Ray Peat Email Advice Depository

mandance said:

Ray Peat continued:


I knew someone who had been addicted to morphine and alcohol for 30 years, who was drinking quarts of beer and wine daily when he didn't have morphine, who had an opportunity for a good job if he could get sober. Starting progesterone at bedtime (and stopping the wine), he said it was the first time he didn't have a hangover in the morning. He used enough progesterone to neuter most people, but said it didn't affect his sex function; he was taking a lot of Cytomel and magnesium, but wasn't drunk again as long as I knew him, and his general health improved.

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The person I described who recovered so completely took about 1000 mg of progesterone during the first night, and more than 1000 mg daily for a few weeks, but that much could make some people comatose; it's a matter of individual hormone status. I think the SSRI drugs continue to do harm, even when they reduce withdrawal symptoms.

Ray Peat sent me this when I asked if long term antidepressant use could cause permanent damage to the brain

Physiol Behav. 2006 Jan 30;87(1):114-9.
Peripheral triiodothyronine (T(3)) levels during escapable and inescapable
footshock.
Helmreich DL, Crouch M, Dorr NP, Parfitt DB.
Department of Biology and Program of Neuroscience, Middlebury College,
Middlebury, VT 05753, USA. [email protected]
Changes in peripheral thyroid hormone levels are associated with changes in human
affective disorders, particularly depression. In the current study we used an
animal stress paradigm, proposed to be an animal model of depression, to examine
peripheral T(3) levels during and after escapable or inescapable stress in adult
male rats. In this model, one animal can control the termination of foot-shock
stress by performing a lever press, and therefore experiences escapable stress.
His lever press also terminates the shock for his yoked partner, who has no
control over the stressor, and therefore experiences inescapable stress. In three
separate experiments, blood samples were collected during and after one or two
sessions of escapable/inescapable stress. We found that exposure to inescapable
stress, but not escapable stress, caused a decrease in T(3) levels 120 min
post-stress initiation. Peripheral T(3) levels were not significantly altered in
animals exposed to escapable stress. In sum, these results add to a large body of
previous data indicating that psychological coping can prevent the effects of
physical stress on many diverse systems.

I hope I didn't ask Ray a question Dan already asked him. Here is my question:

Do you have a preference between with high alpha or high gamma mixed tocopherols?

There is a vitamin E from France, from wheat germ oil, which is high gamma. If that's good in theory, would 14mg (about 20 IU) daily be a good amount? That's what one pill has.

link to the vit E from France

His response:

In similar milligram amounts, I would prefer gamma.

By Ray Peat (from an e-mail):

Ray Peat said:

"While I was (...) a psychology major, I did some surveys (1957) relating to creativity and types of thought and dreaming, following up some ideas I found in Brewster Ghiselin's book The Creative Process. I felt that the current US view of the brain as a computing device with nerves serving as wires and switches was completely inappropriate, even for understanding things such as the perception of odors and musical pitch, and around that time a practical study of creativity was published, in a book called Synectics, and I saw that Pavlov's colleague P.K. Anokhin had been developing a much better understanding of brain function. The fact that sensations and perception of space in dreams can be so convincing led me to feel that biological/metabolic processes in the brain reproduce in fairly direct or literal ways things in the external world, i.e., that our experience of internal colors and smells and sounds are probably a sort of electrochemical resonance within nerves---with a nerve and its surroundings, spatial parts of the brain, taking on energetic states with the frequencies that are closely analogous to the frequencies produced by the external objects, colors, chemical odors, sound vibrations, as well as other kinds of patterned relationships. If "photons" or electromagnetic interactions within the organism are the substance of consciousness, then the electronic properties of nutrients, hormones, and drugs are important, rather than their geometric form, as interpreted by the "lock-and-key" "receptor and ligand" doctrine. I think the active chemical in St. John's wort is hypericin, an anthroquine (very similar to emodin, in cascara, and to vitamin K and tetracycline), which is a large system of conjugated electrons, that interacts powerfully with our cellular regulatory systems.
(...)
I suspect that growing up with creativity involves opportunities that cause the brain to develop various sensitivities and resonances, and that the brain functioning in these ways calls up the energetic and hormonal resources that it needs, and ideally that includes an array of chemicals that enrich and intensify consciousness, allowing very complex internal experiences to be generated."

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Thanks to mother's post, a response from Peat about how he made copper acetate:

Ray Peat said:

I made it myself, soaking a piece of pure copper with aspirin in water, until a very pale blue color developed. Later, the solution became a deeper blue color, and at a certain concentration I think it's toxic.

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This was a response in reference to my questions regarding Estrogen receptors and cancer:

Orange juice and guavas contain aromatase inhibitors, and aspirin and progesterone are other inhibitors. Aspirin and progesterone also oppose the effects of HER2/neu on aromatase and estrogen.

Cancer Res. 2006 May 15;66(10):5504-11.
HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence
for a cyclooxygenase-2-dependent mechanism.
Subbaramaiah K, Howe LR, Port ER, Brogi E, Fishman J, Liu CH, Hla T, Hudis C,
Dannenberg AJ.
Department of Medicine, Weill Medical College of Cornell University, New York,
NY, USA.
Cytochrome P450 aromatase (aromatase), a product of the CYP19 gene, catalyzes the
synthesis of estrogens from androgens. Given the significance of estrogen
synthesis in hormone-dependent breast carcinogenesis, it is important to
elucidate the mechanisms that regulate CYP19 expression. The main objective of
this study was to define the interrelationship between HER-2/neu,
cyclooxygenase-2 (COX-2), and aromatase in mammary tissue. Mammary aromatase
activity and prostaglandin E(2) (PGE(2)) levels were increased in mice with
mammary-targeted expression of a COX-2 transgene. In vitro, overexpressing COX-2
caused both increased PGE(2) production and aromatase activity, effects that were
suppressed by celecoxib, a selective COX-2 inhibitor. Previously, we found that
overexpression of HER-2/neu was associated with increased levels of COX-2 in
human breast cancers. Here, we show that overexpression of HER-2/neu is also
associated with increased aromatase activity. These results suggested the
possibility that COX-2 was the functional intermediate linking HER-2/neu and
aromatase. Consistent with this idea, COX-2 deficiency led to a gene
dose-dependent reduction in mammary aromatase activity in a HER-2/neu transgenic
mouse model. Complementary in vitro studies showed that HER-2/neu-mediated
induction of PGE(2) synthesis and aromatase activity were suppressed by
inhibiting COX-2. Collectively, our data indicate that COX-2 is the functional
intermediate linking HER-2/neu and aromatase and suggest that inhibitors of
PGE(2) synthesis will suppress estrogen biosynthesis in breast tissue.

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..........

Hormone Receptor-Positive or -Negative

Breast cancer cells may contain receptors, or binding sites, for the hormones estrogen and progesterone. Cells containing these binding sites are known as hormone receptor-positive cells. If cells lack these connectors, they are called hormone receptor-negative cells. About 75% of breast cancers are estrogen receptor-positive (ER-positive, or ER+). About 65% of ER-positive breast cancers are also progesterone receptor-positive (PR-positive, or PR+). Cells that have receptors for one of these hormones, or both of them, are considered hormone receptor-positive.

Hormone receptor-positive cancer is also called "hormone sensitive" because it responds to hormone therapy such as tamoxifen or aromatase inhibitors. Hormone receptor-negative tumors are referred to as "hormone insensitive" or "hormone resistant."

Women have a better prognosis if their tumors are hormone receptor-positive because these cells grow more slowly than receptor-negative cells. In addition, women with hormone receptor-positive cancer have more treatment options. (Hormone receptor-negative tumors can be treated only with chemotherapy.) Recent declines in breast cancer mortality rates have been most significant among women with estrogen receptor-positive tumors, due in part to the widespread use of post-surgical hormone drug therapy.

Tumor Markers
Tumor markers are proteins found in blood or urine when cancer is present. Although they are not used to diagnose cancer, the presence of certain markers can help predict how aggressive a patient’s cancer may be and how well the cancer may respond to certain types of drugs.

Tumor markers relevant for breast cancer prognosis include:

HER2 . The American Cancer Society recommends that all women newly diagnosed with breast cancer get a biopsy test for a growth-promoting protein called HER2/neu. HER2-positive cancer usually occurs in younger women and is more quickly-growing and aggressive than other types of breast cancer. The HER2 marker is present in about 20% of cases of invasive breast cancer. Two types of tests are used to detect HER2:

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Asking about salycilic acid intolerance due to reaction to fruits:

The fruits you mention all seriously increase serotonin. A sore throat is a quick effect, but some people get migraines from them. The pectin in raw apples causes the intestine to release serotonin into the blood, so well cooked apples have much less effect. Fruits contain almost no salicylic acid.

Determination of Acetylsalicylic Acid and Salicylic Acid in Foods, Using HPLC with Fluorescence Detection
J. Agric. Food Chem., 1996, 44 (7), pp 1762–1767
We developed a specific and sensitive HPLC method with fluorescence detection for the determination of free acetylsalicylic acid, free salicylic acid, and free salicylic acid plus salicylic acid after alkaline hydrolysis (free-plus-bound) in foods. Acetylsalicylic acid was detected after postcolumn hydrolysis to salicylic acid. With the method for free acetylsalicylic acid and salicylic acid, recovery was 95−98% for acetylsalicylic acid added to foods and 92−102% for salicylic acid. Recovery of added salicylic acid was 79−94% for the free-plus-bound salicylic acid method. The limit of detection was 0.02 mg/kg for fresh and 0.2 mg/kg for dried foods for all substances. We did not find acetylsalicylic acid in any of 30 foods previously thought to be high in salicylates. The contents of free-plus-bound salicylic acid and of free salicylic acid ranged from 0 to 1 mg/kg in vegetables and fruits and from 3 to 28 mg/kg in herbs and spices. Thus the tested foods did not contain acetylsalicylic acid and only small amounts of salicylic acid. Our data suggest that the average daily intake of acetylsalicylic acid from foods is nil and that of salicylic acid is 0−5 mg/day.

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Bold is Peat's

On Acacia Powder/Acacia Gum/Gum Arabic:

Yes, acacia gum is very allergenic. It has taken me two or three weeks to get over symptoms from it, when I accidentally got it in a food. But other irritating foods might keep the symptoms going, so it's good to watch for changes with different foods.

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I asked about Unique E's apparent changes in color/thickness and about some of the promising competing products, highlighting their tocopherol balance, soy/palm/sunflower source, and GMO status. He replied:

I think mixed tocopherols are better than just d-alpha, but with d-alpha it's good to choose one that has a high potency per volume. I have noticed that one of Unique's products seems to be mostly other oil. I think polycosanols account for some of the viscosity, so I prefer the thick ones.

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Do you think eating coconut oil from plastic bottle, as opposed to glass, is always bad?

Ray Peat said:

It depends on the type of plastic; if it's in a big plastic bucket, the plastic isn't as bad as in a 400 mililiter bottle, if it contains harmful chemicals.

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ttramone

Me: Just wondering why some of us get severe withdrawals (headaches, fatigue, drowsiness, low mood) if we don't use coffee daily. We don't get side effects from drinking coffee, just if we don't drink it for 24 hours (sometimes less). These 'withdrawals' can last as long as 5-6 days. Why would this happen? We are thinking there could be issues with our liver? Adrenals?

RP: I suspect that it happens mostly with hypothyroidism, because in the 1970s I averaged dozens of cups a day, and thought about it as soon as I woke up, then suddenly after I took some thyroid, I didn't feel any need
for it.

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About DHT, DHEA, Testosterone, and Pregnenolone.

fermundacheez

"I haven't heard of any bad effects from DHT, but that might be because it's so rarely used. The liver problems I've heard about have always involved slightly modified molecules. I think the tendency to take too much might be a problem with androgens generally--4 milligrams of testosterone and 15 mg of DHEA is a normal daily production for young men, and half of that amount is effective for middle aged men, unless the problem is something else. Pregnenolone is safe, if it's pure, but it's good to be skeptical about purity."

Is the quality of seafood, or other foods, a concern after the Fukushima nuclear disaster, for someone living in the West Coast? Could it have become irradiated and pose dangers to health?

Ray Peat said:

Yes, sea food from the northern Pacific should be tested periodically, but the US government has stopped the radiation testing that had previously been done, which I think means that the radiation is exceeding their previous safety limits.

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livesimply

livesimply said:

Hi everyone. I am new here and reading so many threads with great interest. When I purchased my Progest E it didn't come with any instructions, so I emailed Dr. Peat—here is the exchange:

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livesimply said:

Do you think Progest E is better taken via rubbing on my gums or swallowing?

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Ray Peat said:

Some will enter your blood stream very quickly from the mouth membranes, but taking it with food the effect will be more gradual and prolonged.

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livesimply said:

Since I went through surgical menopause 22 years ago, should I rotate off the Progest E every month for several days or stay on it continuously?

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Ray Peat said:

I think it's most effective when you take it cyclically; imitating the menstrual cycle, with two week on and two off, would be good, unless you are using it to control some symptom.

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Source

Response regarding my 12 yr. old son:

"Around puberty the changing hormones, especially momentarily high estrogen in boys, can cause some obsessive episodes, and I suppose stress could be involved with early high testosterone production. A few small supplementations with thyroid or pregnenolone might reduce the stress and extend his growing years, but he could judge by whether it made him feel better. Lots of milk and fruit are appropriate in the teens, with eggs, seafoods, and meats according to appetite."

Also this regarding Cynoplus dosage for my son. And the use of retin a/retinoids (Whew! This is long :)

"An eighth or tenth of a cynoplus tablet is a good amount for a trial, it's a little less than the body would normally produce in an hour, so it's enough to detect as a change of state, slight change of heart rate, warming of hands, for example. Vitamin A is such a basic metabolic factor, in the brain and endocrine glands, liver and kidneys, etc., I think it's dangerous to experiment with drugs that interfere with it."


Excess Deaths in VA Tretinoin-Retin-A Trial_FDA Silent
Even a seemingly harmless topical ointment may pose unanticipated lethal risks which are undisclosed on the FDA-approved label.
"I would urge you to cultivate a keenly skeptical attitude toward the pharmacopeia as a whole..." Sir William Osler, 1907

Indeed, even a seemingly harmless topical ointment may pose unanticipated lethal risks which are undisclosed on the FDA-approved label.

A concerned dermatologist, a former FDA medical officer, brought to our attention the finding of a 6-year randomized clinical trial conducted by the Veterans Administration involving 1,131 elderly veterans. 566 were randomized to test tretinoin cream (0.1%), and 565 to placebo. Tretinoin, a member of the retinoid class of medications is commonly used for the topical treatment of acne and fine lines and wrinkles. It is marketed as Retin-A and Renova, as well as other branded products.

The purpose of trial was to establish the effectiveness of Retin-A as a chemoprevention intervention for nonmelanoma skin cancer. The trial failed to demonstrate effectiveness as a cancer prevention treatment. Instead, there were statistically significant, unanticipated extra deaths among those applying tretinoin, compared with those given a placebo: the trial was terminated 6 months early (in 2004).

In 2005, the authors published preliminary results in abstract form in the Journal of Investigative Dermatology, stating that there was NOT a statistically significant difference in overall mortality between tretinoin and placebo groups: "We conclude tretinoin did not cause the mortality difference between groups, and in retrospect the termination of the intervention was unnecessary."

Four years elapsed before the study results were finally published in January in Archives of Dermatology http://archderm.ama-assn.org/cgi/content/full/145/1/18

According to published report, there were significant differences in mortality between retinoid users and those on placebo:

Table 1. Cumulative Deaths among 1131 Study Participants,shows that the retinoid treated group consistently had an excess number of deaths compared to the placebo group: by April 2004, there were 135 deaths: 82 (14%) deaths in retinoid group compared to 53 (9%) placebo. Before the end of intervention in 2004 the deaths climbed to 184: 108 (19%) deaths in retinoid group compared to 76 (14%) placebo. And by the end of study (follow-up phase) there were 212 deaths: 122 (22%) deaths in retinoid group compared to 90 (16%) placebo.

Table 3 Cause of Deaths reveals that greatest disparity in deaths between the retinoid group and placebo involved:

lung cancer (15 deaths vs 8), respiratory thoractic disorders (15 vs 7), and vascular disorders (12 vs 3)--when deaths from Arteriosclerosis and Atherosclerosis are added, the vascular risk increases to 22 vs 5.

The study investigators attribute the difference to chance.

However, the accompanying editorial (below) suggests caution:

"While debate will continue regarding whether the association between topical tretinoin and death found in the VATTCresulted from chance or a real biological effect, until additional data from other studies emerge, practitioners should view the results of the VATTC with discretion. Public health ideally uses the precautionary principle—that possible harm should be avoided before harmful effects are unquestionably proven.8 At a minimum, this principle should cause prescribing physicians to discuss the results of the VATTC with elderly men using topical tretinoin."

And a published letter (below) cites earlier controlled retinoid trials with similar results:

"A causal link between tretinoin and mortality due to lung cancer or other lung diseases is consistent with previous RCT data. Specifically, the Alpha-Tocopherol, Beta Carotene Cancer Prevention Trial 7 and the Beta-Carotene and Retinol Efficacy Trial8 both linked vitamin A–related compounds to lung cancer. Ironically, both trials were intended to demonstrate that these compounds could prevent lung cancer. In both studies, however, lung cancer rates in subjects taking vitamin A–related substances were, unexpectedly, significantly higher than in subjects taking placebo, leading to early discontinuation of the vitamin A–related interventions in both trials."

The FDA has shown utter indifference: taking no action whatsoever to alert prescribing physicians to the potential lethal risk. The tretinoin labeling fails to reflect the results of the VA study.

The principle investigator, Dr. Martin A. Weinstock, MD, PhD, discloses receiving financial support from: received support from Galderma Laboratories, Johnson & Johnson, and Ligand Pharmaceuticals. The manufacturer of tretinoin, Ortho-McNeil--Janssen Pharmaceutical is a division of Johnson & Johnson.

Posted by Vera Hassner Sharav



Arch Dermatol. 2009;145(1):18-24Topical Tretinoin Therapy and All-Cause Mortality

Martin A. Weinstock, MD, PhD; Stephen F. Bingham, PhD; Robert A. Lew, PhD; Russell Hall, MD; David Eilers, MD; Robert Kirsner, MD, PhD; Mark Naylor, MD; James Kalivas, MD; Gary Cole, MD; Kimberly Marcolivio, MEd; Joseph Collins, ScD; John J. DiGiovanna, MD; Julia E. Vertrees, PharmD; for the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial Group

Objective: To evaluate the relation of topical tretinoin, a commonly used retinoid cream, with all-cause mortality in the Veterans Affairs Topical Tretinoin Chemoprevention Trial (VATTC). The planned outcome of this trial was risk of keratinocyte carcinoma, and systemic administration of certain retinoid compounds has been shown to reduce risk of this cancer but has also been associated with increased mortality risk among smokers.

Design: The VATTC Trial was a blinded randomized chemoprevention trial, with 2- to 6-year follow-up. Oversight was provided by multiple independent committees.

Setting: US Department of Veterans Affairs medical centers.

Patients: A total of 1131 veterans were randomized. Their mean age was 71 years. Patients with a very high estimated short-term risk of death were excluded.

Interventions: Application of tretinoin, 0.1%, or vehicle control cream twice daily to the face and ears.

Main Outcome Measures: Death, which was not contemplated as an end point in the original study design.

Results: The interventionwas terminated 6months early because of an excessive number of deaths in the tretinointreated group. Post hoc analysis of this difference revealed minor imbalances in age, comorbidity, and smoking status, all of which were important predictors of death. After adjusting for these imbalances, the difference in mortality between the randomized groups remained statistically significant.

Conclusions: We observed an association of topical tretinoin therapy with death, but we do not infer a causal association that current evidence suggests is unlikely.

Trial Registration: clinicaltrials.gov Identifier: NCT00007631

~~~~~~~~~~

Archives of Dermatology. 2009;145(1):18-24

EDITORIAL: Dealing With Unanticipated Mortality in a Large Randomized Clinical Trial of Topical Tretinoin

. . . I would urge you to cultivate a keenly skeptical attitude toward the pharmacopeia as a whole. . . . Sir William Osler, 19071

Millions of people have used topical tretinoin to treat acne and photoaging. [2-4] In this issue, Weinstock et al 5 report an unexpected result that led to the premature halt of their randomized, placebo-controlled Department of Veterans Affairs Topical Tretinoin Chemoprevention(VATTC)trial designed to determine whether topical tretinoin, 0.1%, cream prevents basal and squamous cell skin cancer in US veterans.

Limited topical tretinoin use (up to twice daily to the face and ears) was associated with increased death (end-ofintervention hazard ratio, 1.54; P=.01).

While some argue that topical tretinoin might increase pulmonary-related mortality,6 Weinstock et al5 ultimately reject this explanation and chalk their results up as a chance finding based on the following: (1) minimal systemic absorption of topical tretinoin; (2) the lack of a dose-response association; (3) the lack of specificity of causes of death; and (4) the lack of a statistical interaction between tretinoin use and smoking with mortality.

(On this last point, asbestos provides the classic epidemiological example of an exposure producing a statistical interaction with smoking: smoking and asbestos exposure together result in greater risk of lung cancer than the sum of the risks from the individual exposures.)7 While debate will continue regarding whether the association between topical tretinoin and death found in the VATTCresulted from chance or a real biological effect, until additional data from other studies emerge, practitioners should view the results of the VATTC with discretion.

Public health ideally uses the precautionary principle—that possibleharmshould be avoided before harmful effects are unquestionablyproven.8 At a minimum, this principle should cause prescribing physicians to discuss the results of the VATTC with elderly men using topical tretinoin. More circumspect practitioners may wish to discuss the results of the VATTC with all patients using topical tretinoin. This dialogue should include that the results of theVATTC may have beendueto chance, but also that the outcome of death wasnot initially anticipated, and owing to the adhoc analysis, various important risk factors, such as smoking status, might not have been completely ascertained. These discussions provide an opportunity for all health care providers prescribing tretinoin to emphasize tobacco prevention and cessation with their patients.9

Clearly, future trials of topical retinoids, especially in elderly patients and in current and former smokers, should mortality with validated, sound methods. With increased mortality as a foreseeable outcome, rigorous, predetermined stopping rules and appropriate statistical methods will ensure that trials are not halted prematurely owing to invalid (but essential) interim analyses.10-13 Finally, unlike other investigators who have not emphasized unexpected mortality data,14,15 we highly commend Weinstock et al 5 for reporting and highlighting these results.

Correspondence: Dr Dellavalle, Dermatology Service, Department of Veterans Affairs Medical Center, 1055 Clermont St, Box 165, Denver, CO 80220(robert \n [email protected] ).Financial Disclosure: None reported.

Funding/Support: This study was supported in part by Colorado Health Informatics Collaboration Academic Enrichment Funds from the University of Colorado Denver School of Medicine (Drs Schilling and Dellavalle) and NCI K07 Cancer Prevention and Control Career Development Award grant K-07CA92550 (Dr Dellavalle).

Additional Contributions: Martin Weinstock, MD, PhD, answered additional questions via e-mail regarding the manuscript.

REFERENCES

1. Osler W. The reserves of life. St Marys Hosp Gaz. 1907;13:95-98.

2. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin. JAMA. 1988;259(4):527-532.

3. Swinyer LJ, Swinyer TA, Britt MR. Topical agents alone in acne: a blind assessment study. JAMA. 1980;243(16):1640-1643.

4. Goldfarb MT, Ellis CN, Voorhees JJ. Topical tretinoin: its use in daily practice to reverse photoageing. Br J Dermatol. 1990;122(suppl 35):87-91.

5. Weinstock MA, Bingham SF, Lew RA, et al; Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial Group. Topical tretinoin therapy and all-cause mortality. Arch Dermatol. 2009;145(1):18-24.

6. Katz KA. Topical tretinoin, lung cancer, and lung-related mortality. Arch Dermatol. 2008;144(7):945-946.

7. Liddell FDK. The interaction of asbestos and smoking in lung cancer. Ann Occup Hyg. 2001;45(5):341-356.

8. Goldstein BD. The precautionary principle also applies to public health actions. Am J Public Health. 2001;91(9):1358-1361.

9. Dellavalle RP, Johnson KR. Time for all dermatology societies to adopt smoke free policies. J Am Acad Dermatol. 2006;54(1):149-150.

10. Goodman SN. Stopping at nothing? some dilemmas of data monitoring in clinical trials. Ann Intern Med. 2007;146(12):882-887.

11. DeMets DL, Pocock SJ, Julian DG. The agonizing negative trend in monitoring of clinical trials. Lancet. 1999;354(9194):1983-1988.

12. DeMets DL. Futility approaches to interim monitoring by data monitoring committees. Clin Trials. 2006;3(6):522-529.

13. Nissen SE. ADAPT: The wrong way to stop a clinical trial. PloS Clin Trials. 2006; 1(7):e35.

14. Bombardier C, Laine L, Reicin A, et al; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343(21):1520-1528.

15. Curfman GD, Morrissey S, Drazen JM. Expression of concern reaffirmed. N Engl J Med. 2006;354(11):1193.



~~~~~~~~~~~~~

COMMENTS AND OPINIONS

Topical Tretinoin, Lung Cancer, and Lung-Related Mortality

By Kenneth A. Katz, MD, MSc, MSCE

Amid continuing controversies over drug safety,1,2 results of a trial of topical tretinoin—a commonly used medication for acne3 and skin wrinkles, hyperpigmentation, and roughness4—raise serious concerns for the public health. The Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) trial5,6 was a vehicle-controlled randomized controlled trial (RCT) that studied whether topical tretinoin, 0.1%, cream applied to the face and ears could prevent nonmelanoma skin cancer.

As reported in an abstract published in 2005,6 the study observed 1131 subjects for at least 2 years. After 6 years, and about 6 months prior to the study’s scheduled conclusion, a safety monitoring committee stopped the study because of excess mortality among subjects who applied tretinoin (n=82 deaths [14%]) compared with those who applied vehicle (n=53 [9%]) (P=.01). Differences in mortality from pulmonary disease (12 vs 4) and non–small cell lung cancer (NSCLC) (11 vs 4) were reported.5

A causal link between tretinoin and mortality due to lung cancer or other lung diseases is consistent with previous RCT data. Specifically, the Alpha-Tocopherol, Beta Carotene Cancer Prevention Trial 7 and the Beta-Carotene and Retinol Efficacy Trial 8 both linked vitamin A–related compounds to lung cancer. Ironically, both trials were intended to demonstrate that these compounds could prevent lung cancer. In both studies, however, lung cancer rates in subjects taking vitamin A–related substances were, unexpectedly, significantly higher than in subjects taking placebo, leading to early discontinuation of the vitamin A–related interventions in both trials.

A link between tretinoin and lung-related mortality is biologically plausible, with the putative culprit not tretinoin itself but harmful tretinoin metabolites. This line of association begins with the finding that topically applied tretinoin can be absorbed systemically9 and therefore can reach lung tissue. Once inside cells, tretinoin can induce its own metabolism; continuous dosing with tretinoin may lead not to higher levels of tretinoin but to higher levels of tretinoin metabolites.10 It is those tretinoin metabolites that may injure lung tissue, particularly in the presence of cigarette smoke. This was demonstrated in a study that exposed ferrets to beta carotene (a vitamin A precursor) or cigarette smoke or both or neither for 6 months; lungs of all ferrets exposed to beta carotene showed a strong proliferative response and squamous metaplasia that was enhanced by exposure to cigarette smoke.11 A hypothesis linking lung cancer to adverse effects of tretinoin metabolites is also supported by the finding that patients with certain types of NSCLC (squamous or large-cell carcinomas) metabolize tretinoin more rapidly than patients with another NSCLC type (adenocarcinoma) or patients without lung cancer.12 This study raises the possibility that rapid metabolizers of tretinoin may be more likely to develop lung cancer because, compared with normal metabolizers, they have a relative deficiency of tretinoin and a relative excess of injurious tretinoin metabolites present in their lung tissue.

Additionally, the link between tretinoin and lung disease may be multifactorial; others have proposed that tretinoin- mediated downregulation of defensins in lung tissue contributed to lung-related mortality in the VATTC trial.13

It is not clear whether tretinoin caused the excess lungrelated deaths in the VATTC trial. But concern is warranted, certainly, both because a causal link is plausible and because topical tretinoin is indicated for the treatment of relatively minor conditions.

Correspondence: Dr Katz, 1360 Mission St, Ste 401, San Francisco, CA 94103 ( \n [email protected] ).

Financial Disclosure: None reported.



REFERENCES:

1. Committee on the Assessment of the US Drug Safety System, Baciu A, Stratton K, Burke SP, eds. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: National Academies Press; 2006.

2. Drazen JM, Morrissey S, Curfman GD. Rosiglitazone–continued uncertainty about safety. N Engl J Med. 2007;357(1):63-64.

3. US National Library of Medicine. Retin-A (tretinoin) Cream, Retin-A (tretinoin) Gel, Retin-A (tretinoin) Liquid [ORTHO DERMATOLOGICAL]. http:

//dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=3734. Accessed July 8, 2007.

4. Renova [package insert]. Raritan, NJ: Ortho Pharmaceutical Corporation. http://www.aboutrenova.com/RENOVA.05.pdf. Accessed July 8, 2007.

5. Weinstock MA, Marcolivio K, Bingham S, et al. Topical tretinoin and allcause mortality. J Invest Dermatol. 2005;124:A52.

6. Department of Veterans Affairs. Determine the efficacy of topical tretinoin cream for the prevention of nonmelanoma skin cancer.

http://www.clinicaltrials.gov/ct/show/N ... 31?order=1. Accessed July 22, 2007.

7. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330(15):1029-1035.

8. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.

N Engl J Med. 1996;334(18):1150-1155.

9. van Hoogdalem EJ. Transdermal absorption of topical anti-acne agents in man; review of clinical pharmacokinetic data. J Eur Acad Dermatol Venereol.

1998;11(suppl 1):S13-S19.

10. Rigas JR, Francis PA, Muindi JR, et al. Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole. J Natl Cancer Inst. 1993;85(23):1921-1926.

11. Wang XD, Liu C, Bronson RT, Smith DE, Krinsky NI, Russell M. Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke. J Natl Cancer Inst. 1999;91(1):60-66.

12. Rigas JR, Miller VA, Zhang ZF, et al. Metabolic phenotypes of retinoic acid and the risk of lung cancer. Cancer Res. 1996;56(12):2692-2696.

13. Rosenberg EW, Skinner RB Jr. Topical retinoids: another piece for the retinoidcigarette-lung cancer puzzle? J Thorac Oncol. 2006;1(7):732.

Destiny said:

Yes my progesterone has been low, due to eating the wrong things and being hypo thyroid. I just started eating Peats way a good three months ago. Taking progesterone, before I changed my diet, normalized my periods.

I emailed Dr Peat and he said to continue taking both, increasing thyroid every two weeks while checking my temps and heart rate and that as my thyroid levels are normalized the need for oral progesterone wont be necessary. Taking thyroid started affecting my hormones and over time things will balance out.

Once my thyroid is healed and I cleansed my body of the PUFAs I wont need either thyroid or progesterone ideally.

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Ray Peat said:

"I think continuing the progesterone would help to normalize thyroid responses. If you adjust the thyroid dose every two weeks according to how you feel, and according to your temperatures and pulse rate, there should be a point where your cycle is right, without needing progesterone. During the winter the need for thyroid is higher, because of the short days, so it's important to watch for decreasing need when the days are longer in the spring."

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Source

Dr Peat
You have mentioned that you maintain a very high calcium to phosphorus ratio. What is a very high ratio? Is there a maximum limit for high ratio? Is 2000 mg calcium and 1000 mg phosphorus a safe ratio?

Ray Peat said:

Yes, that's safe. Even a 1 to 1 ratio is probably safe, but the ideal
hasn't been clearly defined.

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Trying to understand why I got some positive effects from cascara, a lot more than carrot or many other pro-thyroid suggestions:

I think cascara's most important effect is the reduction of the
pro-inflammatory nitric oxide, which poisons mitochondrial energy
production. Raw carrot or bamboo shoots can sometimes have a similar
effect by reducing NO synthesis.

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It doesn't entirely answer my question, because I don't see why other pro-thyroid measures wouldn't have reduced NO as well. I eat very digestible foods and not expecting endotoxin to be present in excess, and since NO seems to be caused by endotoxin, I don't know where NO comes from and why cascara specifically was efficient.

leo

leo said:

Peat answered me this a.m. regarding the OJ. He said the citric acid (sour oranges) in commercial OJ could be causing the high BP>.

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Ray Peat said:

" Citric acid binds magnesium and calcium, and if the orange juice was sour (commercial juice usually has added citric acid) that might account for the blood pressure change.""

Clin Nutr. 2006 Dec;25(6):984-93. Epub 2006 May 15.
Tolerable infusion rate of citrate based on clinical signs and the
electrocardiogram in conscious dogs.
Fukuda T, Toyoshima S, Nakashima Y, Koshitani O, Kawaguchi Y, Momii A.
Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical
Factory, Inc., Naruto, Tokushima 772-8601, Japan. [email protected]
BACKGROUND & AIMS: The possible clinical significance of the toxic effects of
citrate has not yet been fully clarified. This study was therefore conducted to
confirm the toxicity and determine the tolerable infusion rate of citrate
administered by rapid intravenous infusion to conscious dogs.
METHODS: Citrate solutions were infused via the cephalic vein of 4 conscious dogs
at 0.33, 0.67, or 1.33mmol/kg/h up to 1.33mmol/kg. Clinical signs and the
electrocardiogram were observed during and after infusion. Serum citrate and
ionized calcium levels were also measured.
RESULTS: Although the mean citrate level increased in accordance with the
infusion rate, the calcium level decreased. No significant changes in clinical
signs or the electrocardiogram were observed during infusion at 0.33mmol/kg/h
despite an increase in the serum citrate level to 1.22+/-0.11mmol/l (pre-infusion
value: 0.38+/-0.01mmol/l) and a decrease in the serum calcium level to
1.28+/-0.03mmol/l (pre-infusion value: 1.50+/-0.05mmol/l). Vomiting and QTc
prolongation were observed at 0.67mmol/kg/h or higher. Salivation and tachycardia
were observed at 1.33mmol/kg/h.
CONCLUSIONS: Based on clinical signs and the electrocardiogram, the tolerable
infusion rate of citrate in conscious dogs is concluded to be 0.33mmol/kg/h.

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Source