pernicious disease.
Considering the doses and time use we are talking about, I think the toxicity issue is a bit overblown.
Dwight Schrute
I am faster than 80% of all snakes
????
Where did I say that? Who's playing tricks on me?
Where did I say that? Who's playing tricks on me?
SilentScream27
Member
from PA@musclegurus: