Interesting article about CV disease prevention with a Vitamin E/Aspirin combo

[40butpumpin]

I thought this was interesting considering so many of us are interested in cholesterol and doing our best to prevent cardiovascular disease.

I really believe in the next few years there will be a shift away from so much fear about 'cholesterol' towards reducing arterial inflammation with simple vitamin supplements.

It's no wonder the pharmaceutical industry and their buddies at the FDA wanted to ban ALL supplements a few years back. Anyway, I hope this generates some interest and conversation.


Combination of vitamin E and aspirin may prevent heart disease

A recent study done at the University of Pennsylvania Depart-ment of Pharmacology and published in Circulation, a journal of the American Heart Association, discovered that a combination of high dose of vitamin E with a low dose of a platelet-inhibiting drug leads to a dramatic reduction of atherosclerosis in mice genetically engineered for high cholesterol and susceptibility to atherosclerosis when fed a high-fat diet. Mice receiving the combination vitamin E plus platelet inhibitor treatment showed more than 80% reduction in atherosclerotic plaque compared to controls.

Vitamin E alone, in a dose equivalent to 800 mg/day for humans, resulted in a 65% reduction in atherosclerotic plaque. In a group receiving vitamin E and indomethacin, an anti-inflammatory drug that, like aspirin, also has anti-platelet activity, the reduction in plaque was especially impressive, reaching 80% to 85%. Indomethacin was administered in a dose equivalent to 25 mg in humans. The researchers concluded that a low dose of aspirin combined with a large dose of vitamin E would have a similar synergistic effect in humans.

The peroxidation of serum lipids and platelet activation, one of the factors in clot formation, have long been thought to interact in a way that leads to the development of atherosclerosis. The University of Pennsylvania scientists measured the urinary levels of an isoprostane that serves as a marker of lipid peroxidation, and those of thromboxane B(2), a marker of platelet activation. Vitamin E alone suppressed the levels of the lipid peroxidation marker, but not those of thromboxane B(2). When platelet-inhibitor indomethacin was used simultaneously with vitamin E, both markers were lowered, as well as soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1. Monocytes are large white cells that engulf oxidized lipids and other debris; their adhesion to arterial lining is an important step in the progression of atherosclerosis.

The spectacular reduction in atherosclerotic plaque resulting from combination vitamin E and indomethacin was achieved without any change in cholesterol levels. The findings suggest that lowering free radicals, inflammation and platelet clumping may be of equal or greater importance in preventing heart disease than lowering cholesterol. The authors urge further investigation of treatments combining antioxidants and platelet inhibitors.

—Ivy Greenwell

Cyrus T et al. Lipid peroxidation and platelet activation in murine atherosclerosis. Circulation 2001; 104:1940-45.

Vitamin E and aspirin delay heart in mice even with high cholesterol levels. EurekAlert, October 18, 2001.

From:

http://www.lef.org/magazine/mag2002/jan2002_itn.html

 

[nandi12]

You bring up some good points. The current views about atherosclerosis and heart disease consider it an inflammatory reaction, which still involves cholesterol related plaque buildup. The degree of inflammatory response is just as much a risk factor as is a poor cholesterol profile. C-reactive protein, a marker of vascular inflammation, has come to be considered an important indicator of vascular disease. If you have elevated C-reactive protein as well as a poor cholesterol ratio, you are at much higher risk for atherosclerosis and heart disease that if only your cholesterol profile were poor.

Fortunately, testosterone administration (as well as DHT administration in other studies) at least up to 600 mg/week does not increase C-reactive protein levels:

"Plasma high density lipoprotein cholesterol and apolipoprotein A-I concentrations were inversely correlated with total and free T concentrations and were significantly decreased only in the 600 mg/wk group (change in high density lipoprotein cholesterol: -8 +/- 2 mg/dl; P = 0.0005; change in apolipoprotein A-I: -16 +/- 2 mg/dl; P = 0.0001). Serum total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, triglycerides, apolipoprotein B, and apolipoprotein C-III were not significantly correlated with T dose or concentration. Circulating levels of C-reactive protein were not correlated with T concentrations and did not change with treatment in any group" (1)


(1) J Clin Endocrinol Metab 2002 Jan;87(1):136-43

The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men.

Singh AB, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan TA, Shen R, Bross R, Berman N, Bhasin S.

Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059

 

[40butpumpin]

You bring up some good points. The current views about atherosclerosis and heart disease consider it an inflammatory reaction, which still involves cholesterol related plaque buildup. The degree of inflammatory response is just as much a risk factor as is a poor cholesterol profile. C-reactive protein, a marker of vascular inflammation, has come to be considered an important indicator of vascular disease. If you have elevated C-reactive protein as well as a poor cholesterol ratio, you are at much higher risk for atherosclerosis and heart disease that if only your cholesterol profile were poor.

Fortunately, testosterone administration (as well as DHT administration in other studies) at least up to 600 mg/week does not increase C-reactive protein levels:

"Plasma high density lipoprotein cholesterol and apolipoprotein A-I concentrations were inversely correlated with total and free T concentrations and were significantly decreased only in the 600 mg/wk group (change in high density lipoprotein cholesterol: -8 +/- 2 mg/dl; P = 0.0005; change in apolipoprotein A-I: -16 +/- 2 mg/dl; P = 0.0001). Serum total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, triglycerides, apolipoprotein B, and apolipoprotein C-III were not significantly correlated with T dose or concentration. Circulating levels of C-reactive protein were not correlated with T concentrations and did not change with treatment in any group" (1)


(1) J Clin Endocrinol Metab 2002 Jan;87(1):136-43

The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men.

Singh AB, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan TA, Shen R, Bross R, Berman N, Bhasin S.

Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059

Exactly, C-Reactive Protein & Homocysteine levels are apparently critical markers that can easilly be checked to determine your CV state of health.

Nice input, nandi12, thanks for contributing to the thread.

 

[hhajdo]

Good post, thanks...
I don't think that chronic administration of aspirin is a good idea, though...
You can read this article if you want..


Drug Update!
by Cy Willson




Given that the FDA and their advisory panels are up in arms about ephedrine and PPA, we thought it might be a good idea to give you some insight about how the FDA works. We've chosen two new drugs that may or may not make it to the market, and author Cy Willson is going to take you and the drugs through the regulatory revolving door known as FDA clinical investigations.

I'm glad to present two brand spanking new drugs that are up for FDA approval. They differ in uses, but I feel it's very important to give you the scoop on these two before they hit the market.

One of them should be reviewed very carefully as it could have some potentially harmful side effects. The other, in my opinion, should easily receive approval. What I want you to do is play the role of the FDA and review the information that I'm about to present. Then, at the end, hopefully you'll come to the same conclusion as I have.

Before we get started, I want to tell you a little bit about these two drugs. Drug A is an anabolic agent with several potential uses, including, of course, increasing muscle mass, decreasing fat, and maybe even male contraception. Drug B is an anti-inflammatory drug with possible additional use in preventing cardiovascular disease or even death. And, just for grins, we'll assume that no graft has taken place; that these trials have not been influenced by any big drug companies. I know, I know, it's preposterous, but play along, okay?

We'll also be going through three of the four phases of clinical investigation that you'll be using (as you play the FDA) to decide whether either drug should be approved. Phase 4 is after-market research, so that's not really relevant right now.

Okay, let's get started.


Phase I

For the most part, the purpose of Phase I is to show the initial and short-term safety of the drug. The studies are usually open labeled and non-comparative, simply because the researchers are trying to see whether humans can tolerate the drug and if any fairly serious side effects will occur in the short term.

Drug A

The anabolic agent was evaluated for safety in the following fields. The agent was given to 31 healthy young men ages 21-29. They received either 100, 250, or 500 mg/week of this substance for 15 weeks. The men were then monitored for any change in prostate size or prostate-specific antigen, since it was previously thought that this anabolic substance might contribute to hypertrophy of the prostate.

After 15 weeks, it was demonstrated that no change in prostate size or the level of prostate-specific antigen occurred.(1)

Another study was conducted using older men, which also demonstrated no ill effects on prostate size, or prostate-specific antigen. Cholesterol profiles were not affected, either.(2)

In yet another study, homocysteine levels were measured after administration of the drug to determine if it could increase the chances for cardiovascular disease. They took 14 normal male weightlifters, aged 19-42 years old, and administered the drug for three weeks. It was found that Drug A didn't alter homocysteine levels, and thereby didn't increase chances of cardiovascular disease.(3)

Drug B

This drug has the potential to cause damage to the gastrointestinal system. So, the following studies were conducted to assess the short-term safety. The first study used a low dosage of the drug (75 mg). They used twenty healthy male volunteers age 19-22 and gave them 75 mg/day for 12 days. At the end of the study, it was found that this drug had caused gastric mucosal bleeding.(4)

This concerned the researchers, because the level of bleeding seen could cause severe illness and even death! The dosages recommended by the manufacturer are around 650 mg, yet dosages as low as 30 mg were shown to cause bleeding in normal subjects over a period of three weeks.(5) Other subsequent studies demonstrated similar results.(6,7,8,9)


Phase II

This portion is dedicated to proving the efficacy of the given drug. Double blind, placebo controlled studies are generally used.

Drug A

This drug's purported effects include increasing muscle size and strength. It may also have a use as a contraceptive agent in men. In order to demonstrate its ability to alter body composition in a safe manner, the following study was conducted. Twenty-one male weight-training subjects were randomly assigned in a double-blind study. The subjects were monitored for 12 weeks. Results were a significant increase in muscle mass and/or arm girth measurements, with a decrease in abdominal skin fold measurements.(10)

In yet another study, similar in design, normal men were given 600 mg/week of this drug for a ten-week period. Men given the drug versus the placebo demonstrated significant increases in muscle size and strength.(11)

In order to test its efficacy as a male contraceptive, three hundred and ninety nine normal men were given 200 mg/week of Drug A. Out of these, only eight men failed to exhibit a drop in sperm count that would categorize them as temporarily infertile.(12) Similar results were found in another study.(13)

Drug B

The efficacy of this drug in terms of pain relief has long been suspected. It's been accepted that this drug does indeed work in those terms. Another benefit may be its ability to reduce the risk of cardiovascular events as well as cancer. In one study, a lower dosage of this drug (125 mg) was given to patients every other day in a randomized, placebo-controlled study. The patients receiving the drug reduced the absolute risk of cardiovascular death by 5.5%. Additionally, the risk of strokes and major cardiovascular events dropped by 2.2% and 8.8% when compared to placebo. Major events were classified as myocardial infarction, stroke, cardiovascular death, and the need for coronary surgery.(14)


Phase III

This phase is used to demonstrate long term safety and continued efficacy of the drug. After this phase has been completed, the drug may be approved for marketing.

Drug A

The drug was administered to normal men for a period of 6 months. Fifty-one men participated. The study demonstrated increased weight as well as suppressed sperm production. No evidence of major adverse health effects was seen.(15)

Another study, this one ten years in duration, tested the effects of Drug A on the prostates of 35 men. No signs of prostate tumors were found.(16) Similar findings were demonstrated in another study, which tracked 11 men for 7-10 years.(17)

In another pair of studies, the drug was found to lower LDL levels in healthy elderly men.(18, 19)

On a side note, some researchers suspected that the drug might increase aggressive behavior. However, in a double blind, placebo controlled study, 43 normal men (age 19-40) were given 600mg/week of this drug and evaluated for ten weeks. It was concluded that this drug had no effect on aggressive behavior in normal men.(20)

Drug B

In one study, 29 healthy humans were given either 10 mg, 81 mg, or 325 mg daily for 3 months. At the end of the study, it was found that all three doses induced significant gastric injury and 3 of the 29 developed gastric ulcers, one while taking only 10 mg/day.(21) Another study had similar findings, leading to the conclusion that even low doses of this drug may convey a risk of gastrointestinal bleeding.(22)

This brings into question of whether or not the potential cardiovascular benefits outweigh the potential for gastrointestinal bleeding.


Phase IV????

In terms of after-market research, I'm going to give you some statistics. Drug A has been used in the US without a single report of death or an illness. According to Dr. Michael Scally, as well as 4 clinical doctors that I know, none has ever seen a case where Drug A had caused death or illness.

According to the DAWN (Drug Alert Warning Network) medical examiner data from 1998, Drug A wasn't implicated in one death during that year. Not even one. Similarly, according to the DAWN detailed emergency department tables of 1999, there wasn't even one mention or episode for hospital visits caused by Drug A.

On the other hand, Drug B was implicated in death by medical examiners 101 times in 1998. Drug B was also implicated in 12,815 hospital visits.


Conclusion

I bet you guys are wondering how in the hell there can be any after-market data on two drugs that haven't even been approved yet. Well, I hate to be a scandalous trickster, but the fact is — in case you didn't figure it out — is that these two drugs aren't new by any stretch of the imagination. Drug A, the "safe" one, is Testosterone and Drug B, the one implicated in all those deaths and hospital visits, is aspirin.

Now, why would I try to pull a fast one on you guys like this? Well, it's to prove a point. Exogenous Testosterone has always been stuck with the stigma of causing severe negative side effects. Only recently has its positive effects been recognized. However, the stigma of being a dangerous drug is still prevalent. Hence, it's often regarded as an effective agent, but one that has possible severe side effects.

Doctors and various people in the medical community have been brainwashed into thinking that Testosterone is dangerous, when the evidence actually points to the contrary. Thankfully, though, not all docs are "brainwashed," My relatives and friends who are MDs actually side with me!

What's even stranger is that something like aspirin, which is generally regarded as safe by the general public and medical community, has been implicated in so many more deaths and complications than Testosterone. Yet, people are popping the white pills like candy in order to prevent a heart attack. Too bad they're probably offsetting any cardiovascular benefits by simultaneously increasing their chances for internal bleeding.

It's crazy that people are being urged to take such a destructive drug when its cardioprotective effects can be matched by supplements like fish oil or flax oil. Vitamin E may help as well. As far as taking it for pain relief, there are far safer — and more effective drugs — readily available.

Additionally, aspirin has also been shown to inhibit the normal increases in Testosterone seen when humans were given hCG. (23)

I'm sorry, but I just can't see how aspirin can be so respected when it has so many obvious faults. I mean internal bleeding and possible death is one thing, but lowered Testosterone levels! Ah! That's truly scary.

Testosterone is and always will be a safe and effective drug. Period. Furthermore, what the FDA does or doesn't approve isn't always the safest or most effective drug.

Hopefully I've convinced you — my little FDA panel — to approve Testosterone and to ditch aspirin. Oh yeah, and while you're at it, how 'bout Testosterone an over the counter? Just kidding. Sort of. Seriously though, Testosterone should be regulated to a much lesser extent. Hopefully it'll be that way one day.


Aspirin… implicated in 101 deaths and 12,815 hospital visits in just one year, 1998. And the FDA is bellyaching about ephedrine and PPA? Puh-leeze!


References

1.Cooper CS, et al. "Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men." J Urol 1998 Feb;159(2):441-3

2.Kenny AM, et al. "Short-term effects of intramuscular and transdermal testosterone on bone turnover, prostate symptoms, cholesterol, and hematocrit in men over age 70 with low testosterone levels." Endocr Res 2000 May;26(2):153-68

3.Zmuda JM, et al. "The effect of supraphysiological doses of testosterone on fasting total homocysteine levels in normal men." Atherosclerosis 1997 Apr;130(1-2):199-202

4.Prichard PJ, et al. "Human gastric mucosal bleeding induced by low dose aspirin, but not warfarin." BMJ 1989 Feb 25;298(6672):493-6

5.Kallmann R, et al. "Effects of low doses of aspirin, 10 mg and 30 mg daily, on bleeding time, thromboxane production and 6-keto-PGF1 alpha excretion in healthy humans." Thromb Res 1987 Feb 15;45(4):355-61

6.Konturek JW, et al. "Gastric mucosal blood flow and neutrophil activation in aspirin-induced gastric mucosal damage in man." Scand J Gastroenterol 1993 Sep;28(9):767-71

7.Murray FE, et al. "Comparison of effects of calcium carbasalate and aspirin on gastroduodenal mucosal damage in human volunteers." Gut 1996 Jan;38(1):11-4

8.Cohen A. "Gastrointestinal blood loss induced by bromfenac sodium, aspirin, and placebo." Clin Ther 1995 Nov-Dec;17(6):1110-7

9.Graham DY, et al. "Gastric adaptation. Studies in humans during continuous aspirin administration." Gastroenterology 1988 Aug;95(2):327-33

10.Giorgi A, et al. "Muscular strength, body composition and health responses to the use of testosterone enanthate: a double blind study." J Sci Med Sport 1999 Dec;2(4):341-55

11.Bhasin S, et al. "The effects of supraphysiological doses of testosterone on muscle size and strength in normal men." N Engl J Med 1996 Jul 4;335(1):1-7

12.World Health Organization. "Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men." Fertil Steril 1996 Apr;65(4):821-9

13.Sukcharoen N, et al. "Contraceptive efficacy and adverse effects of testosterone enanthate in Thai men." J Med Assoc Thai 1996 Dec;79(12):767-73

14.Posada IS & Barriales V. "Alternate-day dosing of aspirin in atrial fibrillation." Am Heart J;138(1 pt 1):137-143

15.Matsumoto AM. "Effects of chronic testosterone administration in normal men: safety and efficacy of high dosage testosterone and parallel dose-dependent suppression of luteinizing hormone, follicle-stimulating hormone, and sperm production." J Clin Endocrinol Metab 1990 Jan;70(1):282-7

16.Gooren LJ. "A ten-year safety study of the oral androgen testosterone undecanoate." J Androl 1994 May-Jun;15(3):212-5

17.Behre HM, et al. "Long-term substitution therapy of hypogonadal men with transscrotal testosterone over 7-10 years." Clin Endocrinol (Oxf) 1999 May;50(5):629-35

18.Uyanik BS, et al. "Beneficial effects of testosterone undecanoate on the lipoprotein profiles in healthy elderly men. A placebo controlled study." Jpn Heart J 1997 Jan;38(1):73-82

19.Zgliczynski S, et al. "Effect of testosterone replacment therapy on lipids and lipoproteins in hypogonadal and elderly men." Atherosclerosis 1996 Mar;121(1):35-43

20.Tricker R, et al. "The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men — a clinical research center study." J Clin Endocrinol Metab 1996 Oct;81(10):3754-8

21.Cryer B, Feldman M. "Effects of very low dose daily, long-term aspirin therapy on gastrie, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans." Gastroenterology 1999 Jul;117(1):17-25

22.Sorensen HT, et al. "Risk of upper gastrointestinal bleeding associated with the use of low-dose aspirin." Am J Gatroenterol 2000 Sep;95(9):2218-24

23.Conte D, et al. "Aspirin inhibits androgen response to chorionic gonadotropin in humans." Am J Physiol 1999 Dec; 277(6 pt 1):E 1032

 

[40butpumpin]

...This concerned the researchers, because the level of bleeding seen could cause severe illness and even death! The dosages recommended by the manufacturer are around 650 mg, yet dosages as low as 30 mg were shown to cause bleeding in normal subjects over a period of three weeks.(5) Other subsequent studies demonstrated similar results.(6,7,8,9)...

...Aspirin… implicated in 101 deaths and 12,815 hospital visits in just one year, 1998. And the FDA is bellyaching about ephedrine and PPA? Puh-leeze!

5.Kallmann R, et al. "Effects of low doses of aspirin, 10 mg and 30 mg daily, on bleeding time, thromboxane production and 6-keto-PGF1 alpha excretion in healthy humans." Thromb Res 1987 Feb 15;45(4):355-61

Wow, this is eye-opening to say the least. I've known about bleeding from aspirin but I thought it was mainly due to excessive use of a non-enteric coated aspirin. I did not know that problems were associated with relatively low doses.

I did a search of my own and found the following study. In the Conclusion section it points out that 3-10mg/d should not cause "significant gastric prostaglandin inhibition and acute stomach mucosal injury." Based on your input and this follow-up search, I think I will be lowering my daily intake of aspirin from 81mg to 10mg just to be on the side of conservatism.

Thanks much, hhajdo, for your input and taking the time to post on this thread.

Dose Effects of Aspirin on Gastric Prostaglandins and Stomach Mucosal Injury
Annals of Internal Medicine, 1 February 1994; 120: 184-189.

Makau Lee, MD, PhD; Byron Cryer, MD; and Mark Feldman, MD

Objective: To determine if a dose of aspirin exists that might inhibit thromboxane-dependent platelet function without causing gastric mucosal injury, we studied the effects of a wide range of doses of aspirin (3 mg/d to 2600 mg/d) on gastric juice prostaglandins (PGE2 and PGF2a), on serum thromboxane B2, and on stomach mucosal injury as reflected by gastric juice hemoglobin and DNA concentrations.

Design: A randomized, placebo-controlled study.

Setting: Research laboratory at a Veterans Affairs medical center.

Participants: 16 healthy volunteers (5 men and 11 women).

Intervention: In the first part of the study, volunteers received placebo; aspirin, 324 mg/d; 1300 mg/d; or 2600 mg/d for 2 days. In the second part, volunteers received placebo; aspirin, 3 mg/d; 10 mg/d; 30 mg/d; or 81 mg/d for 8 days.

Measurements: Gastric juice PGE2 and PGF2a, hemoglobin and DNA concentrations; gastric juice volume and acidity; and serum salicylate and thromboxane B2 concentrations.

Results: In the first part, significant and similar (approximately 50%) inhibition of gastric juice prostaglandin output was observed with daily aspirin doses of 324 to 2600 mg. However, a significant increase in gastric juice hemoglobin output occurred only with 2600 mg/d. In the second part, significant inhibition (approximately 50%) of gastric PGE2 output was noted at a daily aspirin dose of 30 mg. Lower aspirin doses did not reduce PGE2 output significantly, although these doses did significantly reduce serum thromboxane B2 in a dose-related manner.

Conclusions: Aspirin can significantly reduce serum thromboxane B2 at doses of 3 mg/d or 10 mg/d, which are significantly below the threshold dose for significant gastric prostaglandin inhibition and acute stomach mucosal injury.