NATURALLY DANGEROUS: Surprising Facts About Food, Health, and the Environment.
By James P. Collman, Professor of Chemistry, Stanford University
Chapter 2. The Pharmacy
© James P. Collman, 2003. All rights reserved
Monoclonal antibodies are becoming a very powerful class of drugs used to treat many diseases, especially rheumatoid arthritis and cancers. What is a monoclonal antibody? Google knows. A monoclonal antibody is a protein genetically engineered from a single clone of a B cell, especially one produced by fusion with a tumor cell and intended for use as a drug. Refer to page 113 in Naturally Dangerous for a description of B cells in the immune system. Drugs of this type are very expensive to produce and thus are very costly to the consumer. Since they are proteins, monoclonal antibodies must be injected into the blood stream and usually cannot be taken orally. Although monoclonal antibodies are often very effective, they may also have dangerous side effects.
Sometimes a monoclonal antibody is developed and used to treat one disease
and is subsequently found to be effective in treating another disease. Thus
Rituxan was developed to mitigate lymph cancers, this drug was found to be
effective in controlling rheumatoid arthritis. Recently, alemtuzumab, a monoclonal
antibody prescribed for leukemia (cancer of blood cells), has found use in
treating multiple sclerosis, MS, a disabling neuromuscular disease that has
resisted effective drug therapy. Another protein, interferon, has been used
to treat MS, but alemtuzumab appears to be more effective. But a dangerous
bleeding disorder called ITP showed up in 3 percent of the patients taking
alemtuzumab and one person died following treatment. Again, there is no free
lunch, drugs that are effective in treating very serious diseases often manifest
dangerous side effects. (Science News, November 22, 2008, page 9)
A very small (only 10 subjects) double-blinded study from Duke University
reported that caffeine consumption raises sugar levels in patient's blood
- on average the glucose levels rose about 8 percent. These patients were
already coffee drinkers. Other much larger studies have shown that drinking
coffee lowers the risk for diabetes. Maybe something in coffee other than
caffeine has a beneficial effect. The caffeine effect needs to be examined
with much larger groups. Caffeinated drinks other than coffee might be hazardous
for type-2 diabetics. (February's Diabetes Care)
Recent evidence indicates that statins such as Liptor, Mevacor, and Zocor, do not prevent heart attacks by reducing cholesterol levels, but they seem to act through an anti-inflammatory mechanism. Statins have been found to inhibit a nuclear factor, kappa B. This factor is related to our immune system’s ability to express inflammation. Statins do lower the “bad cholesterol”, LDL, and this may have other medical benefits that are not fully understood. Originally statins were developed to reduce cholesterol biosynthesis. (Chemistry & Engineering News, March 14, 2005 , page 7)
Old wife’s-tales often contain a kernel of truth. The claim that human breast milk is good for a child is certainly true, but it seems to contain components that could even be used to treat adults. Catharina Svanborg, a Swedish scientist accidentally discovered that human milk has anticancer activity. Other researchers are finding that human milk can protect or teat a number of human ailments. What are these substances and can sufficient quantities be produced to be used as medicines? You cannot buy human breast milk in the grocery store. Wet nurses are seldom available these days and they could only be used to provide milk for children. It is said that many of the nutritional substances found in human milk are not found in cow’s milk or the milk from other animals, but I am skeptical of that claim. Nevertheless by identifying these protective substances in human milk, they can probably be produced through genetic engineering, by modifying bacteria, rice, goats, or cows.
It has long been claimed that antibodies in breast milk pass immunities to children from their mother’s. Another Swede, Lars Hanson showed in the 1950’s that a mother’s antibodies do occur in her breast milk and that these are passed on to her child. But now other protective agents are being discovered in human breast milk. One class of substances found in breast milk are complex sugars, “oligosaccharides”. These indigestible sugars have been shown to bind to pathogenic bacteria and remove them through the digestive track, but not to bind and remove the friendly bacteria, or flora, which are used to digest foods and protect the system against unfriendly bacteria. These protective oligosaccharides also seem to help beneficial bacteria digest foods. But these concepts are not widely accepted and need to be further studied before they can be considered valid. These oligosaccharides exist in a complicated variety of structures, which seem to vary from one woman to another. There is some evidence from studying mice that these oligiosaccharides can protect the mice from bacteria that cause diarrhea. It has been suggested, but not tested the idea that adults could be given samples of these oligosaccarides to recolonize their digestive tracks after they have received a treatment of antibiotics that have killed most of their beneficial bacteria. But even to test this idea will require production of therapeutic quantities these oligosaccharides, perhaps by using genetically modified bacteria or bioengineered goat’s or cow’s milk.
Genetically engineering goats has already been employed to produce two protective proteins found in human-breast-milk: lysozyme and lactoferrin. Cows and even rice have also been engineered to make substantial quantities of the latter compounds. Lactoferrin has been shown to boost immune activity and suppress inflammation in breast-fed babies. Work with pigs has shown that lactoferrin may be useful in treating septic shock, a dangerous immune-based condition that is often lethal (see pages 114, 138 in Naturally Dangerous). Lactoferrin also is claimed to fight viruses, bacteria, and fungi.
Lysozyme has only one type of activity; it is a sort of antibiotic that destroys cell walls in deleterious bacteria, but usually does not affect the beneficial bacteria. A combination of lactoferrin and lysozyme has been successfully used by an American nutritionist from the University of Davis in California to treat acute diarrhea in children at in a clinic in Peru . These studies are still in early stages but initial results are said to be promising.
Yet another protein found in human breast milk: alpha-lactalbumin, called HAMLET when it has been acidified, is reported to kill tumors. Most of these anti-cancer studies have all been done in lab dishes, but 40 different kinds of tumor cells were affected. Recently, experiments to treat tumors in rats with HAMLET have shown positive results. Currently human trials are ongoing to use HAMLET to treat human bladder cancer.
Thus there is a lot of promise and hope in identifying and establishing medical applications of protective compounds that are present in human breast milk and then to develop inexpensive methods of producing these natural substances by using genetic engineering techniques. Perhaps properly engineered goat’s or cow’s milk will be developed to treat human disease, even cancer. But will some patients accept medicine produced as a “Frankenfood”?? (Science News December 9, 2006 , Vl. 170, page 376)
Blood pressure is measured in millimeters of mercury. Two numbers are involved: systolic (the upper number) and diastolic (the lower number). Systolic represents the pressure of arterial blood flow when the heart beats, whereas diastolic indicates the pressure between heartbeats.
Until recently blood pressure readings over 140 over 90 were considered high and normal was less than 130 over less than 85. Now, on the basis of statistical studies, if your systolic pressure falls between 120 and 139 or your diastolic pressure is between 80 and 89, you are considered “prehypertensive” and you are advised to lower these values to about 115 over 75. Why? High blood pressure, which gives no symptoms, can raise the risk of a heart attack, a stroke, kidney failure and can contribute to the development of mental deficits and dementia. Moreover, with age blood pressure can increase from a normal range to higher, risky values. Ninety percent of those who have normal blood pressure at age 55 develop high blood pressure as they age.
How does one reduce blood pressure? Lose weight, consume less than 2,400 milligrams of salt per day, exercise by brisk walking for over 30 minutes each day, use alcohol moderately (no more than two drinks per day for men and one drink for women), and eat a diet that is rich in vegetables, and fruits, has two servings of fish per week, and consume low-fat dairy products. Above all: avoid smoking because smoking damages your arteries. Many people need medications to reduce their blood pressure, especially in the older years. There are many drugs that accomplish this, but each type has potential side effects. (Jane E. Brody, New York Times, August 12, 2003 , page D7)
One by one as herbal medicines are given a double-blinded test, they usually fail to perform better than a placebo. Now the popular herbal supplement, black cohosh, derived from the roots and stems of black snakeroot (also called bugbane) proved no better than a placebo at relieving hot flashes and night sweats in perimenopausal and postmenopausal women. It was hoped that this herb would show some relief since the effective, but potentially-dangerous hormone therapy is being abandoned by most patients because of concerns over an enhanced risk of breast cancer. The recent randomized, 12 month trial involving 351 women ages 45-55 using black cohosh and several other herbs or a placebo reduced symptoms by only one half symptom per day, a result considered to be insignificant. It is interesting that a general weakness of all herbal medicines in the U.S – that they are never tested for purity – was used to question these results. Only one black cohosh extract was used, that supplied by “Pure World Inc.” Dr. Mary Hardy, director of integrative medicine at UCLA did not take part in this study and claims that two other cohosh extracts: -- from RemiFemin and Klimadynon have previously shown “mostly positive results” in clinical treatments of menopausal symptoms. But have these herbs been subjected to a double-blinded study? (taken from Yahoo: 12/19/06 ).
Even though race is not considered to be a scientific concept, more drugs are being discovered to be more effective depending on the race of the patient. An article in the May 27 issue of the New England Journal of Medicine reported that two standard antiviral drugs used to treat hepatitis C are less likely to knock out that infection in black patients as compared with white patients. Recall that hepatitis C is a liver disease, which affects about 4 million people in the US, but it goes unnoticed and untreated until it causes cirrhosis of the liver or liver cancer. In this study two antiviral drugs, peginterferon alpha-2b and ribvirin were administered to 81 black patients and 79 non-Hispanic white patients for 11 months. At the end of this treatment about 75 percent of the white patients no longer had detectible hepatitis C virus, but only 25 percent of the black patients were free of the virus. This drug combination has been very effective. For example over 90 percent of patients who were freed of hepatitis C virus by treatment with these drugs, were found to be free of the virus 10 years later. The difference in response between black and white patients is not understood, but this pattern of race-based drug responses continues to grow even though the concept is politically incorrect.
Several places in Naturally Dangerous, you can learn about some drugs acting as enzyme inhibitors. Recently an unusual example of this phenomenon was reported. A beneficial protein, GLP1 stimulates the release of insulin, helping control glucose levels. Unfortunately GLP1 is broken down rapidly by an enzyme, called dipeptidyl peptidase. A new drug candidate that inhibits this enzyme and extends the lifetime of GLP1, has been developed in Europe . Preliminary double-blinded studies show that this enzyme inhibitor improves the control of glucose for patients with type 2 diabetes. So far this new drug candidate has shown no significant side effects. Diabetics should keep tuned in, but the trail from preliminary discovery to release of any drug is long and expensive. (Science News, June 19, 2004 , Vol. 165, page 398)
spirin, which as discussed on page 46 of Naturally Dangerous, is one of the oldest drugs, has been found to have yet another beneficial effect: women who take aspirin at least seven times a week have a 26 percent lower risk of developing the most common type of breast cancer. This is according to a report published in The Journal of the American Medical Association. Only certain women who are prone to hormone sensitive tumors get benefit from taking aspirin. The explanation is that aspirin inhibits an enzyme that makes estrogen, a hormone that promotes tumor growth. Breast cancer currently kills approximately 40,000 women each year in the U.S. ; taking aspirin could conceivably prevent 34,000 deaths. But that is a simplistic analysis. The journal editors do not recommend that every woman should begin to take aspirin, unless they are in a high-risk group. There are dangerous side effects from taking aspirin, such as gastrointestinal and intracranial bleeding. It is estimated that for every 1,000 adults who take aspirin for five years, approximately one will suffer a stroke and for people over 70, this number would increase by two or three. As emphasized throughout Naturally Dangerous, nothing is fully safe; there are risks to consider with any benefits. ( New York Times, 5/26/04 )
Two drugs have proved effective in treating rheumatoid arthritis, a previously
untreatable, devastating disease. These drugs, Remicade and Humira are mono-clonal
antibodies that control the body¡¯s mistaken immune reaction in this autoimmune
disease. These drugs are proteins and therefore must be injected or infused
into the patient. Now it has been discovered that these drugs can trigger
unexpected serious infections. In some patients this may contribute to cancers,
such as tumors in skin, lung, and breast cancers. What to do? These drugs
have given remarkable relief to patients who would otherwise have been bedridden
and under severe pain. It is estimated that 2.1 million Americans suffer from
rheumatoid arthritis. The risks of taking these antibodies are not trivial:
one in every 154 patients on these drugs were struck with a cancer. This number
is beyond a similar sample of the population not exposed to these drugs. A
warning to this effect will be given patients on these drugs. Another new
mono-clonal antibody, Rituxan, has been introduced to treat rheumatoid arthritis.
It is remarkable that Rituxan was developed to treat a type of cancer involving
the lymph system. (Scott Hensley, NYT, 2006, page D4).
Studies have shown that if you have been taking aspirin on a regular basis, abruptly quitting because this may increase your risk of having a heart attack or stroke. So if your physician or dentist tells you, to stop taking your therapeutic dose of 81 mg. of aspirin, before surgery or a dental treatment because of the risk of serious bleeding, you might question their advice. What is the evidence? An analysis of the medical records of over 1,000 patients hospitalized in Nice France for heart problems, 50 had quit taking aspirin within one month before their heart attack. These cases constituted about 4% of all coronary patients admitted to that hospital. In a British study, people who stopped taking other NSAIDs (nonsteroidal anti-inflammatory drugs) within one month, were found to have a 50% increased chance of having a heart attack. These NSAIDs include Advil, Motrin, Aleve, and other brands. Are there any exceptions to this advice? Yes, brain surgery has a special risk of bleeding and patients are advised to stop taking aspirin or other NSAIDs before undergoing brain surgery, but not other types of surgery.
Many patients take a coated 81 mg. aspirin pill each day to ward off heart disease. Aspirin protects against heart disease by making blood platelets less likely to clot, and as an anti-inflammatory it may also reduce processes that lead to atherosclerosis, rupture of plaques and blockage of the arteries. (Harvard Health Letter, October 2005, page 6).
Because of increasing news reports, one might imagine that food allergies are becoming more common. But that is not true; it is estimated that 4% of adults and 6% of children suffer from food allergies. It is important to distinguish food allergies, arising from an overactive immune system, from food sensitivities. The latter involve an upset stomach caused by lactose intolerance, sulfite-induced asthma or an itchy reaction from yellow food dye #2, tartrazine. Neither are food allergies caused by the following ingredients that are sometimes added to manufactured foods: monosodium glutamates (MSG), artificial food dyes, and high-fructose corn syrup. All of these additives have been claimed to be allergens (agents that induce allergies) for some individuals. But double-blinded statistical studies have exonerated these substances. For people who do suffer from food allergies, eating natural foods that they are allergic to can be dangerous; these individuals could suffer a life-threatening anaphylactic reaction. Their allergic reaction can become more intense with each additional exposure to that food.
In the U.S. 90% of all documented food allergy reactions come from eight major allergens, all from natural foods. The most serious food allergies derive from eating: shellfish, peanuts, tree nuts (e.g. walnuts, cashews), and fish. What is interesting but not widely known is the phenomenon of cross-reactions, an allergic reaction from one natural chemical to another. For example, there is a protein in natural latex rubber, which workers such as nurses can become allergic to. These individuals then become susceptible to similar proteins contained in certain foods and develop allergies upon eating those foods. Examples are: avocados, bananas, kiwi-fruit, melon, papaya, peaches, potatoes, and strawberries. The opposite cross-reaction can occur: an individual having an allergic reaction from a protein in one of these foods can thus become allergic from exposure to natural latex rubber. Those who believe that natural is safe might be surprised to learn that synthetic (man-made) rubber does not elicit these allergic reactions. There are other cross-reactions: during ragweed season, allergic individuals may suffer a cross-reaction upon eating cantaloupe. (Environmental Nutrition, April 2006, page 2)
Mice are not humans and many drugs that appear to work in mice are not effective in humans. For that reason, I seldom mention new experimental drugs in this web site, unless these have shown promise with human patients. Here is an exception I decided to introduce because no drug thus far has had much of an effect on even slowing the symptoms of Alzheimer’s disease. Now comes a rational drug that has been shown to improve memory and to reduce the production of amyloid-beta, preventing the development of both plaques and tangles in transgenic mice. The latter were developed as models for Alzheimer’s disease. The drug, “AF267B mimics a neurotransmitter, acetylcholine, that is in decline in Alzheimer’s patients. This mimic binds to acetylcholine binding sites, known as M2 receptors. A clinical trial has started to assess the safety of AF267B in humans (Phase I in drug development). The final development of an effective drug against Alzheimer’s disease is still far off and may never materialize, but this is an exciting possibility where there seem to be few other leads. (Neuron 2006, 49, 671, Frank M. LaFerla, et. al.: Chemistry & Engineering News, March 13, 2006, page33).
RECOGNIZING A STROKE.........
Thank God for the sense to remember the "3" steps. Read and Learn!!
Sometimes symptoms of a stroke are difficult to identify.
Unfortunately, the lack of awareness spells disaster. The stroke victim may suffer brain damage when people nearby fail to recognize the symptoms of a stroke.
Now doctors say a bystander can recognize a stroke by
asking three simple questions:
1. Ask the individual to SMILE.
2. Ask him or her to RAISE BOTH ARMS.
3. Ask the person to SPEAK A SIMPLE SENTENCE (Coherently, i.e........ It is sunny out today.) If he or she has trouble with any of these tasks, call 9-1-1 immediately and describe the symptoms to the dispatcher.
After discovering that a group of non-medical volunteers
could identify facial weakness, arm weakness and speech problems, researchers urged the general public to learn the three questions. They presented their conclusions at the American Stroke Association's annual meeting last February. Widespread use of this test could result in prompt diagnosis and treatment of the stroke and prevent brain damage.
A cardiologist says if everyone who gets this e-mail sends it to 10 people; you can bet that at least one life will be saved.
The role of grapefruit juice in raising the potential of certain drugs is discussed on page 50 in Naturally Dangerous. Readers may be interested in learning more about this phenomenon. The effect that grapefruit juice has on the potency of certain drugs was discovered accidentally by Canadian physicians in 1989. Their study was actually designed to measure the possible effect of drinking alcohol while taking a drug designed to lower blood pressure. Grapefruit juice was used in this study as a means of masking the taste of alcohol, so the subjects would not know whether they were drinking alcohol or an alcohol-free placebo. Surprisingly these investigators found that the levels of the blood-pressure lowering drug went up significantly in the control group that drank just grapefruit juice without any alcohol. At first, these researchers were ridiculed when they announced their unexpected findings and they found it difficult to publish these results in a medical journal. A paper on these findings was eventually published in the medical journal Lancet, in 1991.
After further study the science behind the effect that grapefruit has on drugs was explained. When it was found that a natural component in grapefruit juice reversibly inhibits certain members of a class of enzymes known as cytochromes ¨C450. These enzymes metabolize many drugs and toxins by converting them into water-soluble forms that can be eliminated in the urine. Grapefruit juice interferes with the ability of one such enzyme, CPY 34A, thus increasing the potency of some drugs by letting more of that drug enter the bloodstream where it would be carried to the place it acts. This effect results in a larger dose than would occur if that drug was being metabolized and eliminated in the urine. In contrast to what is stated in Naturally Dangerous, grapefruit juice interacts with the enzyme, CPY3A4 in the intestines, not in the liver, where most of the P450 enzymes reside. Because this drug deactivation occurs in the intestines, the effect of grapefruit juice is limited to drugs that are taken orally, not with injected drugs that go directly to the bloodstream. What sort of drugs are most affected by grapefruit juice and is this dangerous? Several statins, drugs that are taken to lower cholesterol levels, such as Lipitor, Mevacor, and Zocor have increased potency when taken with grapefruit juice. Wouldn't that be a good thing because you would get more drug at the same dose? No, because an excessive dose of a statin sometimes leads to a dangerous, even fatal muscle disorder called rhabdomyolysis. The effect of grapefruit juice on drug metabolism varies from one individual to another, so it is dangerous to try and take less of a drug, together with grapefruit juice. to increase that drug's potency. Elderly patients are at greater risk from this effect.
Grapefruit juice interferes with the metabolism of some other drugs. For example selective serotonin reuptake inhibitors such as Prozac, which are used for depression, should not be taken together with grapefruit juice. Patents are also advised not to take antihistamines such as Seldane and Hismanal together with grapefruit juice.
What about other fruit juices; do they have this effect? Grapefruit juice
is the strongest, but lime juice and juice made specifically from Seville
oranges also inhibit the CYP 3A4 enzyme. Bitter orange as in marmalade is
also an inhibitor of this enzyme. (New York Times, page D8, March 21, 2006)
Statistical studies of drugs sometimes reveal an unexpected, beneficial side
effect. This pleasant result is in contrast with the discovery of deleterious,
even dangerous side effects, such as increasing the risk of heart attacks
after taking an 18-month regime of vioxx, a selective COX-2 inhibitor that
is an anti-inflammatory drug. The newest pleasant surprise concerns patients
who are taking a variety of drugs to lower their blood pressure. Bio-statisticians
studied 3,300 people over 65 years old for six years who were taking drugs
for hypertension (high blood pressure). This statistical analysis found that
104 members of this group developed Alzheimer's disease (AD). The number taking
blood pressure medicine and who came down with Alzheimer's is lower than a
control group. These results showed that patients taking any of a number of
drugs that were designed to reduce blood pressure: enzyme inhibitors, beta-blockers,
calcium channel blockers, and diuretics ("water pills") resulted
in a decrease in the risk for Alzheimer's disease. Diuretics were especially
effective in risk reduction, 43 percent on average. One class of diuretics,
potassium-sparing drugs showed a 74 percent reduction in the risk of getting
Alzheimer's. An analysis of these statistics showed another surprising thing;
the reduction in acquiring Alzheimer's is not related to the degree that a
particular class of drug reduced blood pressure. This should be followed up
with a controlled, double-blinded experiment. A co-author of this study, Peter
P. Zandi cautioned that patients who do not need to lower their blood pressure
should not take these drugs so that they may be less likely to acquire Alzheimer's
disease. (New York Times, March 21, 2006, page D8).
One of the most devastating illnesses of old age is Alzheimer's disease. Age is a primary factor in the risk of coming down with Alzheimer's disease. From 65 to 74, five per cent of men and women begin to suffer from this disease; early symptoms are memory loss. By the age of 85 over half of the population have acquired Alzheimer's. There is no cure, for this slow, incurable illness, although some new drugs are said to slow the progression of Alzheimer's. For some people in the early and middle stages of the disease, the drugs tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), or galantamine (Razadyne, previously known as Reminyl) may help prevent some symptoms from becoming worse for a limited time.
The cause of Alzheimer's is uncertain, but there has long been known that
one component is genetic. This genetic link has now been verified by a large
study of twins. A report from the University of Southern California compared
392 pairs of twins, both identical and fraternal, at least one of which had
been diagnosed with Alzheimers. These pairs were compared with a similar group
of twins who were free of the disease. These studies were carried out in Sweden
and all participants were age 65 or older. From this study, published in the
Archives of General Psychiatry, it was concluded that 79 percent of the Alzheimer's
cases have a genetic basis, but environmental effects may also be relevant.
A genetic connection to Alzheimer's may also be found by comparing individuals
who have a particular variant of a protein that carries cholesterol in and
out of the brain. This "apolipoprotein E" comes in three varieties,
which can be tested for in the clinic. One form is associated with a high
risk of Alzheimer's; one with a medium risk; and the third form with a small
risk. These apolipoprotein varieties are inherited. (Reuters 2006)
By Jan TenBruggencate
Advertiser Science Writer
A toxin associated with Alzheimer's disease and related ailments has been found in cyanobacteria, sometimes called blue-green algae, collected from around the world.
The finding, based on research conducted in large part by Hawai'i scientists, is providing what may be the first indication that different cyanobacteria produce the same toxin. It also is raising the possibility of a potential threat to public health.
Researchers are recommending that public health agencies monitor waters that can have blooms of blue-green algae that can produce the algal neurotoxin, B-N-methylamino-L-alanine, or BMAA, which can affect the human nervous system.
"As rising global temperatures trigger more blooms of cyanobacteria in the planet's oceans and rivers, the health consequences of neurotoxins such as BMAA should be monitored," the scientists said in a report in today's edition of the "Proceedings of the National Academy of Sciences."
Ethnobotanist Paul Allen Cox of Kaua'i's National Tropical Botanical Garden led a team of researchers that chased down an intriguing link between cyanobacteria and a class of apparently related nervous system diseases that include Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, also known as ALS or Lou Gherig's disease.
Cox was looking into neurological disease among Guam natives. Those suffering from the disease had high levels of BMAA in their brain tissue, and many of those affected ate a traditional diet that included fruit bats. In tracking down the diet of the fruit bats, Cox and his team found the animals ate the seeds of cycad trees, and that cyanobacteria in the roots of the trees produce BMAA.
"We have recently discovered that potential human exposure to BMAA extends far beyond Guam ," Cox said.
Researchers found that a small sample of people who died as a result of Alzheimer's disease in Canada — where there are no fruit bats or cycads — also had BMAA in their brain tissue. There were indications of similar patterns in people in parts of Japan , where there are cycads but no fruit bats.
Cox said the key seems to be neither the cycad nor the bat, but the cyanobacteria. "It's like a detective story," he said.
Scientists have long known that cyanobacteria can produce dangerous compounds, but this appears to be the first indication that very different cyanobacteria can produce the same poison.
Cox and his team of researchers looked into cyanobacteria samples from very different environments and found that in each of the five major types of these blue-green algae, some species produce BMAA.
Often, there is not much of the neurotoxin and it may take some kind of process to "biomagnify" the poison. Fruit bats in Guam may have done that by eating a lot of cycad seeds. A new question is what might be biomagnifying BMAA in other environments.
Cyanobacteria are among the oldest forms of life on the planet. They are single-celled organisms that behave like bacteria, but can conduct photosynthesis like plants. They generally live in water, but also can live inside plants.
Also contributing to the research were cyanobacterial experts Robert Bidigare and Georgia Tien at the University of Hawai'i at Manoa, Cox said.
Reach Jan TenBruggencate at email@example.com or (808) 245-3074.
Most non-invasive diagnostic medical analyses involve drawing blood. Even diabetics must prick their skin to obtain a drop of blood, which is used to analyze their blood glucose levels. When you go to the clinic laboratory to have your cholesterol levels checked, or to carry out many other tests, the technician must draw a blood sample. The results are not available for days. Wouldn’t it be easier just to spit into a receptacle, and get a rapid diagnosis? Saliva comes from blood filtered through the salivary glands. Therefore blood contains many, but not all the substances in the blood, but not at the same concentrations. For example the oxygen carrying protein hemoglobin is not in the saliva because it is filtered out. The proteins in the immune system are also removed. Many other biological molecules that are markers of health and disease do come through the salivary glands and are present in the saliva, but at very low concentrations (about 0.1 to 1 percent of those in the blood). Using modern analytical techniques some of these biomarkers can be analyzed and this analysis can be accomplished in less than one hour. For example, special RNA segments show a pattern that is characteristic of people who have oral cancer. Recall that RNA is a cousin of DNA. DNA can also be detected by a magnification technique. This DNA can be used to find gene markers that are characteristic of certain diseases. Infections from specific bacteria can also be determined so that appropriate antibiotic treatment can be proscribed when appropriate. This method of medical diagnosis is still under development, but it is very promising and may prove to be painless and even less expensive. (Science News, September 17, 2005, Vol. 168, page 187)
A major health problem is the use of antibiotics in animal feed. For unknown reasons, antibiotic laced feed increases the growth rate of farm animals, but this practice is coming under criticism because antibiotic-resistant microbes evolve, endangering public health. The FDA is moving to prohibit poultry farmers from feeding an antibiotic, Baytril (enrofloxacin), to chickens and turkeys. Baytril is useful in treating people infected with Campylobacter, which causes severe stomach disorders in humans. Campylobacter is the leading bacterial food poisoning agent in the U.S., making about 1.9 million people ill each year. This same bacteria is also found in poultry, but it is asymptomatic (does not cause illness). Exposure of infected poultry to Baytil results in the development of bacteria that are resistant to similar antibiotics (fluoroquinolones). Some poultry sold in supermarkets have recently been found to contain Campylobacter that are resistant to fluoroquinolones. Hopefully, this ban will be carried out in time to keep these antibiotic-resistant bacteria from spreading in the human population. European countries have been much more active than the U.S. in banning the indiscriminant use of antibiotics in animal feed. (Science News, August 13, 2005, vol. 168, page 110)
In 2005 the popular male impotence drugs Viagra and Cialis, was reported to cause partial vision loss in a small number of patients. The FDA subsequently required that a warning be put on the label of these drugs. Viagra was reported to cause vision problems such as bluish or blurred vision or light sensitivity as early as 1998. So far the newest male impotence drug, Levita, has not shown any of these side-effects. The danger may be minimal because this type of blindness is common among men who are diabetic, have high blood pressure, or heart disease – conditions that can contribute to erectile dysfunction.
The public, industries, and government are anxious over the rising cost of health care. The cost of bringing a new drug to market is a major factor. A few facts are helpful in understanding this difficult problem. The biggest expense in new drug development comes from failure of drugs that have been approved, but must then be withdraw because of side effects and lawsuits. But the cost of bringing a drug into the market is also very high. In 2003 this cost averaged at $900 million per new drug compared with $230 million six years earlier. In the current climate where everyone wants longer, larger clinical trials, the cost of introducing a new drug is estimated to become $2 billion by 2010, an unsustainable amount. Clinical trials are divided into four phases. Phase I, which determines dosing and identifies undesirable side effects requires only 100 volunteers. Phase II is designed to establish preliminary efficacy and requires 100-300 patients. Phase III is much more expensive, requiring about 3,000 patients and a longer period of time. If it passes these three phases, the drug can be introduced into the market. Phase IV consists of a follow up designed to detect side effects after a new drug has reached the clinic. The average failure rates add to these costs. A drug entering phase I only has only an 8 percent chance of reaching to market. Only one half of all drugs in late stage trials (phase III) reach the market; the others fail! Drug companies want “blockbuster drugs”, with revenues over $1 billion to match these huge costs. Such high-potential drugs address diseases that have many patients such as diabetes, heart ailments, and mental illness. Their competitors are racing along the same track and must have a more efficacious drug to be approved. Several tactics are being considered to lower these costs. Eli Lilly, the sixth largest American pharmaceutical company, is focusing on drugs that target biomarkers: cellular signals or genes that indicate whether a particular group of patients may be responsive to the drug. Their recent heart drug, NitroMed, which is being marketed for use by self-identified African-Americans, is an early example of this strategy. Another strategy is to “out-source” clinical trials to India. The patients who are subjected to clinical trials should not have been previously treated with other drugs; such patients are easier to locate in India than in the U.S. Moreover, the cost of conducting clinical trials in India is much lower than in the U.s. or in Europe. Only recently are Indian laws being changed to make such international clinical trials feasible. A rush to conduct clinical trials in India is expected to follow these necessary legal changes. India has many physicians and support staff to conduct these trials. Such a strategy may lower the costs of introducing a new drug into the American market. (Chemistry and Engineering News, January 31, 2005. page 17) (New York Times, July 3, 2005, section 3, page 1)
Yet another example of a drug that is ineffective with one category of patient, Caucasians, or blacks proved effective in treating lung cancer in another group of patients, Asians. Asians are more likely to respond well to Iressa, because they more likely to have a certain genetic mutation in their cancer cells that Iressa is targeted on. Thus AstraZeneca is planning to market Iressa in Japan, China, and other Asian markets rather than the U.S. Patients on a placebo lived only 5.5 months and, non-Asian patients on Iressa lived only 5.6 months, but Asian patients on Iressa lived 9.5 months. In the cancer business this is considered an effective therapy. Lung cancer is one of the most lethal cancers, killing about 160,000 patients a year in the U.S. Non-smoking patients from all races seem also to respond better to Iressa, but most lung cancer patients were smokers. (Wall Street Journal, May 5, 2005, page A1)
It would not surprise the general public that men and women are different, even in response to drugs. But this is a rather new thing in studies of clinical trials carried out in the U.S. Of course anything that affects hormones or specific sex organs (prostate versus ovaries for example) are obvious. However, subtle differences have cropped up in the responses of the two sexes to drugs. You may be surprised that over the last 10 years, 8 out of the 10 prescription drugs were withdrawn from the U.S. market because greater statistical health risks were discovered for women. That cost drug companies a lot of money and should get their attention as well as making certain that double-blinded, randomized, placebo-controlled phase III clinical trials include sufficient females and that male and female responses are separated. Beginning in the 1989 it was found that a popular antihistamine, Seldane, causes abnormal heart rhythms in women. It turns out that certain antibiotics, antiarrhythmics, and antipsychotic drugs also produce a higher risk for arrhythmias in women compared with men. Other studies have shown that anticoagulants (warfarin and heparin) cause more bleeding in women, but women respond more positively to certain antipsychotics and to the hypertension (high blood pressure) drug, verapmil. Recently it was discovered that aspirin, which protects men against heart attacks, but not strokes, has exactly the opposite effect with women. Doubtless, when this issue is explored more thoroughly, many more examples will be found, although some physicians remain skeptical.
The reluctance to include women in drug trials can be traced to the thalidomide disaster in the 1950’s and 1960’s, resulting in thousands of birth defects (in Europe; the drug was not released in the U.S. (refer to page 48 in Naturally Dangerous). Young women were kept out of clinical trials to protect fetuses they might be carrying. The clinical trials were largely confined to 154 lb (20 kg) males. Females are now known to have a higher activity of their cytochromes P-450 liver enzymes, which metabolize and thus deactivate about half of all therapeutic drugs (see page 50 in Naturally Dangerous). Women are also smaller on average than men and women have more body fat. Thus fat-soluble drugs can stay longer in a woman’s body. Based on mouse studies, women may be found to respond differently to the COX-2 blocking painkillers such as Viox, because this enzyme hinders estrogen’s protective effects against cardiovascular disease. Perhaps giving these COX-2 inhibitors to young women would put them at greater risk for heart attacks? But who would pay to test that hypothesis? Other strange genetic differences have been found. For example redheaded women, but not redheaded men are more responsive to opiates! (Science, Vol. 308, June 10, 2005, page 1572)
On page 52 in Naturally Dangerous evidence is presented supporting a link between bacterial infections and heart disease. A recent large, high-quality study that examines the possible protection that antibiotics might offer against heart disease is disappointing. This study is negative! In spite of evidence that gram negative bacteria such as Chlamydia pneumoniae are frequently found in atherosclerotic plaque, antibiotics that are effective against these bacteria have no long-term benefit in reducing cardiovascular risk in patients with stable or acute coronary heart disease. Moreover, the level of C-reactive protein, an inflammatory marker and a prime predictor of coronary heart disease is not lowered by long-term antibiotic therapy. But ingestion of antibiotics did have an expected adverse side effect; an upset stomach, probably resulting from killing the patients friendly bacteria (see Chapter 4). Inflammation does have a role in heart disease, but antibiotic therapy is ineffective. This finding leaves an unsolved dilemma. This study was reported in the New England Journal of Medicine, 352; 16, April 21, 2005.
One of the newest statins, the drugs that lower cholesterol, is Crestor. A study of adverse effects for Crestor and the three other major statins, Lipitor, Zocor, and Pravachol, showed that the rate of side effects for Crestor is double that of the other three statins. These side effects include muscle damage, protein in the urine, a reduced ability of the kidneys to filter toxins from the blood, and kidney failure. That sounds bad, but there are actually very few such adverse effects, when one considers that only 145 muscle or kidney problems were reported for 5.2 million people taking Crestor. The “bottom line” is that Crestor should be used primarily by patients whose cholesterol levels are resistant to the other, less potent statins. The Food and Drug Administration (FDA) has rejected a call to remove Crestor from the market, and the FDA “stands fully behind the safety and effectiveness of Crestor when the product is used according to the prescribing information”. This is just another example of a generalization; all drugs have side effects, and pose dangers depending on the dose and the individual taking the drug. There is no gain without a risk of pain. (Chemistry and Engineering News, May 30, 2005, page 15)
Antibiotic resistance is increasing. This serious problem is driving the search for new antibiotics. Whenever a bacterium develops drug resistance, the genetic element that makes this organism resistant to an antibiotic rapidly shared with other bacteria, even other species of bacteria. As mentioned in Naturally Dangerous, the transfer of genetic information between bacteria is rapid and common. Survival of the fittest results in the rapid evolution of antibiotic resistance. Scientists are looking everywhere for new antibiotics. Alexander Fleming discovered penicillin by accident, presumably from an obscure mold that blew in the window onto a bacterial sample while he was on holiday. Since then scientists have search in soil samples from all over the World and from biological samples from the ocean. Recently a new class of antibiotics has been found in fish gills. By using new combinations of enzymes, a Stanford scientist, Khosla have been reprogrammed organisms in order to make new, often more resistant antibiotics. The need for new resistant antibiotics is urgent, but most new drugs take 10 to 20 years from the time they are discovered until they appear in the pharmacy. Moreover, there is less profit in antibiotics; the big moneymakers are to be found in chronic conditions such as depression and diabetes, so that is where the big pharmaceutical companies are investing their research. (Science News, May 28, 2005, Vol. 167, page 347)
I usually refrain from putting emerging drugs in this web site because many of these fail to pass Phase III in the FDA (Food and Drug Administration approval process and when in the clinic new drugs are often found to have serious side-effects or are not as efficacious as once thought. But type 2 diabetes affects 18 million Americans and the available medicines have several drawbacks. Along comes “muraglitazar”, which is currently under review by the FDA. Data from Phase III have been released and they look promising. Over a 24-week period, patients with type-2 diabetes treated with muraglitazar versus a placebo showed a significant decrease in their hemoglobin A1C levels. This factor measures the average blood glucose level over a two-month period. The A1C target level is less than 6.5; 58% of patients receiving 5mg of muralitazar daily achieved this target. An average change of -2.62 in A1C from the initial level (baseline) was observed with this dose over a 24-week period. The placebo showed no change. Increased insulin sensitivity was also detected. Insensitivity to insulin is a primary cause of type-2 diabetes.
More good news: a drop of triglyceride levels from baseline was observed with a 5 mg dose. Moreover, average HDL (“good cholesterol”) levels increased by 16%. So far this new drug appears to be safe: no cases of low blood glucose (hypoglycemia) were reported, nor were any adverse edema events. Muraglitazar is a Bristol-Myers Squibb product. These results were presented at the 14th Annual Meeting of the American Association of Clinical Endocrinologists in Washington D.C.
A new strategy to fight bacteria has been announced by scientists in New York City. Bacteria require iron to grow and therefore to cause disease. Iron is an essential trace element in both bacteria and in mammals such as humans. Bacteria steal iron from their human hosts by the use of a powerful class of iron-binding chemicals called siderphores. Humans store their iron supplies in proteins referred to as transferrins. Siderphores are able to wrestle iron away from the less powerful transferrins. That is why your body tries to hide its iron supplies when infected by a bacterium. Bacteria must manufacture their siderphores using enzymes that are found in bacteria, but not in humans. A new strategy to make selective antibiotics is to develop inhibitors of the enzyme that is involved in the first step of bacterial siderphore synthesis. This inhibitor, “Salicyl-AMS” blocks siderphore synthesis in Mycobacterium tuberculosis, which causes tuberculosis (TB) and in Yersinia pestis, the bacteria responsible for bubonic plague (the agent behind the “Black Death”). Since the enzyme that is blocked is found only in bacteria and not in the human host, few if any side effects are expected. Other bacteria also depend on siderphores so this strategy may be extended to a whole class of new antibiotics. This new approach is very promising, but must be improved so that these inhibitors can penetrate the bacterial membranes. (Chemistry and Engineering News, May 30, 2005, page 13)
In the U.S. there is a slowing growing awareness of an inherited disease: Celiac Sprue. This life-threatening intestinal disorder derives from an allergic reaction to a protein called gluten, which is found in wheat, barley, oats, and rye. Both children and adults are susceptible to this condition, but a wide range of diverse symptoms (diarrhea, abdominal pain, constipation, osteoporosis, anemia, and memory loss) and the fact that this disorder has not been taught in American medical schools accounts for the slow recognition of what is one of the most-common, life-long diseases in the U.S. It seems ridiculous that European doctors have long been much more aware of Celiac Sprue, and yet American doctors thought this inherited disorder rarely occurs in the U.S. When I wrote Naturally Dangerous, I adopted this “party line” and on page 17 stated that Celiac Sprue affects only 1 in 25,000 people. A recent statistical study estimates the prevalence of this disorder is about 1 in 250 people in the U.S., but many of these individual have not diagnosed and may remain undiagnosed for years. A typical period between onset and diagnosis of Celiac is 11 to 13 years. The disease is divided about 50/50 between children and adults. The Celiac disorder appears to be triggered, but the nature of the trigger or the triggers is unknown; perhaps a virus turns on this intrinsic disease. About 1 in 133 people in the U.S. are thought to be at risk for Celiac. It is found in many parts of the World including North Africa and India. How is Celiac Sprue diagnosed? A simple blood test for certain antibodies can rule it out, but a positive blood test requires a biopsy of the intestine to verify the diagnosis. In Celiac patients their immune system attacks villi, small hair-like structures lining the intestine, which serve to take up nutrients during digestion. How is Celiac Sprue treated? The simple, but difficult treatment is to avoid all foods containing wheat, rye, oats, and barley; even small amounts of gluten will produce a serious allergic reaction. Unfortunately gluten is found in many prepared foods and in the U.S. there are as yet no regulations for labeling food “gluten free”, yet such rules are in place in Europe. For example, prepared foods such as ketchup and soy sauce usually contain gluten, unless these items are marked “gluten free”. Stomach cancer can derive from continued exposure to gluten by Celiac sufferers. It is probable that many deaths from stomach cancer derived from the Celiac disorder that was never diagnosed. Don’t expect the pharmaceutical industry to help solve this widespread medical problem because there is no drug to profit from. (American Medical News, Susan J. Landers, August, 18, 2003)
When administered to Asian patients, the potent new cholesterol lowering statin, Crestor, marketed by Asra-Zenica, has been reported to raise twice the risk of a rare side effect, muscle damage, compared with Caucasian patients. The FDA is insisting that Crestor be relabeled, adding a warning that Asian patients should start taking this statin in lower amounts – about 5 milligrams, compared with the maximum dose of 40 milligrams per day. Some instances of kidney failure have also been noted in patients treated with Crestor. This development is another example of a drug that interacts differently with people of different races. This sensitive issue is “politically incorrect”, but it must be faced in the real World. (Wall Street Journal, March 3, 2005, page D4)
Prescription pain relievers such as Vioxx and Celebrex are being removed or questioned. Even over-the-counter drugs such as Aleve are under attack. Perhaps the most common over-the-counter painkiller is Tylenol (acetaminophen is the scientific name). Some of the dangers associated with Tylenol are briefly mentioned on page 53 in Naturally Dangerous – for example overdosing or taking this drug with alcohol. A recent article by a liver disease expert, Dr. William M. Lee, from the Southwest Medical Center in Dallas, challenges the sale of Tylenol as an over-the-counter drug. The U.S. death rate resulting from Tylenol induced liver damage is about 460 per year. That must be weighed against an estimated tens of millions of Americans who use Tylenol to relieve pain. Is Tylenol safe or dangerous? Both are true depending on the circumstances. People should not take over 4 grams: eight 500 mg pills) over a 24 hour period. Typical overdoses have been 34 grams over three days. These overdoses are largely unintentional. Several scenarios explain some of these overdoses. Pain products such as codine are sometimes combined with Tylenol, but patients don’t calculate the Tylenol dose they are getting when they step up the combination pills. When patients can’t calm their pain they raise the dose of frequency of pain pills. Some take a maximum does of Tylenol and drink large amounts of alcohol. In many other cases people taking an over-the-counter drug pay less attention to the small warning on the label. Is more regulation needed? That is a philosophical and political issue, but readers should think about this. No effective drug is free from dangerous overdoses or contraindicated medications.
The science behind the anti-inflammatory COX-1 and COX-2 inhibitors is discussed on pages 46 and 47 in Naturally Dangerous. Selective COX-2 inhibitors appeared to be wonder drugs (super-aspirins) designed to lower pain and inflammation without the side effects (stomach ulcers and bleeding) associated with inhibition of COX-1. Recent long-term studies of the best known and widely used COX-2 inhibitors, Vioxx and Celebrex, have revealed an increased risk of heart attacks. These studies involved healthy people, but larger doses were taken over long periods, typically over one year to see whether the risk of cancer could be reduced. Because an increased risk of heart attacks was uncovered, these studies were stopped and Merck removed its very profitable Vioxx from the market. These studies revealed a twofold increase in heart attacks and strokes after taking Vioxx for more than one year, but not for a shorter period. In contrast, Pfizer left Celebrex on the market with some added warning about doses and the term of use. Other older pain-relieving drugs that inhibit both COX-1 and COX-2, termed non-steroidal anti-inflammatory drugs, NSAIDs, such as aspirin, Iboprofen (“Motrin”), Naproxen (“Aleve”) had never been subjected to this sort of double-blind, long-term studies with healthy subjects. Then Aleve, which is now an over-the-counter drug, was used in such a test to see if it could prevent Alzheimer’s disease. Twice the risk of heart attack and stroke was observed. Because of these findings this study of healthy individuals was suspended, even thought the data are not regarded as conclusive. But Aleve has been left on the market, with some added warnings.
The results from these studies have produced a complex dilemma for patients who have been taking pain relievers. Individual patients and their physicians must weigh pain vs. risk. Should a person be exposed to a slight heart attack risk in order to get relief from arthritis pain? Individuals who have symptoms that make them more susceptible to heart attacks should probably stop using these drugs, and every patient should avoid taking higher doses, continuously over prolonged periods. What about the numerous over-the-counter NSAIDs, which have not yet been examined in the same way? Eventually, all NSAIDs should be subjected to such long-term tests. Patients who fight pain every day from arthritis, have been left frustrated with few choices. Many of the alternative drugs have not been subjected to extensive studies examining their risks. What is safe? Nothing really is safe, but the relative dangers have not been evaluated or even recognized. For example, Naproxen was released in 1976 and may have resulted in dangerous bleeding ulcers as well as an elevated risk of heart attacks. Opiod painkillers such as OxyContin are not the answer because they carry strong risks of addiction. There are other pain-relieving drugs not yet released in the U.S., that may be preferable, but probably none is free from risk. For example, Arcoxia, another COX-2 inhibitor from Merck is available in Europe, Canada, and New Zealand, but has been held back for further analysis in the U.S. I have observed one person who has experienced dramatic relief from her arthritic pain from a single 120 mg dose over a five-day period. (Heather Won Tesoriero, Wall Street Journal, December 21, 2004, page D1; Gina Kolata, New York Times, December 22, 2004, page A1)
Scientists have long known that different races respond differently to some drugs, but race is not a scientifically acceptable classification. Recent strong evidence that race can matter is changing medical practice. A field of race-based pharmacogenomics is emerging with the impending FDA approval of BiDil, a heart medicine that will be marketed specifically to black patients. Five years ago, the FDA rejected BiDil for the general population because clinical trials indicated that this drug is ineffective in the treatment of heart failure. A recent double-blinded clinical trial of BiDil involving 400 black men and women, who had previously experienced heart failure, was so successful that the trial was stopped prematurely. This drug was so effective for these black patients that it was considered unethical to deny it to those participants who were taking a placebo. The mechanism by which BiDil acts is related to its effect on nitric-oxide deficiency, which is more common in black heart failure patients. Recall from Naturally Dangerous, page 138, that nitric oxide is an important hormone.
This development of race-focused drugs would seem like good medical practice based on good science, but this poses thorny questions. The differences between black patients and other groups must have a genetic origin. But geneticists have declared that race has no genetic or scientific basis. Differences between groups such as whites and blacks constitute less than 0.1 percent of the human genome, and this was believed to lie in genes coding for skin color. There must be additional genetic differences but this question has been politically incorrect and scientists have been loath to study such questions. Such studies might result in better health care. For example, it is well established that skin color is correlated with increased hypertension (high blood pressure) among blacks, compared with white Americans. This seems to be related to well-documented differences in salt retention and kidney function that cannot be explained by other factors such as socioeconomic status or lifestyle. There should be a genetic reason for this important phenomenon; now medical scientist may begin to look for the underlying genetic and biochemical origins of these disease patterns. In doing so, geneticists may discover some racial distinctions in the human genome. This issue is very troubling to many scientists because of the poisonous historical record of racial genetics from the 19th century through the Holocaust. (New York Times Sunday Magazine, October 10, 2004, page 47)
In the early days of birth control pills, medical experts worried that taking these combinations of the hormones estrogen and progestin would be subject to a risk of cancer. This anxiety was increased with the recent finding that women who were taking hormones after menopause were more likely to have heart disease and certain cancers. Now a large recent study has found the opposite: women taking oral contraceptives have a lower risk of heart attacks, strokes, high cholesterol, high blood pressure, and other heart related problems. A group of 67,000 women, who had taken the pill, were studied. Compared with a control group, women taking birth control pills had an overall 8% reduction of ever having cardiovascular disease and a 7% lower incidence of developing any form of cancer. Longer exposure was beneficial: those taking birth-control pills for four or more years had a 42% lower risk of ovarian cancer and 30% less chance of developing uterine cancer. So the danger or advantage of taking synthetic hormones depends on the stage of life when they are used; beneficial at an early age and dangerous later on. Since 16 million women currently take birth-control pills and hundreds of women have taken these since they were introduced in the 1960s, this is good news indeed. These data also demonstrate that demographic studies of large numbers of individuals over prolonged periods are the best gauge of the dangers, or the efficacies of drugs. (Wall Street Journal, October 21, 2004, page D3)
There is a recent debate among physicians and confusion among patients about the relationship between the suggested levels of LDL (the bad cholesterol) and HDL (the good cholesterol). Recall that LDL carries the fatty substance, cholesterol to the arteries, where it becomes plaque. HDL has the opposite function; it carries cholesterol away from the arteries to the liver, where it is disposed of. As discussed on page 46 in Naturally Dangerous, cholesterol-lowering drugs, called statins, lower LDL levels, and certain statins (lipitor) can raise HDL levels, but to a lesser extent. There is increasing evidence that LDL levels should be reduced to ultra low levels to protect patients from heart attacks. But how much “credit” should a patient be given for having high HDL levels? On the basis of recent studies, some physicians now say that higher levels of HDL are not as important as low levels of LDL; these doctors advise that some patients begin to take statins or others take higher doses of the expensive statin drugs. Patients are caught in between conflicting medical advice. Additional long-term statistical studies may help resolve this dilemma. (New York Times, March 15, 2004, page 1)
On page 47 in Naturally Dangerous, a new class of drugs, referred to as “superaspirins” are discussed. These were specifically designed to inhibit Cox-2 enzymes, thus reducing inflammation and pain, while not interfering with Cox-1, the enzyme that supports the stomach and kidney. Epidemiological studies involving large numbers of patients over long periods of time are the deciding factor in demonstrating the efficacy of a drug and its side effects. On September 30, 2004, the pharmaceutical giant, Merck announced that it was withdrawing its blockbuster anti-inflammatory drug, Vioxx from the market, World-wide!! Over two million people have used this drug, which netted Merck $2.5 billion in 2003. This shocking announcement brought down Merck stock to the extent that it lowered the entire Dow Jones Market. There is a lesson in this example and a reason that physicians should be cautious about prescribing new medications. Merck had financed a study of Vioxx in the context of preventing the recurrence of potentially cancerous polyps in the colon and rectum. They discovered that, compared with the placebo group, those patients taking Vioxx showed an increased risk of heart attacks and other adverse cardiovascular events. Merck stopped this study and withdrew Vioxx from the market. The danger observed in this study was a doubling of cardiac events after18 months of continued Vioxx use compared with a placebo; no increased risk was observed over a shorter duration.
What about Celebrex, the original Cox-2 inhibitor that is described in Naturally Dangerous? Beware of earlier small studies in the literature questioning the safety of Celebrex or a less prescribed Cox-2 inhibitor, Bextra, and watch for further developments. Also beware of a third, apparently safer, selective Cox-2 inhibitor, Meloxicam, approved in Canada, and sold by the German company, Behringer Ingelheim. This drug has been taken by 45 million patients in over 100 countries, and, as a result of 35 clinical trials involving 27,000 patients, is said to be safe and efficacious. But a European agency for the evaluation of drugs has stated that all Cox-2 inhibitors carry an increased cardiac risk.
Another lesson in this tragic episode lies in drug advertising. Merck spent about $45 million in recent ads for Vioxx. Future pharmaceutical ads are likely to give more attention to potential side effects. One way to lower drug costs might be to sharply restrict advertisement of drugs. (Wall Street Journal, October 1, 2004, page B1) (CNN News, September 30, 2004)
These pills often make patients feel better; they cost little or nothing, and have not side-effects. It has been known as far back as Hippocrates, that sugar pills or fake medicine have a positive, “placebo” effect on some patients. Physicians in some other countries such as Israel and Denmark prescribe placebos, but this is considered unethical in the U.S., and is apparently not done. One wonders whether such a “non-medicine” could be prescribed, what it would cost, and what the insurance companies would pay for it. This unethical deception also creates a risk of a malpractice suit. The positive effect of a placebo illustrates the effect the brain can have on symptoms, some of which may be imagined. Patients who are given this false medicine include women in labor, people suffering from pain, anxiety, vertigo, sleep problems, and asthma. One could say that placebos are natural and that they are safe; this combination is rarely found in Naturally Dangerous. (New York Times, September 28, 2004, page D5)
The 2,000-year-old Chinese acupuncture therapy is gaining acceptance among American physicians. This development is helped by a study at Duke University showing that acupuncture is more effective in relieving postoperative sickness than a widely use dantinausea drug. There is some rational for the effect of this needle therapy; it is thought to release endorphins, natural hormones that soothe pain. At an average cost of between $50 – $100 per treatment, acupuncture is relatively inexpensive. Acupuncture can lower blood pressure, alleviate morning sickness, and relieve pain from conditions such as shingles, and carpal tunnel syndrome. This procedure is being taught at Harvard and (of course) the University of San Francisco. Even veterinarians are using acupuncture – on pets and in animals in the zoo. (New York Times, September 28, 2004, page D6)
On page 56 in Naturally Dangerous you can learn that morphine like many older drugs is, derived from the opium poppy. This powerful natural drug has long been used to alleviate severe pain. Recently it has been discovered that human cells also manufacture morphine. The role of this potent “endogenous” analgesic in the human body is unknown. Scientists speculate that the morphine generated in our body may be involved in functioning of the immune, vascular, and nervous systems. Still, it is remarkable that a complicated plant products also produced by animals. (Proc. Natl. Acad. Sci. USA, 101, 14091 (2004))
Illegal drugs are described on page 57 in Naturally Dangerous. There is now direct evidence concerning the danger of taking such substances. A recent high resolution Magnetic Resonance Imagining (MRI) study shows substantial brain damage in the brains of methamphetamine addicts. This illicit drug is an addictive stimulant made in clandestine laboratories around the U.S., including rural areas. This stimulant acts by releasing the brain’s reward chemical, dopamine. Methamphetamine is snorted injected or smoked; the addicts that were studied used about four grams a week and had been high for 19 of 30 days prior to the time their brains were studied. The addicts were depressed and unable to concentrate – no wonder, because they had lost significant sections of their brain tissue! In the hippocampus, where new memories are formed, the average loss was 11 percent, comparable to early Alzheimer’s patients. Some cells were dead and gone, but other regions were inflamed, but not yet destroyed. With abstinence the inflamed brain tissue might recover. (New York Times, July 20, 2004, page D1)
Aspirin is the oldest, the cheapest, and the most common cardiovascular drug in the World. It works by inhibiting blood clotting. According to studies summarized in the New York Times (July 20, 2004, D1) aspirin does not inhibit blood clotting for a substantial group of patients (between 5 and 40%). For unknown reasons these individuals are not responsive to aspirin and remain at risk for heart attacks and strokes. However, such aspirin resistant people do respond to aspirin’s other benefits in the sense of getting relief from pain and inflammation. Should you get tested for aspirin resistance? If you are taking aspirinto ward off heart attacks and strokes, such a test might be useful in spite of the cost (between $30 and $100). Otherwise you would be at greater risk of heart attacks and strokes and you might benefit from a more expensive anticlotting drug such as Plavix ($3 per day). It is also interesting that people might be more resistant to the clotting effects when taking coated aspirin that is intended to minimize stomach irritation, a common side effect of aspirin. Aspirin inhibits an enzyme, cyclo-oxygenase that is involved in making thromboxane, an agent that induces platelets to clump during blood clotting. Perhaps aspirin resistance is the result of a genetic difference?
A statistical study has revealed that frequent use of antibiotics is linked to an increased risk of breast cancer. Those women who took the most antibiotics ran twice the risk of breast cancer. The reason(s) behind this troubling correlation is/are unclear. Perhaps the lowered levels of protective, benign intestinal bacteria are responsible. Or the development of more aggressive antibiotic-resistant bacteria is involved. It is well known that some physicians tend to prescribe antibiotics when they are not needed, as for example for a viral infection against which antibiotics are ineffective. Doctors should not overuse antibiotics, but in many instances they are essential and patients need to take antibiotics. As usual, there must be a balance. (New York Times, February 17, 2004, page A11)
A common strategy for developing new drugs is to discover enzyme inhibitors as is discussed on page 46 in Naturally Dangerous. An alternative, novel strategy for treating diabetes type II has been announced by scientists at Hofmann-La Roche (Science, 07/18/03, page 290). Recall that type II diabetes is caused by an upset in the delicate balance between blood sugar and insulin, the enzyme that escorts sugar (glucose) from the blood into cells, where it is metabolized. Type II diabetics have ineffective insulin and too much glucose accumulates in their blood, which results in damage to the blood vessels, the kidneys, the eyes and many other serious ailments. Current drugs to treat type II diabetes are designed to enhance insulin activity, but such drugs are often ineffective. There is a single enzyme called glucokinase, which regulates two different functions that are out of balance in type II diabetics: release of insulin from the pancreas and production of glucose in the liver. By searching over 120,000 drug candidates, researchers found a chemical that activates this enzyme in both kinds of cells. They showed that this drug causes islet cells to release insulin and liver cells to release less glucose. It is really unusual for a single drug to target two different cells at the same time. When this drug was tried on diabetic mice, their blood sugar levels dropped dramatically. They confirmed that the new drug candidate effects both inlet and liver cells. Patients must be patient because several years and many tests will be required before this new drug is ever approved. Many things could go wrong. Blood glucose levels may drop too low or the liver may accumulate fat because it contains too much glucose. Such a delicate balance is difficult to maintain; remember the concept of homeostasis, discussed on page 48 in Naturally Dangerous.
On page 50 in Naturally Dangerous the reader learns that grapefruit juice contains a natural chemical that inhibits several drugs, in particular the popular cholesterol lowering statins and a blood-pressure medication, felodipine. This problem is currently under active study. Compounds known as furanocoumarins are the major substances in grapefruit that raise the level of certain drugs in your body. Other substances in grapefruit have a similar effect, but these are still being explored. It is still uncertain as to which drugs are not affected by these natural substances, but in the interim, it is wise to avoid drinking grapefruit juice within a 10 hour period of taking prescription medicines. As this problem has become publicized, sales of grapefruit juice have been declining. (Wall Street Journal, 7/17/03, page 1)
An article in the New York Times (7/15/03), page D7, by the well-regarded science writer, Jane Brody summarizes the good news on high-density-lipoprotein, HDL, sometimes called the good cholesterol. For background refer to page 46 in Naturally Dangerous. Having high levels of HDL predicts good health; those with low HDL levels have a greater risk of experiencing a heart attack, even if their total cholesterol levels (HDL + LDL) are low! The bad cholesterol, LDL (low-density lipoprotein) level is less important, but as you will see, the ratio is significant. To be relatively secure, one needs a HDL level over 45 for men and 55 for women (units of milligrams per deciliter of blood). A reading below 40 is considered a risk factor in heart disease. The actual figures are more complicated but are easily calculated. The ratio of total cholesterol over HDL is what counts. A ratio of 3:1 is very desirable; such people have a low risk of heart attacks. A ratio of 5.5:1 is typical of individuals with heart disease. The average value is 4.5:1. Male patients are usually advised to keep their total cholesterol below 200. Such individuals would need a very high HDL of 70 to maintain the most desirable ratio of 3:1. That would be unusual. If a patient had a low total of 150, then an HDL level of 50 would be good and that is often accessible.
The next question is how does one raise their HDL level? There are four approaches: weight loss, aerobic exercise, diet, and drugs. Weight loss is difficult and the HDL gain is modest. For every 7 lbs lost one experiences an HDL gain of only1 unit. Cardiovascular exercise is a little better; one gains 1unit of HDL for every 5 miles a week that one runs. Of course you must keep up this activity. The effect of diet is surprising. Carbohydrates do not raise HDL levels, but certain fats do. In fact, high carbohydrate, low fat diets substantially lower the HDL levels! Statistical studies indicate that consumption of monounsaturated fats such as those in olive oil, canola oil, many nuts, and avocados selectively raise HDL levels, but surprisingly polyunsaturated fats in corn, safflower and soybean oils lower both HDL and LDL levels. Of course, as discussed in Naturally Dangerous on page 19, trans fats are bad. It has been said that saturated fats are also undesirable, but I have not seen figures on the effect that these fats have on HDL levels. Another effective nutrient is alcohol; in moderate amounts, one to two ounces of ethanol each day raises the HDL level from 5 to 10%. A model diet to follow is the Mediterranean diet, which features vegetables, fruits, nuts, red wine, and fish (especially salmon, mackerel, and other fish containing large amounts ofomega-3 fatty acids). About 35% of calories in this diet are derived from fats and limited amounts of meat, poultry, and high-fat dairy products. It is interesting that the faddish, but currently popular Atkins diet discussed in this web-site, also has been shown to raise HDL levels, but Atkins diet is disfavored by traditional nutritionists and is not discussed in this Brody article. Of course drugs can also be effective in raising HDL levels. The most commonly used drugs that lower HDL are the remarkable heart-protecting statins, which are discussed in Naturally Dangerous, on page 46. The B vitamin, niacin has the most dramatic effect, raising HDL by up to 30%, but there are side effects limiting extensive use of niacin.
In Naturally Dangerous, there are warnings and examples are given of contraindicated drugs; however, some drugs combinations are very efficacious. A striking new example is the combination of Remicade with methotrexate in treating rheumatoid arthritis, a disease in which the patientÕs immune system attacks and progressively destroys their joints. A new study shows that this combination is clearly superior to methotrexate alone (previously the standard treatment for rheumatoid arthritis). Remicade is a new type of drug; it is an antibody, a type of protein that neutralizes another protein, tissue necrosis factor, which plays a role in inflammation. In 2002 Remicade sales rose to $1.3 billion. This exotic drug is not cheap, it typically costs from $13,000 to $16,000 a year, when given by periodic injections; however, when administered by “infusion” every two months, this treatment is covered under Medicare, but the injections apparently are not. Recall that drugs which are proteins must normally be injected directly into the bloodstream; otherwise they are deactivated by the digesting enzymes in the patientÕs stomach. (Wall Street Journal, 6/19/03, page D2).
There are many lessons in the anticoagulant coumadin that bring together themes found throughout Naturally Dangerous. This life-saving, but treacherous drug, which is also called Warfarin, is still used as a rat poison. Medical applications of coumadin tread a very narrow path between danger and efficacy. Too much warfarin can cause serious, sometimes fatal bleeding, but too little will not prevent life-threatening blood clots. The timing and amount of each dose must be very closely monitored and the patient must be aware of contraindicated drugs, over-the-counter medicines, vitamins, herbs, and even some foods. This drug inhibits blood clotting by interfering with clotting factors that are dependent upon vitamin K, which is given as an antidote for warfarin overdoses. Among contraindicated medications are aspirin and ibuprofen; the statins; and several antibiotics; barbiturates, and vitamins K and C. Herbal medicines such as gingko biloba and ginseng should be avoided. Even large portions of foods such as kale, spinach, broccoli, and turnip greens, that are rich in vitamin K, should be eaten with caution. (New York Times, April 29, 2003, page D7)
There is an old molecule that is becoming a new tool in diagnosing heart disease. C-reactive protein (CRP) has been known since 1929 and over many years CRP has been associated with inflammation. It is generated in the liver during acute phases of trauma or disease. Recently a test has been developed which measures precise levels of CRP in the blood. In Europe and Japan CRP levels have been routinely measured to detect the presence of inflammation and infection. Medical researchers have recently discovered that a patient’s CRP level is an outstanding predictor of heart disease, more powerful than the more traditional measurement of LDL (low-density-lipoprotein – the “bad cholesterol”). Moreover CRP and LDL levels are not correlated as measures of cardiovascular health. For example, even in patients with low LDL levels, CRP levels serve as potent predictors of risk of first-time heart attacks or strokes! These findings may explain why some people who had very little blockage of their arteries may nevertheless have a heart attack, whereas others who had significant blockage might never experience a coronary event. This is not to say that cholesterol levels are not also important, but CRP levels should also be taken into account. Both variables are valuable indicators of coronary heart disease. High levels of either LDL or CRP are bad news; high levels of both are very bad news. It is not certain whether CRP is a causative factor or a symptom of heart disease. There is preliminary evidence that CRP is a causative agent in heart disease.
It is also interesting that an individual’s CRP level can be lowered, either by taking aspirin, or one of the cholesterol-lowering drugs called statins (see page 46 in Naturally Dangerous). This is good news for pharmaceutical companies that are selling statins such as Lipitor, because patients having high CRP levels might be advised to take these drugs even though their LDL levels are normal. Many physicians are resisting the addition of CRP determinations in their patientÕs blood tests even though these tests are relatively inexpensive. One reason is that these physicians may be pushed to prescribe a statin for an otherwise well patient and statins have their own side effects. As lay persons read about CRP, this situation may change. Tell your doctor that President Bush got his CRP level measured during his last medical exam.
High CRP levels have also been correlated with several other risk factors that are associated with heart disease: cigarette smoking, obesity, type II diabetes, heavy drinking, and hormone replacement therapy in postmenopausal women. Interestingly, non-drinkers have higher CRP levels than those who drink one or two glasses a day. (Gary Taubes, Science, Vol. 296, April 12, 2002, page 242) (N Engl. J Med, Vol. 347, No. 20, November 14, 2002, page 1557)
The “super-aspirins”, selective inhibitors of the inflammatory enzyme, Cox-2, have come under new scrutiny because of studies that indicate a possible increased risk of heart attacks and questions about whether these expensive, prescription drugs really lower the incidence of adverse effects compared with conventional, cheaper pain medicines. Both Cox-2 inhibitors, Celebrex and Vioxx have been questioned. Patients are from two to four times more likely to have a heart attack when taking Vioxx compared with older non-steroid anti-inflammatory drugs. Some patients taking aspirin show unwelcome gastrointestinal effects. More thorough epidemiological studies should be carried out before these questions can be fully evaluated. Some patients are reporting good pain relief from these super-aspirins, but keep your eye out until this situation is clarified. Celebrex also has its problems with bleeding ulcers, a symptom Celebrex is designed to avoid. In a study released December 22 in the New England Journal of Medicine, Celebrex was found to be only marginally superior to a combination of the common painkiller diclofenac and the ulcer drug Prilosec. Moreover, there is a new Cox-2 inhibitor on the market (since November 2001) and it is not free of unpleasant side-effects ether – no drug is. It is only after years of statistical studies with a large population that the whole inventory of side effects from a new drug can be evaluated (Read about aspirins and cancer in Chapter 5).
Now we know better how Tylenol works! Remember from Chapter 2, the super-aspirins, Celebrex and Vioxx, that are specific COX-2 inhibitors? Now another COX enzyme, COX-3 has been discovered. Unlike COX-1 and COX-2, the newly discovered enzyme, COX-3 seems to have no role in inflammation, but COX-3 does play a role in pain and fever. This enzyme is inhibited by the analgesic acetaminophen, the active agent in Tylenol. This over-the-counter drug does not inhibit COX-1 and COX-2 (Chemistry & Engineering News, September 16, 2002, p. 16).
There continues to be good news about the “statins”, drugs that lower cholesterol levels, such as Mevacor, Provachol, and Lipitor, have unexpected positive side effects. Statistical studies of people taking statins reveal lower incidence of Alzheimer’s disease and reduced inflammation of blood vessels. Such inflammation is thought to be a major cause of heart attacks. My physician joked: they should put statins in the water supply.
C-reactive protein (CRP) is a marker of inflammation and is a strong indicator of impending heart disease. CRP levels are potent predictors of heart attacks and strokes in both men and women. CRP levels are independent of cholesterol levels – they are unrelated. Individuals with low cholesterol, but high CRP levels or vice versa are at high risk of heart disease. Those with high levels of both CRP and cholesterol are at the highest risk. CRP is a long-lived protein in your blood; CRP levels in blood samples remain stable and measurable for decades. That is how the importance of this marker was determined by studying blood samples taken from patients over many years and correlating these levels with what happened to those patients. CRP levels are a superior predictor than cholesterol levels and the clinical measurement of CRP is relatively inexpensive. Nevertheless, some physicians have resisted measuring CRP levels in their patients. Statins, the cholesterol lowering drugs such as lipitor significantly reduce CRP levels. Aspirin is also effective. Moderate consumption of alcohol lowers CRP levels, but heavy drinkers or non-drinkers have higher levels. Smokers have significantly higher CRP levels. These levels correlate with obesity and type II diabetes. Hormone replacement therapy in postmenopausal women doubles CRP levels. All of these effects parallel past experience connecting drugs, lifestyles and heart attacks. Is CRP part of the cause of a heart attack or a symptom of impending heart disease? That question is presently unanswered. It is curious that CRP levels are not correlated with direct infections such as Chalydia pneumoniaeor Helicobacter pylori, which have been though to be related to heart attacks. A heightened immune response to a low grade infection seems a likely culprit in raising CRP levels. (Science, 12 April, 2002, Vol. 296, p. 242)