Antioxidants in Nutrition, Health, and Disease

John M.C. Gutteridge, Barry Halliwell
Oxford University Press, 70 Wynford Dr, Don Mills, ON M3C 1J9
1994/143 pp

Strengths

Summarizes current thought on free radicals and antioxidants. A clear, pithy, scientific, informative text

Audience

Physicians, medical students, nurses, biologists, nutritionists, and chemists

The authors have written a short textbook introducing antioxidants to clinical practice. They also refresh readers with a review of the basic clinical sciences.

A short, informative preface asks succinct questions on using antioxidants for treating heart disease, cancer, and degenerative illnesses. The authors answer their questions with sufficient information on free radicals, cholesterol, and oxidative stress for readers to use in laboratories and practices.

A historical discussion of oxygen, oxidation-reduction definitions, and electron transport is followed by scientific information on the Krebs cycle, vitamins, and nutrients and a timely presentation of free radicals as contributing to cardiovascular and degenerative disease.

Later, epidemiologic and pathologic evidence on nutrient use is presented. This evidence allows us to understand information applicable to a scientific study of tissue damage and regeneration. Clearly, interest in the effects of nutrition and vitamins on health has increased. This short text will help practitioners upgrade current knowledge and share the information with patients.

The authors acknowledge the brevity of their text. They have challenged readers to examine modern concepts that might be discussed with our patients in the office. They also give us sufficient information to provide our patients and colleagues with current thinking on the activity of essential vitamins A, E, and C.

The style of this book flows well with diagrams, bold headings, illustrations, and informative tables. I enjoyed the quotations from The Beatles and Butch Cassidy and the Sundance Kid mixed with Paracelsus and Francis Bacon, which set the tone for the discussion in each of the seven chapters.

Appendices supplementing chapters 1, 4, and 5 provide further information on cholesterol, saturated and unsaturated fats, and their effect on the cardiovascular system. The authors raise questions not only for academics, but also for the less scientific. Skillfully, they then lead us through a historical discussion of the building blocks of life: carbon, hydrogen, oxygen, and nitrogen. Are antioxidants elixirs or media hype? Are human phagocytes useful? Does oxidative stress help or hinder our health? Should vitamins and minerals be used as supplements? What is the window of optimum activity of antioxidants?

Although the jury is still out on the results of antioxidant research, the authors present much food for thought. This book is valuable, and a few nights’ perusal should give readers sufficient vital information on antioxidant therapy to guide application.

Experts predict that one out of every two men will eventually develop lower urinary tract symptoms that require medical treatment during their lifetime. Given these numbers, finding the best treatment for the cause of these symptoms— benign prostate hyperplasia (BPH)—is an important goal.

Prostate resection, an operation in which part of the prostate is removed, has been the standard therapy for benign prostate hyperplasia for decades. In recent years, treatments based on removing prostate tissue using heat have been developed. These include microwave therapy, ultrasound, and needle ablation.

A recent study in the” Journal of Urology” compared the success of prostate resection and transurethral needle ablation in 121 men with benign prostate hyperplasia. The men were randomly assigned to receive one of the procedures, and their progress was followed for six months. In addition to several measures of symptoms, the researchers evaluated objective measures of free urinary flow and pressure flow. The study took place at seven centers around the United States.

Measured after treatment and again six months later, both procedures produced significant improvements in symptoms, quality-of-life, and free urine and pressure flow. Resection, however, produced significantly more improvement in urine flow than ablation. There were no other differences between the two groups at six months after treatment.

The researchers also wanted to know if objective measures of urinary flow can predict how well patients will respond to treatment. These measures, however, did not predict response either right after treatment or at the six-month follow-up. The researchers concluded that these tests do not help doctors decide which treatment is best for each individual patient.

Even though there was no difference in how much patient symptoms improved, resection did decrease urinary obstruction more than ablation. On the other hand, the degree of obstruction did not predict how well patients would respond to treatment. The researchers concluded that more research is needed in this area before conclusions about the “best” treatment can be made.

Until recently, there was little data about risk factors for acute urinary retention (AUR). Men with enlarged prostates seem to get it more, but that’s about all that was certain about this problem. Now, a new study published in the “Journal of Urology” sheds light on who’s most at risk for this painful condition.

Over 6,000 men from a long-term health study completed questionnaires about AUR and lower urinary tract symptoms. These men also filled out general health questionnaires every other year.

Overall, four to five men per 1,000 had acute urinary retention episodes each year during this two-year study. Chances of AUR increased with age, severity of urinary symptoms, and diagnosis of benign prostatic hyperplasia (BPH). Men with BPH who also had high symptom scores were nine times more likely to have an AUR episode than men without severe symptoms or benign prostatic hyperplasia.

About two-thirds of the men with AUR episodes had either high symptom scores or BPH, but about 20 percent of episodes occurred in “low-risk” men with no urinary problems or benign prostatic hyperplasia.

The urinary tract symptoms that made up the scale are:

Sensation of incomplete bladder emptying,
Having to void again after less than two hours,
Stopping and starting several times during voiding,
Difficulty postponing voiding,
Weak urinary stream,
Having to push or strain to begin voiding, and
Typically got up three times/night or more to void during the past month.

Having one of these symptoms more than 25 percent of the time doubled or tripled the risk for acute urinary retention, as did worsening of symptoms over a two-year period. Symptoms of urinary irritation or obstruction (incomplete emptying, urinary frequency, weak urine stream) particularly increased risk for AUR. Men taking calcium blockers, beta-blockers, or antiarrhythmic drugs were also at increased risk.

This research confirms that lower urinary tract symptoms are an important risk factor for AUR, whether measured by severity or increased frequency — a fact that has been inconclusively studied in the past. The study also confirms that acute urinary retention risk increases with age and presence of benign prostatic hyperplasia.

Results from a Phase I human study of a new treatment option for benign prostatic hyerplasia (BPH) helps men overcome problems associated with an enlarged prostate gland without the need for surgery.

BPH accounts for a variety of urinary difficulties in men over the age of 50. These symptoms typically include a need to pass urine more frequently (especially at night), an urgent need to urinate, weak or interrupted urine flow, a feeling that the bladder is not completely empty, and a delay or hesitation at the onset of urination. It is estimated that 50 percent of men over age 50 suffer from BPH.

Produced by Celsion Corporation, this exciting new therapy uses two mechanisms to overcome the problem of an enlarged prostate. First, a microwave balloon catheter system shrinks the prostate through the delivery of microwave heating. Second, simultaneous expansion of the balloon catheter compresses the walls of the urethra, enlarging the urinary opening.

Since the system is designed to relieve obstruction, it concomitantly relieves uncomfortable urinary symptoms. The procedure can be performed on a one-time, outpatient basis.

The results of the Phase I trial, conducted by researchers at the Montefiore Medical Center in New York, are reportedly encouraging. Principal investigator Dr. Arnold Melman stated that “(The) preliminary results suggest that the system, when fully tested and approved, could provide immediate symptomatic relief.” He added, “If Phase II studies are successful, I believe Celsion’s system should encourage a greater number of men with BPH to seek treatment, particularly those who suffer from milder forms of the condition.”

The company is in the midst of seeking approval from the U.S. Food and Drug Administration (FDA) for multi-site Phase II clinical studies. The studies are required to determine the safety and effectiveness of the system in benign prostatic hyperplasia patients. Pending FDA approval, Celsion plans to start Phase II studies in the summer of 1999. If the results obtained are positive, the company will then apply for premarket approval from the FDA to market the system in the United States.

Several studies in the past year have reported racial variations in the incidence of benign prostatic hyperplasia (BPH). Some have suggested that African-American men are more likely to get this condition than white Americans. Others report no differences. A new study looked at different definitions of race and BPH to try to sort it all out.

Researchers from the Harvard Medical School and Brigham and Women’s Hospital, both in Boston, examined data from the Health Professionals Follow-Up Study, a long-term study of more than 50,000 male healthcare professionals. The men were aged 40 to 70 when the study began in 1986, and have completed questionnaires and physical examinations every other year since.

Of the 31,775 men in this study, 3345 were defined as having benign prostatic hyperplasia, based on symptom reports, surgery for the condition, or diagnosis from a rectal exam.

After accounting for age, alcohol intake, smoking, weight, and other factors that affect BPH, the researchers found that black and Asian men were no more or less likely to develop benign prostatic hyperplasia than white men. They were, however, less likely to have surgery for it. The researchers also measured a number of hormones related to prostate symptoms, and again found no racial differences.

When Caucasians were split into groups, those of southern European origin were slightly more likely to have a variety of prostate problems, including BPH, than other white men, and those of Scandinavian origin were slightly less likely.

In the February issue of the Journal of Urology, the researchers explain that they used three different ways of classifying race and ethnicity to analyze the data, and the results were similar each time. They also used different combinations of benign prostatic hyperplasia symptoms, and again the results were the same.

The men in this study were well-educated professionals, the researchers point out, so they may not represent the general population of American men in health behaviors — diet, lifestyle and other factors that influence BPH. On the other hand, none of the factors measured in the study, including diet, obesity, lifestyle, vasectomy, blood pressure, or heart disease, accounted for the racial differences.

The researchers conclude that the “common contention” that black men are at higher risk, and Asian men at lower risk, than whites was not supported. They recommend further study of differences among different Caucasian groups.

If you are an older adult with recurring episodes of cough, wheezing, chest tightness, or difficulty breathing, you may have asthma. Are you surprised? There is a common misconception among health-care providers and the general public that older people are not at risk for asthma. Most people figure that it is a disease that only affects children or young adults. Actually, statistics reveal that six to 10 percent of older adults may suffer from asthma. It is a cause for serious concern in the elderly, because patterns of the disease are usually more severe and complete symptom remission is rare.

Asthma is a disease of the lung’s airways. With asthma, the airways are inflamed and react easily to certain triggers, such as viruses, smoke, or pollen. When the inflamed airways react, they become narrow and make breathing difficult.

According to the National Heart, Lung, and Blood Institute, the older adult with asthma typically experiences a more complicated course of events. Asthma severity usually ranges from moderate to severe in older adults, and age-related changes in lung structure and function tend to exacerbate asthma symptoms. This makes wheezing and acute attacks more common. Respiratory problems caused by other illnesses can also contribute to or worsen asthma. The older adult may also face medication-related difficulties. Once again, age-related physical changes make the older adult more susceptible to side effects of asthma medications. In addition, drugs used to treat a pre-existing ailment may aggravate asthma symptoms.

Asthma in the elderly is often difficult to diagnose because it can be confused with or hidden by other diseases, such as bronchitis, emphysema, or various cardiac conditions. Following a careful examination that includes a medical history, physical examination, and laboratory testing, asthma can usually be differentiated from other coexisting illnesses.

Despite these difficulties, the goals of diagnosis and treating remain the same for the older asthmatic. Education, monitoring, controlling asthma triggers, and providing appropriate drug therapy are all high priorities. Compared to younger patients, however, many older patients need to be monitored more closely.

If you have respiratory symptoms that will not go away, please consult your doctor. There are many programs in place to provide assistance and follow-up to asthma sufferers. Even though you may face greater challenges, your asthma can be managed.

A recent study concludes that viral infections may cause asthma attacks in a significant proportion of asthma patients. Researchers at the Baylor College of Medicine studied 122 asthmatics treated for acute symptoms of asthma at hospital emergency departments and 29 asthmatic adults treated at a pulmonary clinic to collect data. The study found that 55% of asthma attacks treated at emergency department were linked to respiratory tract viral infections, while 44% of attacks in asthmatic pulmonary clinic patients were associated with similar infections. Authors say the findings suggest that more effort should be placed on preventing respiratory tract viral infections among asthma patients.

Questions and Answers:

1. How can a person be sure that their asthma symptoms are caused by exposure to something at work? Are there specific tests?

There are three types of work-related asthma. The first type is related to an allergy to something in the workplace. In that case, patients note that the asthma clears up whenever they’re not at work or they’re on vacation. The second type is where there is pre-existing asthma; irritants at the work site will constantly aggravate the existing asthma, so that they always have a lot of minor attacks at work because there may be several things that bother them. The third type is irritant-induced asthma or reactive airways dysfunction syndrome (RADS), reactive airways dysfunction syndrome, which is due to a high level of exposure. In these cases, patients become immediately ill and require medical care, and they would have asthma subsequent to that.

The most common are the first two types. Testing for these would require seeing a specialist, who may do a variety of tests involving specific challenges. For instance, a doctor might do what is called a natural challenge, in which a peak flow meter is used to measure asthma attacks. A peak flow meter is routinely used by family doctors to monitor asthma. By blowing into a cylinder, the meter shows high or low numbers which represent a reliable, objective measurement of the severity of asthma. This device can easily be used at home or in the workplace. Patients can take measurements themselves using a peak flow meter for about two weeks at home, and then go back to work and do the same, to document for the physician if there are differences: this way you can tell if they are really having more asthma at work than at home. By keeping a diary of peak flow measurements, patterns can emerge: asthma may be better or worse at certain times of the day, which may also help in tracking irritants that may be exacerbating the asthma.

2. Are asthma symptoms very different in asthma with latency and asthma without latency?

Basically, asthma is asthma; symptoms are the same whether it is with or without latency. Only the initiation of attacks will be different. Asthma with latency, which is the allergy-related asthma, requires a long exposure of several months or years during which time a person develops an allergy or sensitivity to a chemical in the workplace. This is the type that gets better when the patient is away from work, on the weekends or on vacation. The other type of asthma, without latency, is the high-dose, sudden-onset asthma, which can be put down to a single exposure at one moment in time.

3. Can you explain briefly why you don’t have to be allergic to a substance to have an asthma attack?

Asthma without latency is due to an irritant. The irritant is of such high magnitude that it actually produces injury to the airways of the lung, similar to a respiratory infection or the type of injury induced by an allergic response that causes inflammation of the lungs. This inflammation persists for reasons that aren’t clear, but it is due to this persistent inflammation that they suffer from asthma.

4. Why is taking appropriate asthma medication to keep you on the job site not a good idea?

If you have the type of asthma that is irritant-induced (RADS) or if it is aggravated by some substances at work like cigarette smoke or welding fumes, medication in many cases will allow you to tolerate these exposures and be able to work. In contrast, if you are allergic to something specific, every time you’re exposed to it, your asthma worsens, and continues to increase in severity. There have been a few reports of allergic-type asthma or asthma with latency where the exposure has led to the death of a person. Once you are allergic or sensitized, it is recommended that you have no further exposure to the substance, because it can produce significant worsening and may have serious consequences. In these cases we recommend the person not return to work if the exposure can’t be avoided. This is in contrast to the irritant-type asthma, where the aggravation, even if it is acute and precipitates attacks, doesn’t severely injure the airways. Generally, this type of asthma is not specific to the workplace. In these people, medication seems to improve response to irritants and they can usually stay on the job.

For asthmatics in general, avoiding irritants is probably a good idea, as is getting appropriate medication.

A myriad of factors are implicated in causing asthma in the workplace: the nature of the job being done, the location of the work site, the degree of exposure to irritants, and what kind of materials — vapours, fumes, as well as dusts — are being inhaled, among others. Various ways of defining asthma caused by work site conditions have been proposed but a newer classification system suggests two primary types of occupational asthma, asthma with latency and asthma without latency. Asthma with latency is precipitated by prolonged exposure (the latency period) to a substance present on the work site, which eventually causes allergic sensitization. This sensitization process eventually changes the way the respiratory and immune systems react, causing asthma symptoms. Asthma without latency occurs after only a single contact with an irritant substance that produces a sudden reaction that affects the airways without an allergic component necessarily being present. This leads to a condition called reactive airways dysfunction syndrome (RADS), which keeps the airways hyperresponsive.

To date, over 200 substances have been linked to occupational asthma with a latency period. Depending on the level of exposure, these triggers lead to asthma by precipitating immune responses characterized by IgE antibodies — the same function that sets off an allergic reaction to ragweed in many people.

Sudden onset of asthma (no latency period) can take place within minutes or hours of exposure, precipitate RADS, and can continue to cause asthma symptoms for years. In most cases, this kind of onset is due to an industrial accident, or ventilation of the workplace being compromised. Documented cases of such asthma attacks were triggered by uranium hexafluoride gas, spray paint with ammonia, fumigants, metal coating remover and smoke inhalation.

By-products of industrial manufacturing are heavily implicated in causing asthma symptoms. Allergic sensitization (associated with a latency period) is commonly caused by such materials as baking products and cotton dust. How much exposure is involved plays a large role in inducing symptoms of asthma, particularly in very dusty types of work. Polyurethane processing and foundry work are notable causes of asthma; millers and bakers exposed to grain dust have an asthma prevalence of up to 40%. If more hazardous activities are added to the list — pouring chemicals, blasting, sawing — the rate goes up even more.

Where the job site is located will affect asthma rates. For instance, western red cedar causes asthma in the western U.S., where it is native, and in Japan, where dock workers are exposed to it while unloading the ships that import the wood. An epidemic of asthma was caused in Barcelona, Spain, when a shipment of soybeans was unloaded in weather conditions that allowed dust from the beans to spread, demonstrating how climate conditions also affect the rate of asthma.

What can be done to reduce the risk factors for asthma in the workplace? Obviously, the ideal solution is to stay away from the kinds of employment that trigger asthma. As this is not always possible, employers should consider adopting strategies such as ensuring proper ventilation, providing personal protective devices (masks), rotating jobs to cut down on the amount of time a worker spends in a particular environment, and enforcing safety measures that eliminate the risk of an accident, such as a chemical spill.

While symptoms may clear up once a worker is no longer exposed to the irritant, many people find that the asthma persists and leads to the chronic airflow problems (hyperresponsiveness) typical of RADS. Further, the longer the exposure, the more chronic the asthma. Once asthma is diagnosed as being occupational in nature, it is not enough to merely open more windows or take a few more puffs on a bronchodilator. A serious discussion regarding options needs to take place between patient and doctor — away from the workplace.

Questions and Answers

1. Are oral corticosteroids not effective enough in treating asthma?

The problem is not the effectiveness of corticosteroids. Patients respond to corticosteroids, but because of the toxic effects of the drug, we’re always looking for what we call a corticosteroid-sparing effect. We want to reduce the use of steroids through alternative medication, but it’s not a question of one drug being better than the other.

2. Are you concerned about dependency on corticosteroids, or about other side effects?

Corticosteroids are not like cocaine, which creates a physical dependency. We’re much more concerned about toxicity, particularly in children. Steroids stunt growth, can cause cataracts, high blood pressure, hair all over your body, and can induce a diabetic-like state. But the major concerns are that it stunts growth and weakens bones. Some patients can fracture their ankle just stepping off a curb.

3. What is IgE and why do some people have more of it than others?

Immunoglobulin E or IgE is the allergic antibody, discovered in Denver in the 50s. Clearly, it’s one of the major causes of allergy-induced problems, whether it’s rhinitis (people who have ragweed allergy or hay fever), skin disease such as eczema, or in some cases, asthma. A high percentage of asthmatics manifest this allergic reaction, particularly children. In most cases of asthma it’s the allergy to whatever is in the environment that triggers the allergic response, which in this case targets the airways.

3. Is asthma caused by IgE reactions to allergens harder or easier to treat than non-allergic asthma?

It depends. Some people have what’s called exercise-induced asthma, and they can take a bronchodilator just before they exercise and they’ll be fine. Others have aspirin-sensitive asthma, and as long as they avoid anything containing aspirin, they’ll be fine. It’s not that one is easier or harder to treat. It’s just that one has to identify and then target different mediators and causes with different drugs in the various types of asthma.

4. What is inflammation?

Let’s say that you’re allergic to dogs. Your family has a history of allergy, because there’s a big genetic component to it. You encounter a dog, and inadvertently inhale some of the dog dander. What happens is: the IgE binds to mast cells, which are a type of cell that is present throughout the body’s airways. The allergen also binds to the IgE. The mast cells then degranulate and release a lot of mediators. Other cells, such as lymphocytes (white blood cells), also get activated. This activation process calls in a lot of inflammatory cells. In the case of asthma and other allergic reactions, a major cell that’s called in is the eosinophil. The eosinophils accumulate around the airway, probably releasing their own mediators that break down the epithelium (lining) of the airways. That leads to altered control of some of the nervous functions of the airways. You get smooth muscle hypertrophy (swelling), and contraction and constriction of the airways.

4. Are immune globulin injections as effective in treating asthma as corticosteroids?

One has to think of the therapy of asthma. There are controllers of asthma and there are relievers of asthma. The relievers of asthma are those drugs that go straight to the airway such as beta-agonists — ventolin, for example — where they act to relieve bronchoconstriction. You take the inhaler, and within seconds you get relief. But if you’re looking for a more prolonged effect to keep inflammation down, you need something that’s going to work to keep those inflammatory cells from coming in. The first line therapy is drugs such as cromolyn and nedocromil, which are weak drugs. They may be okay, however, taken as a prophylactic by people with mild asthma. The really effective anti-inflammatory that is available today is corticosteroid; nothing can beat it. But if you take these drugs by mouth, the toxicity is great, particularly if you take it on a continuing basis. Hence the big push to taking steroids by inhalation. The next step after cromolyn or nedocromil is now inhaled corticosteroids. The toxicity is clearly much lower than when taken by mouth, because they act locally with as little systemic absorption as you can get away with. But some patients continue to have inflammatory changes and asthmatic symptoms, so they need oral corticosteroids. And once you’re on oral corticosteroids as a requirement for control, you start to look at experimental therapies for inflammatory control, because you just want to get the patient off the steroids if you can. A lot of what has been tried has followed from the rheumatoid arthritis literature. Arthritis is also an inflammatory disease, and it’s been treated using things like methotrexate, gold and chloroquin. All of these anti-inflammatory drugs have been tried with asthma, without any great success. Also, some of these drugs are themselves quite toxic: methotrexate, for example, is an anti-cancer drug. We were looking for something that had an anti-inflammatory effect without the toxicity, and we were pleasantly surprised to find that gamma globulin (IgG) has that effect. We were able to significantly reduce the need for steroids without losing control of the disease.

Editorial:

This is an experimental therapy. Double-blind, placebo-controlled studies need to be done to determine the efficacy of gamma globulin, and pilot studies have already been done which have supported its efficacy. It’s also a very costly therapy, and that fact is likely to limit its use. But we’re talking about using this therapy in the very small subset of asthmatic patients whose asthma cannot be controlled using conventional methods. Probably no more than one in 100 to one in 500 asthmatics really have severe steroid-dependent asthma. Of course, when you consider that there are 16 million asthmatics in the United States, that’s still a pretty large number of people who stand to benefit.