The Homocysteine Factor Is Crucial In Combatting Heart Disease
February 23, 2004

If you or a friend or relative have survived a heart attack or stroke, you know that life afterwards is forever changed. A victim of cardiovascular disease (CVD) lives in fear of when the next attack might strike. And if you haven't been stricken yet, count your blessings – because in the United States alone, someone suffers a heart attack every 20 seconds, and a stroke every 53 seconds.

The pharmaceutical industry offers plenty of temporary fixes, including statin drugs for reducing cholesterol, aspirin for thinning the blood and anti-hypertension medications for reducing blood pressure. Essentially, they all help prolong the life of a patient with CVD. But none of these drugs is without risk or side effects. And none of them fight the very cause of atherosclerosis – homocysteine.
Although we have discussed the role of homocysteine in past bulletins, several readers have asked for a more detailed explanation they can take to their doctors. It seems that, even though high homocysteine levels are an even greater risk factor for CVD than high cholesterol, most doctors don't test for it. But they should – especially in their older patients, since homocysteine levels naturally rise as we age.

First, let's tackle the basics. Homocysteine is a by-product of the amino acid methionine, which is naturally found in food and your body. If the right cofactors are present, it will eventually convert to cysteine and other beneficial compounds. If the cofactors are lacking, it will build up to toxic levels, generate free radicals that increase injury to the arterial walls, and accelerate oxidation and the buildup of cholesterol in blood vessels, setting the stage for heart attack and stroke.

Here's what happens: Homocysteine sets off a dangerous chain of events by irritating the inner lining of arteries and veins. Eventually, the inside of the arteries and veins become rough instead of smooth.

As they become diseased, the inner arterial wall thickens and results in arteriosclerosis. Cells lining the artery proliferate and combine with protein and lipids in a mass called an atherosclerotic plaque. Plaques are typically the first sign of cardiovascular disease. With time, plaques gather cholesterol and fat, finally becoming atheromas. Atheromas distort the artery wall, allowing for calcification. When an atheroma blocks blood to the heart, it is referred to as a heart attack. When it blocks blood to the brain, it is a stroke.

If that weren't enough, it was recently reported that homocysteine interferes with the production of nitric oxide, a substance that impairs the blood vessels' ability to dilate — which also contributes to the risk of heart attack and stroke.

The aging-Alzheimer's link

A recent study at the National Institute on Aging found that homocysteine does more than just damage the arterial wall. As a major consequence of folic acid deficiency — a particular problem with the elderly — elevated homocysteine impairs DNA repair.

People with elevated levels of homocysteine also have nearly double the risk of developing Alzheimer's disease, according to a new report from scientists at Boston University. The findings, in a group of people participating in the long-running Framingham Study, are the first to tie homocysteine levels measured several years before with later diagnosis of Alzheimer's and other dementias. The report, which appeared in the New England Journal of Medicine, provides some of the most compelling evidence yet of an association between high plasma homocysteine and eventual significant memory loss.

Another report published last year reiterates the finding that a high level homocysteine in blood serum and spinal fluid have consistently been found in individuals who suffer from Alzheimer's disease.

Luckily, there's a simple (and natural) fix. Since most people with a high homocysteine level don't get enough folic acid, vitamin B6 or B12 in their diet, supplementing with these vitamins helps return homocysteine to normal levels.

In 1969, Kilmer S. McCully, M.D. of Harvard Medical School found that heart patients had nearly 80 percent less vitamin B6 than healthy individuals. As a result of his work, he postulated that B6 might help protect the arteries from the damage that precedes heart disease. In addition, a deficiency of vitamin B12 is associated with elevated homocysteine levels and folic acid is essential for its proper metabolism.

It's estimated that by supplementing with just 400 mcg. of folic acid daily the number of heart attacks suffered by Americans each year would be reduced by 10 percent. It's also estimated that individuals with low vitamin B6 levels have a five times greater risk of having a heart attack than individuals with higher B6 levels!

More than 20 case-control and cross-sectional studies on more than 2,000 subjects have provided what Harvard epidemiologist Meir J. Stampfer, MD, calls "remarkably consistent" findings regarding the relationship between homocysteine levels and cardiovascular diseases. Specifically, patients with stroke and other cardiovascular diseases tend to have higher blood levels of homocysteine than subjects without disease. Dr. Stampfer points out that homocysteine levels do not have to be elevated by very much to increase risk, since most of the patients in these studies had levels that were within what is generally regarded to be the normal range.

Decades after Dr. McCully's breakthrough study, the data continues to pour in. One of the largest studies was reported in the 1992 report from the Physician's Health Study. The study, which included 14,916 male physicians, found that men whose homocysteine levels were in the highest five percent were three times more likely to have a heart attack over a five-year period than men with lower homocysteine levels.

So here's the bottom line – have your doctor order a blood test to check your homocysteine levels. While most labs claim that anything under 15 micromoles per liter (mmol/L) is in the normal range, new evidence is emerging that homocysteine levels above seven cause a progressive risk of heart attack.

What do the numbers mean? In one study of 248 patients, Dutch researchers found that each 3-mmol/L increase in homocysteine caused a 35 percent increase in heart attack risk. And since homocysteine levels increase substantially as we get older, it's important to know where you stand.

Unfortunately, even though the test is FDA-approved, Medicare won't cover it because it doesn't believe that the test is "medically reasonable and necessary." But some private insurers will, so you might want to check with your insurance company. If you do have to pay out-of-pocket to have your level tested, the average cost is $185. But it just may be the best money you ever spent.

References:

Klerk M, et al. "Effect of homocysteine reduction by B-vitamin supplementation on markers of clotting activation." Thrombosis and Haemostasis. 2002;88:230-235.
Mattson MP, et al. "Folic acid and homocysteine in age-related disease." Ageing Research Reviews. 2002 Feb;1(1):95-111.

Mayo Clinic study finds natural progesterone offers more health benefits to post-menopausal women

ROCHESTER, MINN.-- A new type of natural progesterone improves the quality of life for post-menopausal women, according to a new Mayo Clinic study published in the May issue of the Journal of Women's Health. The study reports that women who include naturally occurring progesterone in their hormone replacement therapy are more satisfied with their overall quality of life. The natural hormone, called micronized progesterone, does not negate the positive effect of estrogen on cholesterol levels, like synthetic progesterone does.

Investigators interviewed 176 women whose prescribed hormone replacement therapy combined the natural progesterone with estrogens. In the study, 80 percent of the participants reported increased satisfaction with the new, natural progesterone as compared to previous therapies that used synthetic progesterone. Subjects indicated a significant improvement in bleeding patterns and in control of symptoms when the micronized progesterone was compared with previous therapy.

The results of our study indicate that natural progesterone may offer a wider range of benefits to women taking hormone replacement therapy," says Lorraine Fitzpatrick, M.D., Mayo Clinic endocrinologist and the lead investigator of the study. "We already know that progesterone decreases some of the risks of estrogen replacement therapy such as increased risk of endometrial cancers. Now it seems that naturally occurring progesterone can reduce the occurrence of sleep disorders, hot flashes, anxiety and symptoms of depression."

Half of the study participants reported an improvement in vasomotor symptoms such as "hot flashes." Of the participants, 45 percent felt that psychological symptoms such as feelings of depression and anxiety improved, and 32 percent saw a decrease in sleep disorders. Other areas of improvement included menstrual problems, cognitive difficulties and sexual functioning.

The natural hormone, micronized progesterone, is made from yams and is chemically identical to the naturally occurring progesterone found in the body. Micronized progesterone also is more finely ground for better absorption.

In a large study of menopausal women published in 1998, micronized progesterone also had the most favorable effect on LDL and HDL cholesterol levels associated with cardiovascular risk.

Omega-3 fatty acids are polyunsaturated fatty acids that are considered essential because they cannot be synthesized by the human body. Dietary sources of omega-3 fatty acids include plants (particularly flax, canola, walnuts and hemp) and fish (particularly ocean fish such as sardines, anchovies, salmon and mackerel). Plants contain the parent omega-3, alpha-linolenic acid (ALA), which can be converted into eicosapentanoic acid (EPA) and docosahexanoic acid (DHA).1

Dietary fish and fish oil supplements are a direct source of EPA and DHA. The influence of ALA, EPA and DHA in human health has been the subject of intense research over the last three decades. Although best known for cardiovascular benefits, new findings indicate that the influence of omega-3 fatty acids in mental health, particularly EPA, may currently be underestimated. Epidemiological, experimental and new clinical studies have all shown a strong connection between omega-3 fatty acids, or a lack thereof, and major depression.

These exciting new findings are not entirely surprising when one considers that the brain itself is 60 percent fat and that one-third of all fatty acids are of the polyunsaturated variety.2,3 As discussed below, the current research highlights the critical role of these fatty acids in the central nervous system (CNS).

Omega-3 Intake Declines, Depression Rates Climb

There has been a significant drop-off in omega-3 fatty acid intake within Western countries over the last century. The opposite can be said of omega-6 intake. Although essential, omega-6-rich oils are found in abundance in the North American food supply. Currently these omega-6 oils (corn, safflower, sunflower, cottonseed, sesame) are outnumbering omega-3 fatty acids by a ratio of up to 20:1.4,5

This ratio is a long way off the close to 1:1 omega-6 to omega-3 ratio as recommended by the international panel of essential fatty acid experts in the Journal of the American College of Nutrition.6 The average daily intake of EPA/DHA combined is 130mg in North America, 520mg short of published recommendations and 870mg short of the 1000mg recommended by the American Heart Association in cases of heart disease.1

In direct contrast to the depletion of omega-3 fatty acids from the Western food supply, the rates of depression have dramatically increased in Western countries. In addition, depression is now occurring more commonly in younger persons. The average age of onset of depression has continued to dip over the last 100 years. Scientists investigating the change in rates of depression have made it clear that these findings cannot be explained away by changes in attitudes of health professionals or society, diagnostic criteria, reporting bias, institutional or other artifacts.7,8 Perhaps the inadequate omega-3 intake, the major deviations in fatty acids ratios and the quarter-century-old message that all fat is unhealthy has had an untold influence on rates of depression.

Fish Consumption and Depression

There have been a number of studies that have examined national and international fish consumption data and compared them to rates of depression. Dr. Joseph Hibbeln of the National Institutes of Health is a pioneer in this area. He, and his group, have shown that higher national consumption of fish for a nation equals lower rates of depression versus countries consuming the least amount of fish.9 He has also shown that higher fish consumption is correlated with lower risk of postpartum depression10 and seasonal affective disorder.11

Other researchers have shown that even within a nation, fish consumption is associated with lower risk of depression and higher mental health status.12,13 Finally, researches are now observing increasing rates of depression in regions of the world that are moving away from traditional omega-3-rich diets to typical Western foods.14

Laboratory Tests in Depression

The epidemiological studies clearly suggest that adequate omega-3 fatty acids may be an important protective factor in depression. Correlation, however, does not prove causation. To add to the strength of the epidemiological studies, scientists have examined the levels of omega-3 fatty acids in the blood cells and fat storage cells of those with major depression.

Four studies have shown that those with depression do indeed have lower levels of omega-3 fatty acids in the blood.15-18 One of the studies showed that the lower the level of EPA, the more severe the clinical depression.15 In addition, a recent study showed that the patients with depression have 35 percent less DHA in fat storage cells versus healthy controls.19

Experimental Studies

Over the last decade, neuroscientists have been examining the consequences of omega-3 deficiencies in the central nervous system. Alterations in serotonin and dopamine levels, as well as the functioning of these two important neurotransmitters is evident in an omega-3 deficiency. The changes observed in omega-3 deficiency in animals is strikingly similar to that found in autopsy studies of human depression.20

In addition to changing serotonin and dopamine levels and functioning, omega-3 deficiencies are known to compromise the blood-brain barrier, which normally protects the brain from unwanted matter gaining access.21 Omega-3 deficiency can also decrease normal blood flow to the brain,22,23 an interesting finding given the studies which show that patients with depression have compromised blood flow to a number of brain regions.24,25 Finally, omega-3 deficiency also causes a 35 percent reduction in brain phosphatidylserine (PS) levels.26 This is also of relevance when considering that PS has documented antidepressant activity in humans.27,28

Mechanisms of EPA/DHA Regulation of Mood

DHA is found in high levels in the cells of the central nervous system (neurons); here it acts as a form of scaffolding for structural support.29 When omega-3 intake is inadequate, the nerve cell becomes stiff as cholesterol and omega-6 fatty acids are substituted for omega-3.30 When a nerve cell becomes rigid, proper neurotransmission from cell to cell and within cells will be compromised.

While DHA provides structure and helps to ensure normal neurotransmission, EPA may be more important in the signaling within nerve cells.32 Normalizing communications within nerve cells has been suggested to be an important factor in alleviating depressive symptoms.33 In addition, EPA can lower the levels of two important immune chemicals, tumour necrosis factor alpha (TNFa) and interleukin 1 beta (IL-1ß), as well as prostaglandin E2.34

All three of these chemicals are elevated in depression.35-38 In fact, higher levels of TNFa and IL-1ß are associated with severity of depression.39 Finally, EPA has been hypothesized to increase brain-derived neurotropic factor (BDNF), which is known to be lower in depressed patients.20 BDNF is neuroprotective, enhances neurotransmission, has antidepressant activity and supports normal brain structure. BDNF may prevent the death of nerve cells in depression.

Clinical Studies

There have been some published case reports indicating that flaxseed oil may be helpful in cases of bipolar depression and the anxiety disorder agoraphobia.40 The first controlled clinical trial indicating that omega-3 fatty acids may be of benefit in depression was published in 1999. In this case, 9:6 g of EPA/DHA versus placebo led to longer periods of remission and improvement in depressive symptoms in those with bipolar depression.41

Some researchers theorize that such high doses of EPA/DHA may not be necessary and that low levels of pure EPA may be of benefit.32 In a study published in the American Journal of Psychiatry, researchers showed that just 2g of pure EPA could improve the symptoms of treatment-resistant depression. The researchers found that the EPA (versus placebo), when added to an ineffective antidepressant for one month, significantly improved depressive symptoms.42

A larger study published in Archives of General Psychiatry replicated these findings, however, this time various doses of EPA were examined. Those on ineffective antidepressants were given 1g, 2g or 4g of pure EPA or a placebo in addition to the medication. Interestingly, the 1g daily dose of EPA led to the most significant improvements over the three-month study; it appeared that less was more. There were significant improvements in depressive symptoms, sleep, anxiety, lassitude, libido and thoughts of suicide.43

Researchers from Taiwan Medical University published a recent study in which they found that a 4.4g EPA and 2.2g DHA mix could alleviate depression versus placebo in those with treatment-resistant depression. This was a two-month study involving patients who were on antidepressants that were not working. As with the other omega-3 studies discussed, the fish oil was well tolerated and no adverse events were reported.44

There is also evidence that omega-3 oils may be of benefit in treating depressive symptoms outside of major depressive disorder. Canadian researchers showed that Antarctic krill oil (400mg EPA, 240mg DHA) could improve depressive symptoms associated with premenstrual syndrome.45 Harvard researchers have also shown that just 1g of pure EPA is beneficial in the treatment of borderline personality disorder. This personality disorder, which is particularly difficult to treat, is characterized by both depressive and aggressive symptoms. This was a two-month placebo-controlled study and the results showed that EPA has a mood-regulating effect, improving both depression and aggression versus placebo.46

To date, with one exception, all studies conducted on omega-3 fatty acids and mood have had a positive outcome. The singular negative study examined pure DHA in patients with depression. The results in the case showed that DHA alone was no better than placebo in alleviating depressive symptoms.47

Conclusion

Although an influence of EPA and DHA on brain physiology and structure is apparent, the precise mechanisms whereby omega-3 fatty acids may alleviate depression remain unknown. The results of the clinical trials reinforce the epidemiological and experimental studies, underscoring the importance of adequate omega-3 intake in those with depression.

The long-term studies of fish oil supplements in the area of cardiovascular health, some spanning three-plus years, have shown that they are safe and well tolerated.48,49 Patients with depression or depressive symptoms should discuss omega-3 fatty acids with their health care providers. While scientists continue to unravel the neuropsychological influences of omega-3 fatty acids, it should be recognized that they are not a substitute for appropriate mental health evaluation and care.

Alan C. Logan is a naturopathic physician licensed in Connecticut. Valedictorian of the Canadian College of Naturopathic Medicine, class of 2001, his recent medline-indexed article "Neurobehavioral Aspects of Omega-3 Fatty Acids: Possible Mechanisms and Therapeutic Value in Major Depression" is available to medical professionals by writing to Dr. Logan at aclnd@cfs-fm.org.

More Data Reveals Risks of Statin Cholesterol Drugs

Side effects have included lost memory in some patients

March 27, 2004

It was hot on the golf course, and, with every hole, the mysterious pain that vibrated through Jeff Bryden's body worsened, finally forcing him into the locker room.

Statins And Memory

In one study, 308 men were given a placebo or two different doses of the statin Zocor for six months. In memory tests and a test involving a complex maze, the statin users did not perform as well as those on the placebo. The difference was subtle but significant, said the study's lead author, Matthew Muldoon, an associate professor of medicine at the University of Pittsburgh School of Medicine.

Horror Stories

Jeff Bryden of Brookfield still has the sensation that his muscles are vibrating, almost three years after discontinuing statin use.

Duane Graveline forgot that he had a family and had been a NASA astronaut.

He drank some Gatorade and took a shower, but the pain only intensified, seeming to engulf every muscle in his body.

"I literally couldn't move," he said. "It looked like the exorcist had gotten ahold of me. It was excruciating pain."

As he lay on a bench, a fellow club member who is a doctor saw him and immediately suspected he was suffering a reaction to a drug.

Bryden, 48, of Brookfield, had been taking the cholesterol-lowering drug Lipitor,which he and his doctor now believe may have caused extensive damage to his muscle cells, a condition that could linger for years.

Bryden's case is unusual, maybe even rare. But a growing number of researchers, doctors and patients are wondering whether so-called statin drugs are associated with significantly more side effects, both minor and more serious, than previously thought.

Those complications include muscle pain, kidney and liver conditions, and cognitive problems.

It's a complex and dicey issue, being raised at a time when 36 million Americans are being told they should take the drugs, although currently only 11 million are following that advice.

Four years ago, the makers of the statins Pravachol and Mevacor asked the Food and Drug Administration to allow lower-dose versions of those drugs to be sold over-the-counter. An FDA advisory committee voted against the application.

"But it will come back again," said physician Sidney Wolfe of the advocacy group Public Citizen. "People want to put it in the drinking water."

Although many doctors don't think statins should be sold over-the-counter, some, including cardiologist James Stein, say the statin guidelines should be broadened to include more patients. Stein, an associate professor of medicine at the University of Wisconsin-Madison, said he believes that most of the complications reported by patients are overstated.

For many patients, especially those with heart disease or high-risk conditions such as diabetes, statins can be lifesavers. Numerous clinical trials have showed that the drugs can significantly reduce heart attacks, strokes and the need for bypass surgery or angioplasty.

Measuring side effects

As more people take statins, the number of side effects has grown. Some doctors now say they suspect the incidence of side effects is much higher than what has been shown in various clinical trials, including several funded by the drug makers.

"If you believe the clinical trial data, the problems occur at very modest rates," said Beatrice Golomb, an assistant professor of family medicine at the University of California, San Diego, who is conducting two studies on statin side effects.

Those trials generally report side effects in less than 1% to 2% of patients. And many of those complications are minor and disappear if the drug is discontinued or the dose lowered.

But, "there are clinicians whose personal experience is substantially different than what is reported in the trials," Golomb said.

She said that based on her experience and that of other doctors, 20% or more of patients encounter some side effects.

People may be excluded from a trial for a variety of reasons, including medical conditions. Others may be sought out for inclusion because of their ability to tolerate drugs, for example. In addition, people in trials often are paid and receive free care and medication. That may create a disincentive to report side effects for fear of losing those benefits, Stein said.

"People in clinical trials aren't like the rest of the world," he said.

Weighing a drug's risks against its benefits is crucial for people who may have a risk factor or two for heart disease but aren't in the high-risk groups for which statin therapy clearly is recommended.

Group pushes FDA

The issue took on more urgency this month when Public Citizen asked the FDA to remove the statin Crestor, which came on the market in September.

The group cited four cases of kidney failure, five additional cases of kidney damage, six cases of abnormal bleeding, and seven cases of life-threatening rhabdomyolysis in patients taking the blood-thinning drug coumadin, which can interact with Crestor.

Otherwise considered rare, rhabdomyolysis is one of the most serious statin side effects. It's a condition in which muscle tissue is destroyed and released into the blood.

In 2001, Bayer Corp. was forced to remove its statin, Baycol, from the market after it was linked to more than 52 deaths, including 31 in the United States. Most of the deaths involved rhabdomyolysis.

Wolfe, of Public Citizen, said there is even more reason to be concerned about Crestor. He noted that Crestor, unlike Baycol, was linked to rhabdomyolysis cases before it was approved.

The FDA is looking into the status of Crestor and hopes to respond within 180 days, said Mary Parks, a physician and deputy director of the FDA's metabolic and endocrine drug products division.

Gary Bruell, a spokesman for AstraZeneca, the maker of Crestor, said the drug was tested in more than 10,000 patients and "is the most-scrutinized statin ever."

Statin problems ongoing

However, for patients such as Bryden, those assurances are not convincing.

Bryden said he had been suffering muscle cramps and fatigue for more than a year before the incident on the golf course in July 2001. He also had switched statins - from Zocor to Lipitor.

He saw a neuromuscular specialist at the Medical College of Wisconsin, who diagnosed his condition as a disease in his muscle cells brought on by statin toxicity, he said. His muscles are still sore, despite the fact that he has been off statins for nearly three years.

"I still have that constant feeling that my muscles are vibrating," he said.

Wendy Peltier, the associate professor of neurology at the Medical College who diagnosed Bryden, said she and other specialists at the college have seen between 30 and 50 patients with statin-related muscle problems in the past few years.

The drugs seem to cause a variety of muscle problems in some people, she said. Most of the time, the problems disappear when the drug is discontinued or the patient is given a supplement. Cases such as Bryden's are rare, she said.

Still, she estimated that about 10% of statin users encounter some kind of muscle problem.

In addition, there have been numerous accounts of statin users experiencing mental problems.

For Duane Graveline, a retired doctor and astronaut, the memory problem was so bad that he wrote a book about it: "Lipitor, Thief of Memory," which was published in February.

Graveline began using Lipitor four years ago after his annual NASA physical showed an elevated cholesterol level. He was put on a low dose of the drug. About six weeks later his wife found him wandering in their front yard. He could not remember recent events, he said.

"I didn't know who she was," Graveline said.

Within about six hours, his memory returned. A neurologist determined that he had had a bout of transient global amnesia. Graveline said he suspected it might be related to Lipitor, so he stopped taking it.

A year later, NASA doctors again told him he needed to get his cholesterol down and persuaded him to go back on Lipitor.

Six weeks later, he said, he had another bout of amnesia, only this time he lost memory of everything after high school.

When he was told that he was a former astronaut and that he was married and had children, "I laughed," he said. "I thought that was absurd."

It took about 12 hours for his memory to return to normal, Graveline said.

The Pill That Ends Aging
The November, 2003 Issue of Reader's Digest features a headline "The Pill That Ends Aging." I suggest you pick up this issue and read it carefully. This story features two of Young Again's featured supplements: Acetyl L-Carnitine or ALC and Alpha Lipoic Acid or ALA. The benefits of supplementing with the proper dose of both alpha-lipoic acid (ALA) and acetyl-L-carnitine seem endless, and we have summarized them in the following article.

The Reader's Digest is accurate except it gives the impression this is a new discovery. It may be new to the readers of the Reader's Digest but not to any of the 180,000 subscribers to the Longevity News.

DHEA Effectivly Aids Lupus Patients' Recovery

Declining levels of DHEA may have just as much to do with the autoimmune disease lupus as they do with growing old, reports the June 1998 issue of Seminars in Arthritis and Rheumatism.

Lupus is characterized by immune changes akin to those associated with normal aging. DHEA, short for dehydroepiandro-sterone, is an adrenal hormone that drops significantly with age. In addition to calming stress-induced hormonal reactions such as inflammation--a symptom of lupus--DHEA is also linked to immune function.

In one study, animals given DHEA avoided some of the immune function disruptions caused by aging and survived what are normally lethal infections. Previous research shows that people with lupus have low DHEA levels, and now studies indicate DHEA may help treat the disease.

In the first trial, 10 women with lupus received 200 mg DHEA daily for six months and showed improvement. A controlled clinical trial followed, involving 28 women with lupus who also received 200 mg DHEA or a placebo daily for three months. The women who took DHEA felt better and were able to decrease their daily dose of prednisone, a corticosteroid commonly prescribed for lupus.

The researcher suspects that low DHEA levels may be linked to the immune system changes that characterize both lupus and aging and calls for further clinical studies.

Vioxx, Blood Pressure Medications Don't Mix

Study Shows Combination Doubles Risk of Heart Attack

March 11, 2004
March 11, 2004 (New Orleans) -- The popular arthritis drug Vioxx is once again causing concern among heart specialists. This time, a study suggests that taking both Vioxx and high blood pressure medications doubles the risk of a heart attack.

Andrew Whelton, MD, of Universal Clinical Research Center in Hunt Valley, Md., tells WebMD he analyzed medical insurance claims from more than 34,000 arthritis patients to determine if arthritis drugs such as Vioxx and Celebrex, as well as ibuprofen, naproxen, and aspirin, increased the risk for heart attacks.

After accounting for other factors that increase the risk of a heart attack, such as age and a history of heart attack, Vioxx was the only drug that increased the risk of a heart attack. But the risk was only significant among people taking medications to treat high blood pressure.

Whelton, who presented his findings at the American College of Cardiology Scientific Session 2004, says he isn't recommending that arthritis patients avoid Vioxx. But he says he thinks that doctors should carefully consider using the drug in patients who are also being treated for high blood pressure.

Asked why Vioxx appeared to increase the risk for heart attack when other arthritis treatments did not, Whelton says, "We think it is a problem with the molecule, rather than with the drug's effect on inflammation." But he says that more research is needed for a definitive answer.

Vioxx Under Scrutiny

This isn't the first time that Vioxx has come under fire from heart specialists. In 2001, researchers at The Cleveland Clinic reported in The Journal of the American Medical Association that people taking Vioxx or Celebrex for arthritis were twice as likely to have a heart attack as patients taking the arthritis drug naproxen. In 2002, the FDA required that the Vioxx label be changed to include information about possible increased risk of heart attack.

Vioxx and Celebrex are newer versions of anti-inflammatory drugs for arthritis called Cox-2 inhibitors. They were created to help decrease some of the side effects of older anti-inflammatory drugs, such as ulcers and bleeding in the stomach. Bextra is the third and newest drug in this group.

Robert Harrington, MD, professor of medicine at Duke University in Durham, N.C., tells WebMD that a head-to-head trial between Vioxx and Celebrex would be the only way to "really answer this question about increased risk." Harrington was not involved in Whelton's study.

FDA Requiring Suicide Warning on Popular Anti-Depressants

There are Effective Natural Alternatives Without Risks and Side-Effects. See links Below

March 22, 2004 -- The FDA is issuing a warning about the possibility of worsening depression or suicidal thoughts in people, particularly children, who take any of 10 popular antidepressants, especially at the beginning of treatment or when the doses are increased or decreased.

The FDA has sent a letter to drug manufacturers requesting labeling changes on these antidepressants -- warning of possible suicide, worsening depression, anxiety, and panic attacks in adults and children.

Antidepressants involved in this warning label request are:
Prozac (also sold generically as fluoxetine)
Zoloft
Paxil
Luvox
Celexa
Lexapro
Wellbutrin
Effexor
Serzone
Remeron

"We don't know that the drugs are responsible for these behavioral changes, but nonetheless we're telling physicians and families to be aware of this and that if the behaviors do emerge, to get treatment right away," said Russell Katz, a director with the FDA's Center for Drug Evaluation and Research, in a news teleconference today.

The proposed warning label will "include information about behavioral changes that may occur in patients who are prescribed antidepressant drugs," said Katz.

"This applies to adult and pediatric patients and involves the potential for suicidal thinking or suicidal behaviors and warns the physician and family about any behaviors that might emerge that haven't been experienced before," he added.

But the FDA stopped short of recommending people discontinue taking their antidepressants.

"We specifically decided not to tell people not to use these drugs," said Katz. "We don't think that is necessary at this point."

In addition to looking for signs of worsening depression, the following symptoms may also be a sign of a problem:
Anxiety
Agitation
Panic attacks
Insomnia
Irritability
Hostility
Impulsivity
Severe restlessness
Mania in both adults and children being treated with antidepressants for major depression

If these changes appear, treatment should be evaluated, the FDA says. Medications may need to be discontinued when symptoms are severe, begin abruptly, or if they signal a new disorder.

There also is concern for people who have bipolar disorder (manic depression) but don't know it. Antidepressants have the potential for provoking a manic episode in these people, the FDA says. Doctors, patients, and family members should be on the lookout for any symptoms of mania, including feeling extremely happy or very irritable, inflated self-esteem, not needing as much sleep as usual, talking, or being more active than usual.

Glucosamine May Stop Knee Arthritis

March 29, 2004

Supplement Likely Benefits All Types of People, All Joints, Say Researchers

The popular supplement glucosamine could do more than just ease arthritis knee pain. New research indicates that it may actually stop disease progression -- and possibly reverse it.

In the latest of an ongoing series of studies, European researchers studied the effect of glucosamine specifically in postmenopausal women already diagnosed with knee osteoarthritis. After age 50, knee osteoarthritis becomes more common in women -- possibly because of waning estrogen levels although medical research has not yet shown that, say the researchers. Osteoarthritis, caused by degeneration of cartilage that occurs with age, is the most common type of arthritis.

"What we found in studying postmenopausal women is what we found with our other population groups -- glucosamine sulfate certainly prevents the destruction of cartilage, slows progression of osteoarthritis, and improves symptoms of the disease," researcher Lucio C. Rovati, MD, of the University of Milano, tells WebMD. "And it may also rebuild cartilage in some people."

His new findings, published in the March/April issue of Menopause, come from two studies involving 414 women with knee osteoarthritis, most of whom had already experienced menopause. Half took 1,500 milligrams of glucosamine sulfate daily while the other women took a placebo. After three years, those taking glucosamine had experienced no further loss of cartilage as measured by knee X-rays, whereas the placebo group continued to experience cartilage destruction.

In addition, pain and function significantly improved among the women taking glucosamine compared with the placebo group where there was no such improvement in knee stiffness seen.

This improvement is of major clinical significance in terms of well-being, says Rovati, a professor of pharmacology. "The condition of women taking a placebo pill, meanwhile, worsened."

In previous studies, published in Archives of Internal Medicine and The Lancet, Rovati's team -- who include researchers from Belgium and the Czech Republic -- found similar levels of improvements when the same daily dosage was given to men and younger women with knee osteoarthritis.

What makes his new findings so important is that following menopause, rates of knee arthritis skyrocket in women. Up until now, that group of women had not been specifically studied, although postmenopausal women have been included in previous studies.

"There is certainly a good reason to believe that estrogens are important for cartilage, and this continues to be an active area of interest -- determining exactly how menopause impacts osteoarthritis," says John H. Klippel, MD, head of the Arthritis Foundation.

"What's really unique about this study is that they are able to look at a relatively homogeneous population -- postmenopausal women, as opposed to the whole world of osteoarthritis -- and have been able to confirm that in this population, glucosamine improves function and retards (measurable disease) progression."

All Joints Can Benefit

Rovati says his findings are the latest to show what his research team has long suspected: "Based on our studies and others, it appears that everyone with knee osteoarthritis can benefit from glucosamine sulfate," he tells WebMD. "And we suspect that this data can be transferable to all weight-bearing joints. The reason we and others primarily study knee osteoarthritis is because it's the most common type and there are more patients."

Glucosamine is naturally produced by the body and found primarily in joint cartilage, where it's believed to help maintain joint health and resilience. Although glucosamine supplements have long enjoyed a reputation for easing knee pain, only recently have they garnered convincing scientific evidence to back up these claims.

These supplements, which are not regulated by the FDA, contain glucosamine extracted from tissues of shellfish. They come in two forms: glucosamine sulfate, like that used in Rovati's studies, and glucosamine hydrochloride.

"The difference between the two is the added salts used," says Klippel, former clinical director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. "Glucosamine is the active ingredient, so one would suspect a similar result from either type." The prescription product used in Rovati's study is chemically similar to glucosamine sulfate products sold in the U.S., but did not contain chondroitin or methylsulfonylmethane (MSM), as many do.

Still, Klippel tells WebMD that there is no evidence to indicate that glucosamine should be taken as a preventative measure before menopause onset, to reduce a woman's later risk of knee problems. "On the other hand, this study confirms that if you already have osteoarthritis, taking glucosamine may be a good thing to do."

But it may not be enough: "Although glucosamine may be helpful, it's also part of a much larger treatment plan -- and that should include weight management and physical activity," says Klippel. "Both are important, not only to reduce the risk of osteoarthritis, but also reducing symptoms once it has been diagnosed."

Green Tea May Combat Leukaemia

April 1, 2004

The active component in green tea, epigallocatechin-3-gallate (EGCG), already shown to fight several types of cancer, also appears to kill cells of the most common form of leukaemia, reports a US team this week.

The researchers found that EGCG interrupts the communication signals needed by cancer cells to survive, prompting them to die in eight of 10 patient samples tested in the laboratory.

The cells came from patients with B-cell chronic lymphocytic leukaemia (CLL), most often diagnosed in patients in their mid-to-late 60s and currently without cure. While chemotherapy is administered in the most severe cases, doctors have tended to stall use of this treatment in early stage patients, some of whom may live with it for decades and not require treatment. Green tea could however offer a less harmful, but effective alternative for this category of patients.

"We're continuing to look for therapeutic agents that are nontoxic to the patient but kill cancer cells, and this finding with EGCG is an excellent start," said Neil Kay from the Mayo Clinic. "Understanding this mechanism and getting these positive early results gives us a lot to work with in terms of offering patients with this disease more effective, easily tolerated therapies earlier."

The findings are reported in an early electronic article in the journal Blood.

"With these findings we may be able to pursue the idea of culling out early-stage patients who have historically not been treated and perhaps use an EGCG-based treatment. That's our next step with our research," said author Yean K. Lee.

"Our research goal is to identify new treatments for CLL that have a favourable side effect profile and can be used in patients with early stage disease to prevent progression. I think we're getting there," added Mayo Clinic researcher Tait D. Shanafelt.

Since the 1970s, epidemiological studies of cancer have shown that in parts of the world where green tea is consumed, the incidence of solid tumour cancers such as breast, lung and gastrointestinal cancers is lower. Mouse-model testing of green tea's cancer-prevention properties and lab tests on EGCG have confirmed that they protect against solid tumours and induce death in cancer cells from solid tumours.

The Mayo Clinic research suggests EGCG works by inhibiting a pathway in the leukaemia cells related to angiogenesis -- the complex process that maintains nourishing blood flow to a biological structure, in this case a cancer cell.

Green Tea May Help Prevent Skin Cancer

Green Tea in Drink Form or in Skin Cream May Help Prevent Skin Cancer
April 28, 2003, American Cancer Society

Green tea is already thought to protect against some cancers because it contains antioxidants. A recent review of previous studies finds drinking green tea may help prevent skin cancer – and it may even be effective when added to skin care creams.

Santosh K. Katiyar, Ph.D., and colleagues in the department of dermatology at Case Western Reserve University, reviewed several studies about green tea and reports that it may be useful in preventing and treating a variety of human skin disorders. The substances in green tea thought to protect against cancer are called polyphenols, which have antioxidant properties that can cancel out the damage caused by free radicals. Free radicals are molecules that damage cells'' DNA and as a result can begin the process of a cell turning cancerous.

Dr. Katiyar says it is better to drink green tea to benefit from its antioxidants. But he adds that it could be useful if applied topically on the skin. It may protect against damage from environmental pollutants, especially ultraviolet radiation from the sun, according to the researcher.

"Supplementation of skin care products with green tea may have a profound impact on various skin disorders in the years to come," he says.

Tea is commercially available in three forms: green tea, black tea and oolong tea. "Of the total tea production, about 78 percent is consumed as black tea, mainly in Western countries … while about 20 percent is consumed as green tea, mainly in Asian countries," the study authors write.

Green tea is made from the fresh leaves of the tea plant by steaming and drying them at high temperatures. Although skin-care products containing green tea are already available on the market, the products most likely have not been tested in clinical trials and the concentration of green tea polyphenols they contain is not uniform, according to the researchers.

"The next area of research will be to study whether the data we obtained in animal models is equally useful for human beings," Dr. Katiyar says. Experiments with human skin cells grown in laboratory dishes already has begun, but much more research needs to be done, he adds.

Although a diet high in fruits and vegetables has been proven to lower risk of some cancers, results of studies about tea consumption have not been consistent, Dr. Ringer adds. Until research proves there is a definite benefit from tea and finds the best source of it as well as the right frequency of consumption, it should be considered an addition to – not a substitute for – a diet high in fruits and vegetables, he says.

Lycopene Mechanism Against cancer, New Findings

March 30, 2004

Tomato-derived carotenoid lycopene may reduce risk of cancer by activating special cancer preventive enzymes, according to a new lab study by an Israeli team.

The researchers incubated breast and liver cancer cells with lycopene and found that natural chemical stimulated production of phase II detoxification enzymes, which remove harmful carcinogens from the cells and the body.
As expression of phase II enzymes is regulated by the 'antioxidant response element' (ARE), the new research suggests that this could be the mechanism behind the cancer-preventive effect of tomatoes, said Dr Joseph Levy and colleagues from Ben-Gurion University of the Negev, Beer-Sheva, Israel, speaking at the American Association for Cancer Research annual meeting this week.

A number of epidemiological studies looking at consumption of tomato products, shows that they can reduce risk of certain types of cancer when consumed regularly. It has also been proposed that this is due to a number of different compounds in tomatoes, rather than lycopene alone.

Testing other carotenoids for expression of phase II enzymes revealed that they were inferior to lycopene however. Beta-carotene had a lesser effect, while asataxanthin and another tomato carotenoid called phytoene had no impact on the cancer cells.

"The transactivation was dose-dependent and unexpectedly specific for lycopene, since astaxanthin, beta-carotene and phytoene had no effect. This specificity suggests that activation of ARE-mediated transcription by carotenoids is not related solely to their antioxidant properties," noted the researchers.

But the findings do not rule out the role of other compounds in tomatoes, Dr Yoav Sharoni told the Longevity News.

"Beta-carotene did not activate the ARE transcription but there are probably other pathways to enhance the phase 2 enzymes," he said.

"We have seen that when you combine lycopene with other carotenoids there is a synergistic effect and all of the epidemiological evidence comes from consumption of tomato products rather than pure lycopene."

Despite this, a number of companies are currently developing synthetic or fungus-derived lycopene for sale to supplement companies. Lycopene has also been linked to reduced risk of heart disease and protection against breast cancer.

March 30, 2004

A little-known molecule created in the intestine when soy is digested is a powerful blocker of a potent male hormone involved in prostate cancer and male pattern baldness, shows a new animal study.

Equol, the major metabolite of the phytoestrogen daidzein - one of the main isoflavones found abundantly in soybeans - completely stops in its tracks the male hormone dihydrotestosterone (DHT), which normally stimulates prostate growth and causes male pattern baldness.
Several human studies have suggested that eating soy reduces the risk of prostate cancer. This new study could explain why, and also lead to treatments for other hormone-related diseases in men.

"These findings are of immense clinical importance because blocking the action of the potent androgen (male hormone) DHT has been one of the holy grails of the pharmaceutical industry as a strategy for treating prostate cancer and other related diseases," said Kenneth Setchell, from the Cincinnati Children's Hospital Medical Center, who first identified equol in humans 20 years ago.
Mp>In recent years, the pharmaceutical industry has developed drugs that inhibit a certain enzyme that converts testosterone to DHT. Unfortunately, these drugs have side effects. Equol, on the other hand, does not prevent DHT from being made but prevents it from functioning by stopping it from binding to the androgen receptor and thereby preventing the prostate from growing.

This may be particularly important for men who have been diagnosed with either an enlarged prostate (benign prostatic hyperplasia, or BPH) or cancer of the prostate.

"Directly binding and inactivating DHT without influencing testosterone gives equol the ability to reduce many of the harmful effects of androgens without affecting the beneficial ones," said Robert J. Handa, senior author of the study, published in the April edition of Biology of Reproduction(70: 1188-1195).

"The novelty of equol is that it both inhibits androgen hormone and influences oestrogen hormone action. We do not know of any other molecule that possesses these important biochemical properties," added Edwin Lephart, director of the Neuroscience Center at Brigham Young University, which also participated in the research.

Two experiments demonstrated that injections of equol into male rats reduced the size of the prostate. In one study, the testes of male rats were removed, thereby eliminating all DHT production. When investigators injected DHT into rats, their prostates grew. When they gave rats equol, nothing happened at all. When they injected rats with both equol and DHT, the equol prevented the DHT from functioning as it normally would – as a stimulator of prostate growth.

In other words, equol did not change hormone levels but completely blocked the effects of DHT in rats. This could explain why men in Japan, who eat more soy than men in the Western world but suffer equally from BPH as they age, rarely go on to have prostate cancer, said Dr Setchell.

The researchers added that, given the importance of DHT in the skin, it is possible that equol may offer a means of controlling hair loss and promoting healthy skin. They have started further studies to assess equol's potential as a treatment for a variety of other androgen-mediated conditions.

Lycopene Reverses a Precancerous Mouth Condition
April 30, 2004

Taking the antioxidant lycopene can reduce symptoms of or even reverse a mouth condition called oral leukoplakia, reports a study in Oral Oncology (2004;40:591–6). This study found that lycopene reduces the size of mouth plaques and reverses the precancerous cell changes associated with oral leukoplakia.

Oral leukoplakia is a precancerous condition of the inside of the mouth characterized by white patches or plaques that cannot be scraped away. These plaques most commonly occur on the inside of the cheeks, but can also appear on the gums, tongue, palate, and inside of lips. People who use tobacco products such as cigarettes or chewing tobacco have the highest risk of developing this condition. Studies have found that people who eat large amounts of tomatoes and tomato-based foods are less likely to have oral leukoplakia, and have a lower risk of developing some cancers, including cancers of the mouth, larynx (voice box), throat, and esophagus. The cancer-protective effect of tomato is attributed to its high content of the red-colored antioxidant lycopene.

In the current study, 58 people with oral leukoplakia were randomly assigned to one of three treatment groups: group A received 8 mg of lycopene each day for three months; group B received 4 mg of lycopene each day; and, group C received an inert pill (placebo). People in all groups were examined and patches of leukoplakia were measured every seven to ten days during the treatment period. Biopsies to evaluate the degree of precancerous changes in the cells were performed at the beginning and end of this period. A complete response, defined as the absence of visible plaques for at least four weeks, was observed in 55% of the people in group A, 25% of those in group B, and 0% of those in group C. The average overall improvement was 80% in group A, 66% in group B, and 12% in group C. A review of the biopsy samples confirmed that both doses of lycopene were effective, though the higher dose was more effective than the lower.

This study shows that taking lycopene can reverse precancerous cell changes and reduce plaques in people with oral leukoplakia. A daily dose of 8 mg was more effective than 4 mg. (A five-ounce tomato contains approximately 8 mg of lycopene.) Studies have shown that the lycopene in tomato paste can be absorbed by the body more efficiently than the lycopene in raw tomatoes or tomato juice. Lycopene is also available as a nutritional supplement and in foods besides tomatoes (such as watermelon and pink grapefruit), but it is unknown whether lycopene from other sources will have the same benefit for oral leukoplakia.

Calcium, Vitamin D Work Together Against Colon Cancer

Calcium and vitamin D appear to work together, not separately, to reduce the risk of colon cancer, say researchers in the Journal of the National Cancer Institute (2003, vol.95, no.23:1765-1771). In the study, researchers assessed the independent and joint effects of calcium supplementation and vitamin D status on recurrence of adenomas—benign tumors that are precursors of colon or rectal cancer—in more than 800 participants. They found that calcium supplementation was only associated with reduced risk of adenoma recurrence in those subjects with above average vitamin D levels (29.1 nanograms per milliliter). Similarly, vitamin D levels were associated with reduced risk only among subjects taking calcium supplements.