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Sleep: An Evolutionary Imperative. Are You Getting Enough?

Post author By Pine Street Foundation
Post date November 29, 2010
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INTRODUCTION

Everyone knows that sleep is important. Yet, as a nation, we’re sleeping a full hour less per night on average than we were just ten years ago.(Jean-Louis, Kripke et al. 2000) This trend is certainly not new; for more than 25 years, Americans have been sleeping less and less each night and, in a recent study, up to half of all American adults report having sleep problems in any one year. (Becker 2006) Of all the sleep disorders, insomnia is, by far, the most common, affecting nearly 70 million of us; in a recent sur- vey, 35% of respondents had insomnia every night and nearly 60% reported insomnia at least a few nights per week. Sleep problems have been dubbed “a hallmark of modern living.”(Bollinger, Bollinger et al. 2010)

Why this is happening is not clear. Is it because we often favor work, play, socializing, or learning over sleep? Are we sleeping less because of problems with our local living environ- ment? Are sleep disturbances really a sign of some underlying disease? Is the problem, as many want to suggest, simply stress? While most people do experience some level of stress in their lives, one theory is that it’s a deficiency in positive coping skills, rather than the stress itself, that lets the body veer out of balance and causes sleep problems. Also interesting to note, recent re- search suggests that high positive emotions (not just high nega- tive emotions) can also cause a poor night’s sleep, too.(Baglioni, Spiegelhalder et al. 2010)

Given that so many of us aren’t getting enough high-quality sleep, it is worthwhile to educate ourselves on how sleep or sleep deprivation affects our health. What do scientists know about sleep? Why do we even need to sleep? How many hours of sleep do we really need each night and what happens if we sleep for less than this optimal number? Equipped with answers to these questions, we will be more apt to make healthy choices regarding sleep.

WHAT IS KNOWN ABOUT SLEEP?

What Happens During Sleep & Why Do We Need It?

Sleep may have given humans an evolutionary advantage, pro- ducing immobility at times when activity would be unproductive (preventing wasteful energy expenditure) or dangerous (prevent- ing unnecessary exposure to predators).

Sleep was first described physiologically in the 1930s(Loomis, Harvey et al. 1935) and our understanding was greatly enhanced by the discovery of rapid eye movement (REM) in the 1950s.(Aserinksy and Kleitman 1953) Our sleep is usually divided into various phases, based on the differences in brain activity throughout the night. During these various phases, our bodies repair and our memories are organized.

Current research suggests that the interplay between ho- meostasis and circadian rhythm determines our sleep pattern. Homeostasis, which is the ability of the body to adjust its physi- ology in response to fluctuations in the outside environment and the weather, would have us sleeping in small increments through- out the day to balance our wakeful hours.

Circadian rhythm, on the other hand, is the 24-hour cycle in physiological functioning found in most living organisms. Until recently, it was assumed that the human circadian rhythm was also 24 hours in length. However, there are several curious anomalies to human circadian rhythm for which a clear answer is not yet available. Two unique features of the human circadian system are (1) an internal tendency toward “desynchronization,” in which core body temperature has a cycle of about 25 hours, and (2) a sleep-waking cycle of about 30 hours.(Yamanaka, Honma et al. 2009) While it is now known that exposure to bright light appears to re-synchronize the body to the planetary 24-hour cycle,(Yamanaka, Honma et al. 2009) it is not yet clear why the body’s day/night clock is longer than the duration of one day.

A comparison to simpler organisms is also curious: hu- man beings experience drastic disturbances to our biological clocks with sudden shifts in our daily schedules, leading to sleep disorders, mood disorders, and impaired performance. Honey- bees, on the other hand, do not have this liability and are able to very quickly adjust their own physiological rhythms when they are subjected to drastic changes in their work schedules. It is the complex and highly interactive social environment of the honeybees that help them in making these nimble adjustments. (Shemesh, Eban-Rothschild et al. 2010) Perhaps this tendency for the human nervous system to drift toward desynchronization is the result of having a very well-developed brain; it is analogous to high-performance sports cars, where greater sophistication requires more frequent maintenance and tune-ups.

The Problem Doesn’t Start at Bedtime

One reason a person’s night can become disturbed is because their day is out of balance. If you can’t get to sleep, the problem didn’t begin just at that moment, but can have its roots much further back in time. In the physiology of the body, timing is a critical issue and a person’s misuse of time can lead to loss of coordina- tion between important body functions, a term called chrono- disruption. Whether this chrono-disruption, or “physiological bad timing,” is the result of poor sleep, or can itself cause sleep disorders, is not clear. However, both common sense and the following research data would suggest that conducting oneself contrary to one of nature’s most fundamental cycles of time, the diurnal rhythm (or daytime-nighttime cycles), is probably not a good idea.

The Role of Light

Light plays a key role in our sleep cycle, centered on critical light-receptive cells on the retina of the eye that help regulate not only circadian timing and neuroendocrine function, but also a person’s behavioral responses. When exposed to bright light, those photoreceptive cells stimulate parts of the brain that are not image-forming centers, but serve primarily as the body’s master biological clock. Furthermore, when the retinas are exposed to light much more dim than sunlight (as is most indoor lighting),

this light deficiency causes an information deficiency in the brain that sets in motion a chain-reaction of harmful side-effects in- cluding insomnia, depression, and impaired cognition.(Turner, van Someren et al. 2010) In other words, if you spend most of your daytime hours indoors, you may well be “light deficient.” This daytime light deficiency may be a common cause of night- time sleep disorders.

Recent research from the Institute of Medical Microbiology and Hygiene in Germany provides detailed insights that were first explained by 3rd Century BC medical texts from China: That circadian rhythm is controlled by both central control systems in the brain as well as local/regional cellular centers in other body tissues. For the immune system specifically, the effect of sleep deprivation can be to inhibit immune function by disrupting the circadian rhythms within immune system cells themselves, which in turn may be a long-term consequence of disturbances in hormonal cycles and circadian rhythms. These researchers also suggest that sleep, through the lowering of body temperature, “primes” the cells of the immune system and by doing so provides a timing signal for circadian clocks in the blood cell-producing bone marrow. It is chronic sleep disruption that desynchronizes these different time clocks, which in turn leads to dysregulation of the body’s immune responses.(Bollinger, Bollinger et al. 2010)

Sleep & Learning

One important function of sleep that is of interest to students is that it consolidates or reorganizes memory.(Kopasz, Loessl et al. 2010) Based on the results of three separate meta-analyses of 17 studies conducted by a team in the netherlands, successful learning and school performance are linked to sleep quality, sleep duration, and the absence of daytime sleepiness.(Dewald, Meijer et al. 2010) This means that in order to remember what you stud- ied during the day, you need to get a good night’s sleep at night. Renowned sleep researcher Matthew P. Walker at the University of California at Berkeley has also added important understand- ing to the relationship between sleep and learning; not only does sleep help the brain integrate individual bits of information into broader themes and patterns, it may fundamentally enhance the brain’s capacity for creativity. (Walker, 2009)

NON-REM & REM: THE TWO STATES OF SLEEP

Non-REM Sleep

This is the “deep” phase of sleep, which conserves energy, restores the central nervous system (CnS) or components of the CnS (such as the frontal cortex and glycogen stores), cools the body and the brain, and promotes immune function.(Dement and vaughan 2000)

REM Sleep

This is the more active “rapid-eye-movement” (REM) phase of sleep that helps the mind with psychological and/or emotional adaptation. By virtue of its stimulating effect, REM sleep also promotes development of the central nervous system and compensates for the deep brain stillness and brain cooling that happens during non-REM sleep. Furthermore, REM sleep facilitates periodic awakening to help a person survey their environment.(Dement and vaughan 2000)

SLEEP AND THE IMMUNE SYSTEM

When we get sick, we tend to feel tired and sleep more. But is this coincidental or is sleep a recuperative immune function? One study showed that infected rabbits that slept more had a better prognosis, suggesting that sleep might enhance recovery. But it’s unclear whether other factors, such as stress, might have been the cause of disrupted sleep in the rabbits that didn’t fare so well. (Dement and vaughan 2000)

In humans, there’s an increasing amount of research evi- dence that suggest that the right amount of sleep might prolong life; one study of 185 people aged 60 to 80 found that the quality of their sleep predicted the length of their remaining lifespan. (Dew, Hoch et al. 2003)

As more research is conducted on this subject, it is hoped that the exact nature of the relationship between sleep and the immune system’s role in controlling tumor growth can be ascertained.

GETTING A “GOOD” NIGHT’S SLEEP

What is the Definition of Good Sleep?

What constitutes “good” sleep is highly subjective, but most people would agree that an evening of high quality sleep is one in which you’re able to fall asleep quickly, stay asleep throughout the night, and wake up feeling refreshed. To achieve this sort of sleep, there are several approaches, from behavioral to pharmacological.

Good sleep can be defined in terms of sleep architecture – it is characterized by an optimal length of each sleep stage (which is age and gender specific), an appropriate distribution of sleep stages throughout the night, and a low frequency of arousal from sleep. Good sleep can also be defined in terms of general physi- ological activity; non-REM sleep, which constitutes approxi- mately 80% of sleep in a night (when optimal), is characterized by reduced physiological activity, such as reduced metabolism.

A person’s subjective assessment of their sleep quality and daytime functionality also define their “sleep health.” These tend to correlate well with objective performance estimates of daytime functioning.(Dement and vaughan 2000)

WHAT ARE THE DIFFERENT TYPES OF SLEEP DISORDERS?

Sleep Debt

Homeostasis in the human body dictates that for every two hours of wakefulness, we require one hour of sleep. If sleep cycles become disturbed, we end up “owing” hours of sleep and these hours are our “sleep debt.” Sleep debt is cumulative and carries over from one day to the next. The number of hours of sleep required per day varies with age and with individuals. On average, adults need to sleep eight hours per day, but this decreases with age.(neikrug and Ancoli- Israel 2009) Children and teens require ten hours per day on average.

Chronic Versus Acute Sleep Loss

While chronic sleep loss has been shown to be harmful to well-being, there is growing evidence that the occasional acute sleep disturbance might actually boost the immune system. (Rechtschaffen, Gilliland et al. 1983; Everson 1993; Landis and Whitney 1997)

In a study involving sleep-deprived rats, the animals’ ability to defend against infection was dependent on the length of their sleep deprivation. Evolutionarily, it may be that the immune sys- tem needs to be enhanced by brief total sleep loss, such as when being hunted by a predator. But without sleep, the immune sys- tem does eventually fail.(Dement and vaughan 2000)

WHAT CAUSES OR EXACERBATES POOR SLEEP?

In addition to the obvious causes of poor sleep that are a function of lifestyle and choice, there are many medical problems that can lead to poor sleep, some of which we review here.

Serotonin Dysfunction

A core part of brain function involves the compound serotonin, which is a neurotransmitter that is biochemically derived from the amino acid tryptophan and is critical to the transmission of nerve signals between neurons. The cells which produce this neurotransmitter, although few in number, are essential to the regulation of important brain functions including those that fol- low circadian rhythms: Sleep and waking, thinking, mood, appe- tite, sexual interest, body temperature, and behavioral regulation of aggression and impulse.(Jacob and Fornal 1995) Insufficient production of serotonin has widespread effects on the brain, play- ing a role in insomnia and mood disorders including depression, anxiety, and obsessive compulsive and bipolar disorders.(Davis, Charney et al. 2002)

Chronic Pain & Sleep

While people generally recognize that chronic pain can interfere with sleep,(Wells, Li et al. 2009) new research has shown that the effect goes in both directions, and that sleep disturbance con- tributes to increased pain levels.(Moldofsky 2010)

In people with cancer, there frequently occurs a combination of pain, fatigue, and sleep disturbance. A recent meta-analysis has provided evidence that these symptoms can all be improved by guided imagery/hypnosis and cognitive-behavioral therapy and coping-skills training, relaxation training, meditation training, and music.(Kwekkeboom, Cherwin et al. 2010)

Obstructive Sleep Apnea

In the Wisconsin Sleep Cohort study, which began over 20 years ago and monitors the sleep health of over 3000 people, re- searchers discovered that for every 10 persons, 1 to 2 suffer from untreated sleep apnea.(Young, Palta et al. 2009) Sleep apnea is a breathing problem in which a sleeping person frequently snores, often becoming louder until interrupted by a period of silence in which breathing stops and is then restarted after a loud gasping. This snoring returns often very frequently during the night. The problem stems from anatomical abnormalities in the back of the throat; usually, the body can compensate by the brain’s input to the muscles which dilate the upper airway, but those signals are suppressed during sleep, leading to the collapse of the airway in the throat.(Dempsey, veasey et al. 2010)

It has long been known that the frequent nighttime episodes of lower oxygen levels that result from this airway collapse are linked to sexual problems (erectile dysfunction), cardiovascular problems (heart disease, high cholesterol, stroke, and swelling in the legs), performance deficits (daytime drowsiness, waking up groggy, depression, hyperactivity, insomnia, memory problems, headaches, personality changes, cognitive impairment, and poor concentration), liver disease (liver inflammation and fibrosis), and to an increasingly more common health problem: diabetes. (Zias, Bezwada et al. 2009; Brondel, Romer et al. 2010; Drager, Jun et al. 2010; Eastwood, Malhotra et al. 2010; Tian, Zhang et al. 2010; Tsai 2010)

The relationship of sleep problems to diabetes has been much better understood with recent research. Compared with men, the odds that a woman with sleep apnea developing diabetes are 11 to 1, based on the results of a 16-year follow-up study. (Celen, Hedner et al. 2010) Furthermore, the type of sleep prob- lems a person has can predict their subsequent risk of developing diabetes: sleep of short duration (less than 5 to 6 hours per night), sleep of very long duration (over 8 to 9 hours per night), or dif- ficulty in getting to sleep or maintaining sleep all increase the risk of developing diabetes between 28% and 84% (nearly double). (Cappuccio, D’Elia et al. 2010)

While sleep apnea can sometimes be successfully treated by surgery,(Ye, Liu et al. 2009) there are no clearly established evidence-based guidelines for assessing suitability for surgery as based on a patient’s degree of airway obstruction and the likeli- hood of receiving surgery depends on the level of clinician expe- rience and resources available at individual hospitals.(Georgalas, Garas et al. 2010)

Although not widely used by sleep medicine centers, it has been known for the past 15 years by Japanese researchers that abnormal positioning of the jaw during sleep (too far to the back) can cause sleep apnea.(Masumi, nishigawa et al. 1996; Smith 1996) Continued research on this discovery in Japan, China, Italy, and the US has led to the development of small splints that can be inserted into the jaw, helping move the jaw forward and opening up the airway at the back of the throat to allow for better air passage during sleep. Besides improving sleep, this also helps correct the heart rate abnormalities caused by sleep apnea.(Smith 1996; villa, Bernkopf et al. 2002; Coru- zzi, Gualerzi et al. 2006; Arai, nakayama et al. 2007; Tsuda, Tsuda et al. 2007; Zeng and Gao 2009) Dentists who have special training can use an x-ray examination of the skull and jaw to identify whether or not a patient is likely to benefit from a splint(Monteith 2004) and can also provide special exercises that a patient can perform to improve jaw positioning.(Ueda, Almeida et al. 2009)

In people not helped by the splint or exercises, sleep apnea can still be successfully treated by a device called C-PAP, which blows air at a prescribed pressure through a mask worn during sleep, helping keep the airway open. Although awkward and unsexy, the devices can still be effective. A new oral device based on the splint, called OPAP, was tested at Stanford University for use in combination with C-PAP and recently received FDA approval (more information available at opaphealthcare.com).

Although overnight evaluation and treatment at clinical sleep centers can be helpful in treating obstructive sleep apnea, it is nevertheless a daunting (and expensive) process. Encour- agingly, researchers at the University of Saskatchewan this year published an excellent clinical study demonstrating that at-home diagnosis and treatment using a take-home device was just as good as that same procedure being done at a sleep center. This equivalence was demonstrated in terms of outcomes in sleepiness scores, sleep quality, quality of life, blood pressure, and compliance in the use of the CPAP device.(Skomro, Gjevre et al. 2010)

Hepatitis C

A wide range of other physical ailments can also cause sleep prob- lems. In hepatitis C, up to 60% of patients will experience newly diagnosed sleep problems, which is encouragingly reduced to 30% of patients who undergo treatment with interferon.(Socka- lingam, Abbey et al. 2010)

Cancer

It is known that anxiety and sleep problems can follow a cancer diagnosis.(Price, Zachariae et al. 2009; Savard, villa et al. 2009) It can also work in the other direction: sleep problems (and the resulting disturbances in day/night variations of melatonin levels in the blood) can predate diagnoses of breast and prostate cancer by many years. new research from Case Western Reserve University has found that sleeping less than 6 hours per night increases the risk of colon cancer by nearly 50%.(Thompson, Larkin et al. 2010) Additionally, in a large- scale survey of 363 people newly diagnosed with breast cancer, researchers found that compared to age-matched controls, those diagnosed were 40% more likely to have reported keep- ing lights on while sleeping, 40% more likely to sleep during the daytime, and 20% more likely to regularly close the win- dow shades while sleeping at night. These results, while not statistically significant, nevertheless suggest a plausible theory. (Li, Zheng et al. 2010)

Hospitals

As the intention in going to a hospital is usually to get better, it is ironic that the noise levels in most hospitals can interfere with pa- tients’ sleep, particularly in intensive care units.(xie, Kang et al. 2009) This is especially problematic in that poor sleep is associ- ated with poor intensive care unit medical outcomes.(Weinhouse, Schwab et al. 2009; Weinhouse and Watson 2009)

WHAT ARE THE CONSEQUENCES OF NOT SLEEPING WELL?

Your Own Safety and the Safety of Others

A curious anomaly in human performance is that people often overestimate their own abilities to perform critical tasks, such as driving. Most people also misjudge their level of sleepiness and amount of sleep debt and are usually wrong about how likely they will fall asleep in the near future, which leads people to think they’re alert enough to drive when they really aren’t. Unfortunately, sleepiness behind the wheel is a major cause of fatal crashes(Abe, Komada et al. 2010; Sagaspe, Taillard et al. 2010; valent, Di Bartolomeo et al. 2010; vennelle, Engleman et al. 2010) and people with sleep apnea are six times more likely to have traffic accidents than those people without this problem. (volna and Sonka 2006) And when you add alcohol to the mix, combining even a small amount of alcohol while you’re already tired is the functional equivalent of having a lot of alcohol when you’re well-rested.(Rodenstein 2009)

Medical Errors

Researchers at the Institute of Medicine, an independent federal research agency, recently published a comprehensive report in which they found that the frequency of serious medical errors goes up when medical residents are deprived of sleep. Medical residents are physicians who have graduated from medical schools, but are practicing medicine in a hospital or clinic under the supervision of fully licensed physicians. Almost all hospital stays involve being cared for by a medical resident at some point.

The problem involving medical errors centers around the difference between being awake and being competently alert. It is possible to use stress (adrenaline), exercise, and caffeine or other stimulant drugs to stay awake. It is not possible, however, to use these stimulants to overcome the damaging impact of sleep depri- vation on job performance and judgment.(Czeisler 2009) In this way, medical personnel being underslept leads directly to medical errors because of impaired skill and judgement.

This poses numerous ethical dilemmas for hospitals. Should hospitals limit physicians’ work hours to protect patient safety? Because sleep disorders increase substantially with age, should medical personnel be tested for suitability for long work shifts over the course of their careers?(Czeisler 2009)

Resident physicians at US hospitals are allowed to work for up to 30 hours in one shift. (Olson, Drage et al. 2009) Two-thirds of medical residents report that “sleep loss and fatigue have a major impact on my personal life” and nearly half report that “sleep loss and fatigue have a major impact on my work.”(Rosen, Gimotty et al. 2006) The number of medi- cal errors that can result from these working conditions are, not surprisingly, quite high. For example, in a survey of 254 internal medicine resident physicians, 41% reported that their own fatigue directly caused the most serious medical error they had made, and that a third of these errors led to the death of a patient.(Wu, Folkman et al. 1991)

Lurking beneath these issues of human performance are the financial incentives for hospitals, which depend on the profit mar- gin between payments they receive from Medicare or third party insurers and the low wages they pay to their resident physicians- in-training.

Emotional & Psychiatric Health

Mood disorders, anxiety, dementia, emotional instability, and the use of antidepressant medications, are all associated with sleep disorders. In many of these disorders, it is not yet known which came first: the sleep problem or the psychiatric problem.(Diekel- mann, Wilhelm et al. 2009; Sateia 2009; Teman, Tippmann- Peikert et al. 2009)

Lack of Sleep May Lead to Overeating

In a study published March 2010 in the American Journal of Clinical nutrition, researchers reported, “sleep restriction could be one of the environmental factors that contribute to the obe- sity epidemic.” They closely followed the eating, sleeping, exer- cise, and eating activities of 12 healthy young men during two 48-hour periods. The researchers first observed those men for a two-day “baseline” or control period. They then followed them closely for an active two-day study period. On the first day, the men in the study were asked to go to bed at 12 am and wake up at 8 am; on the second day, they went to bed at 2 am and woke up at 6 am. What the researchers found was that after sleeping only four hours, the men in the study ate an average of 22% (or over 500) more calories per day than they did after eight hours of sleep.

HOW TO SLEEP BETTER: UNDERSTANDING OUR NEEDS AND PATTERNS

The first step to better sleep is to determine your sleep needs and circadian pattern. This can be accomplished by keeping notes on the times when you are at peak alertness during the day. These peaks in alertness are ideal times for tackling your most challeng- ing tasks. During troughs in alertness are appropriate times for napping, resting, not driving, and other inconsequential tasks. Having then determined those optimal cycles, you can then make choices that help you lead a lifestyle that respects your body’s natural sleep patterns.

Treat sleep like exercise and diet. It is essential to pay atten- tion to it and manage it for the sake of health and longevity.

Sleep Clinics

A website sponsored by the American Academy of Sleep Medi- cine provides a list of sleep clinics. This site can be searched geo- graphically and is available at www.sleepcenters.org.

Music

A recent study from researchers in Taiwan found that people who listened to soft, slow music at bed time “experienced physical changes that aided restful sleep, such as lower heart and respira- tory rates.” Participants listened to 45-minute relaxing music tapes at bedtime for three weeks. The study found that this resulted in “significantly better sleep quality” and that “sleep improved weekly, indicating a cumulative dose effect.” (Lai and Good 2005)

Yoga

A recent study showed that participants who attended regular yoga sessions reported “significantly lower sleep disturbance” as com- pared to a control group. In this study, the benefits of yoga included better quality of sleep, the ability to fall asleep quicker, longer sleep duration, and less use of sleep medications. (Cohen 2004)

SLEEP HYGIENE TIPS

SLEEP ONLY WHEN SLEEPY

This reduces the time you’re awake in bed. If you can’t fall asleep within 20 minutes, get up and do something boring until you feel sleepy. Avoid bright light during this time.

DON’T TAKE NAPS

This will help make you tired at bedtime. If you must nap, sleep for less than an hour before 3pm.

GO TO BED ON TIME

Get up and go to bed the same time every day, even on weekends. It’s easier to sleep when you have a regular sleep cycle.

TIME YOUR EXERCISE

Regular exercise can help improve your sleep, but don’t do so too close to bedtime (at least 4 hours).

DEVELOP SLEEP RITUALS

It is important to give your body cues that it is time to sleep, such as listening to relaxing music, drinking herbal tea, or meditating.

ONLY USE YOUR BED FOR SLEEPING

Refrain from using your bed to watch TV, pay bills, do work, or read.

AVOID CAFFEINE, NICOTINE, AND ALCOHOL

Caffeine and nicotine are stimulants and alcohol can cause poor, fragmented sleep. Avoid them all for at least 4 hours

before bedtime.

HAVE A LIGHT SNACK BEFORE BED

Sleeping on too empty or too full a stomach can interfere with sleep, but eat your last heavy meal at least 3 hours before bedtime.

TAKE A HOT BATH

While a hot bath 90 minutes before bedtime will initially raise your body temperature, the subsequent drop in temperature afterwards may make you feel sleepy.

COOL YOUR ROOM

Sleeping in too hot an environment can be difficult. A cooler room, at a sleep-promoting 65 degrees with enough blankets to stay warm, is recommended.

KEEP THINGS DARK AND QUIET

Blackout shades or an eye mask can help block out light and earplugs or a white noise machine can help reduce noise.

RESET YOUR BIOLOGICAL CLOCK

As soon as you get up in the morning, go outside and turn your face to the sun for 15 minutes.

WHAT ABOUT WORKING NIGHT SHIFTS?

European researchers have done extensive research on the effect of shift-work (defined as work at times other than the normal 9 to 5 work schedule) and found that the people whose sleep is impacted most by their work hours are those who work nights and early-mornings as well as those who work slowly backward- rotating shifts (as compared to rapidly forward-rotating shifts). (Sallinen and Kecklund 2010)

PHARMACOLOGICAL APPROACHES

Melatonin

Melatonin was first isolated roughly 50 years ago(Lerner, Case et al. 1960) and is a chemical that has been functionally linked to the body’s regulation of circadian(Malpaux, Migaud et al. 2001; Malpaux, Tricoire et al. 2002) and seasonal rhythms,(Reiter 1993) immune function,(Guerrero and Reiter 2002) and tumor inhibition.(Blask, Dauchy et al. 2002; Blask, Sauer et al. 2002) Melatonin is not a hypnotic or soporific but rather seems to func- tion as a chemical that “opens the gate” to sleep, not something that induces sleep itself.(Kennaway and Wright 2002)

Melatonin production takes place in the brain and is mostly regulated by ambient light; only during darkness does the major- ity of melatonin production take place. The amount of melatonin an individual produces is also genetically determined, but age can also be a factor as people tend to produce less melatonin as they grow older.

Melatonin: Timing Is Everything

Researchers have revealed a substantial body of evidence on how melatonin influences sleep. That some of this information is conflicting suggests that the full story is not yet fully understood. Medicine is a work in progress and new research in the next few years should help fill in some of the gaps in knowledge on this important topic.

Melatonin has been shown to “open the gates” to sleep, so timing is very important depending on the desired effect.

IN GENERAL
Bright light exposure after darkness should be avoided since it disrupts the melatonin rhythm and alters the circadian clock. When used for night-time sleep pro- motion, melatonin is best taken 30 minutes before desired sleep onset.

WHEN TAKEN AT DUSK
Melatonin advances the internal clock, making you feel like it’s later than it really is.

WHEN TAKEN EARLY AT DAWN
Melatonin delays the internal clock, making you feel like it’s earlier than it really is.

TAKIN MELATONIN WHEN TRAVELING EAST
If you were traveling from san Francisco to Paris, take melatonin at dusk san Francisco time (which may be on the plane). Then take melatonin at dusk Paris time when you’ve arrived. a day or so before head- ing home, take melatonin at dusk Paris time and then, once home, at dusk san Francisco time.

TAKING MELATONIN WHEN TRAVELING WEST
If you were traveling from san Francisco to Beijing, take melatonin once you arrive at dusk Beijing time. Before you leave, take melatonin at dusk Beijing time and then, once home, at dusk san Francisco time. note: it has been suggested that westbound travel causes less jetlag. also, it has been suggested that melatonin is not very effective for westbound travel of less than four time zones.

Source: Reiter 2003

Tryptophan

Dietary tryptophan, which can cross the blood-brain barrier,(Young and Gauthier 1981) is a precursor to serotonin production in the brain. The levels of serotonin in the brain can be increased by up to two-fold with a dose of tryptophan of 3,000 mg,(Young and Gauthier 1981), which is an amount capable of improving mood and cognitive function, reducing anxiety, and helping to achieve better sleep. Tryptophan achieves this by increasing the release of melatonin. Melatonin helps facilitate restful sleep, shortening the time it takes to get to sleep, increas- ing average duration of sleep, and improving sleep quality.(Shell, Bullias et al. 2010; Silber and Schmitt 2010)

Although its reputation was marred by a single manufacturing malfunction that caused serious medical problems in a small group of people back in the mid-1990s, tryptophan is now back on the market and is backed by numerous studies supporting its benefits. Because it is a mild sedative, tryptophan, like other sleep medications, can reduce reaction time.(Silber and Schmitt 2010)

Post-thanksgiving Drowsiness: It’s how much you eat, not the turkey

While many people think it’s the tryptophan in turkey that makes people sleepy at Thanksgiving, the real culprit that leads to drowsiness may really just be the overeating that comes with this high- calorie meal. it’s been known for over 60 years that the tryptophan content of turkey is similar to both other meats in general and other poultry in particular.(greenhut, Potter et al. 1947)

Tryptophan is found in nearly all protein-based foods as well as many vegetables. it is abundant in dairy products (milk, yogurt, cottage cheese), sweets (chocolate, dried dates), grains (oats) and meats (red meat, eggs, fish, poultry), nuts and seeds (sesame, sunflower seeds, pumpkin seeds, and peanuts), and legumes (chickpeas, soybeans). among the foods with the highest amounts are eggwhites, atlantic cod, and spirulina.

Prescription Drugs

One of the fastest growing segments of the prescription drug market are sleep aids. These drugs are generally effective in making it easier to fall asleep, stay asleep, and increase total time asleep. There are, however, adverse affects, such as dependency, withdrawal, and tolerance. The World Health Organization broadly defines dependence as “the state of needing or depending on something or someone for support or to function or survive,” and as applied specifically to alcohol and other drugs, “a need for repeated doses of the drug to feel good or to avoid feeling bad.” Withdrawal symptoms are generally defined as those that start after a drug is discontinued or reduced (i.e. symptoms not present before treatment). Tolerance is defined as a decrease in a drug’s effect with continued administration, which results in the need to increase the dose of the drug.(World Health Organization 2010)

not all users of hypnotics become dependent, tolerant, or expe- rience withdrawal. There are various strategies, such as intermittent use, that can minimize adverse effects. It’s important to evaluate the potential benefits and risks with your doctor before beginning any prescription sleep drug program. However, because many sleep-aid drugs can cause side-effects, it’s worthwhile to improve sleep hygiene and work with other exercise, relaxation, or natural medicine ap- proaches before going the sleep medication route.

PUTTING IT ALL TOGETHER

Several key points emerge from our systematic review of the re- search on human sleep patterns:

» Sleep is essential to health. Optimal functioning of almost every body system requires sleep.

» The body needs to be re-synchronized on a daily basis through food, exercise, and face-to-face interaction with other peo- ple. Benjamin Franklin’s saying, “early to bed, early to rise…”, and what your grandmother told you about frequent exercise and regu- lar mealtimes are all true and supported by very recent research.

» Prescription medications, while helpful on an occasional or short-term basis, can have unwanted consequences that include the “rebound effect,” where sleep becomes worse after stopping the use of medication.

» Avoiding information overload is helpful, particularly in the evening.

» Helping the body get in the right mood for sleep is essen- tial, like an airplane taking the proper approach to landing.

» Sleep is a body function most people can’t consciously con- trol, but the way you treat yourself during the day can have a direct impact on whether your body can achieve good sleep at night.

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Becoming Your Own Advocate

When the Answer Isn’t So Clear: Interpreting the Results of Medical Research

Post author By PSFJA
Post date June 21, 2009
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There are few things in life that are black and white and medical research is certainly no exception. Being able to skillfully evaluate the authority, usefulness, and reliability of medical information is a crucial step towards making informed decisions in one’s own healthcare. While discerning what’s what and making sense of all the jargon can be intimidating, through this article, we will address some of the important issues surrounding medical research and to give you useful tools that will help you better review and draw conclusions from evidence-based literature. We’ll also describe some of the “red flags” to watch for.

A Daily Dilemma
We make thousands of decisions every day, big and small. In terms of medical diagnosis and treatment, these decisions can have profound implications for a patient’s future health and longevity: “Which treatment do I choose?”, “Do those test results mean I should change my treatment?” and “Is eating that bacon a bad idea?” While each of these decisions are often influenced by factual medical data, the way in which this information is interpreted and presented can often be unclear or misleading.

How information is reported: bad writing, bad reporting
Many people correctly perceive that the quantity of available medical information is overwhelming. Thus it’s often desirable to have a succinct summary of a medical report that gives the purpose, approach, and result of the study in question. The abstract (summary) section of a published research article fulfills this purpose and is the section that is most likely to be read. But up to a third of the abstracts of medical studies “contain data that were either inconsistent with corresponding data in the article’s body (including tables and figures) or not found in the body at all,” even in major medical journals. Reading the full text of a study can usually clear up these discrepancies, but often requires significant time and experience to read and interpret.

Who’s paying for the research?
It has long been known that trials funded by a drug manufacturer are often biased.(Barden, Derry et al. 2006) C. Seth Landerfield, a researcher from the University of California at San Francisco, found that among abstracts presented at a national medical society, industry support increased by 30-fold the odds that the result of a study would be favorable to the drug being researched.(Landefeld 2004)

Medical sensationalism
It should perhaps not come as a surprise that this financial bias is often not acknowledged by news media reporting on the results of clinical studies.(Hochman, Hochman et al. 2008) Media reports, perhaps in their zeal to grab attention with a great headline, often fail to mention important facts about studies on which they report. A review of 187 media reports found that 34% did not mention study size, 53% did not mention or were ambiguous about the study design, 40% did not quantify the main result, and only 29% mentioned the possibility of side effects.(Woloshin and Schwartz 2006) Given these problems in reporting the results of research, it’s often difficult to answer fundamental questions such as, “When is a number a correct number?” and “When is a number an important number?”

The bias effect of commercial funding extends even further, and can include the prescribing of medications. Much of the educational prescribing information being read by medical providers, and the lavish conferences where they learn about these medications, are also funded by major pharmaceutical manufacturers.(Rutledge, Crookes et al. 2003) Fortunately, efforts are underway to avoid commercial funding bias in the way drug information is presented to medical students.(McMahon, Neubauer et al. 2003) For example, both researchers and the World Health Organization have begun to issue calls for the establishment of independent grant-making institutes for funding pharmaceutical research.(Hardon 2003)

Math and medical literacy
All too often, one hears the phrase “I’m not good at math.” Nevertheless, medical writing is also a type of writing, and should follow basic principles of clarity and common sense. A well-written medical article is well-presented and clear to understand because the authors avoid using too much technical jargon.

A considerable amount of research has been published that focuses not only on how research should ideally be presented, but also on how well readers actually understand what they’re reading (this is especially important among those who should know how to read research, such as practicing clinicians). Whether patient or doctor, the issue of math illiteracy is unfortunately very common and can significantly undermine the process of informed decision making.(Gaissmaier and Gigerenzer 2008) The results of a medical study on treatment effectiveness, for example, are apparently much better understood when the results are presented as frequencies (e.g. “4 out of 5 people”) rather than as probabilities (e.g. “80%”). Although the difference might seem trivial or obvious, the way research is presented is important and can be an example of “when framing influences judgement.”(Gigerenzer 2003)

Closely related to math literacy is fundamental medical literacy. There is a substantial volume of information involved in any domain of medical care, and patients diagnosed with rare medical conditions often find themselves knowing more about their conditions than some of the medical providers with whom they consult. This is understandable, as who would be more motivated than the person diagnosed with the medical problem in question? This has been confirmed by researchers conducting a study on basic medical knowledge, who examined a concept they called the “minimum medical knowledge” needed to understand typical signs and/or risk factors of common medical problems such as heart attack, stroke, chronic obstructive pulmonary disease, and HIV/AIDS. They found that people with a university degree, some medical background, or personal illness experience had only a moderately higher “minimum medical knowledge” than those without these advantages. Among other things, this suggests that no one person can possibly have all the answers, and should have the effect of encouraging patients in a medical consultation to ask questions about their diagnosis and treatment.

Am I like those people?
When considering the results of a medical study, it is important to ask questions about whom the study included as volunteers. Clinical trials often select a very narrow group of volunteers to participate; quite often the age, gender, or other important criteria of clinical trial volunteers are not representative of the general population, nor of a specific individual considering a healthcare decision that may require information based on research.

In a strident call for equality in research, Dr. Somnath Saha, a researcher at the Portland VA Medical Center, has pointed out “a historical bias favoring white men.” As with most other institutions in the United States, medical research no longer actively excludes women and minorities. But the history of these institutions, the way they were designed and built – predominantly by and for white men – slants them in a way that continues to limit access for other groups.”(Saha 2009) Dr. Saha is careful to point out that “the distrust of research is usually applied to the research enterprise – the people and institutions carrying out research – not to the concept of research per se.” People want the results of research, but they expect it to be conducted in a rational and sensible way.

Simple tools for presenting information clearly
With the vast sums of money being spent on medical research, it’s reasonable to expect that a considerable amount of time and effort would be spent making sure the results are clear and well-presented. Although this is not always the case, there is hope. For the past twenty years, Edward Tufte has been writing books advocating clear communication of information reporting, which include Visual Explanations, Envisioning Information, The Visual Display of Quantitative Information, and Data Analysis for Politics and Policy. These principles have slowly begun to contribute to improvements in the clarity with which results of medical research are presented.(De Amici, Klersy et al. 1997)

Another important contributor to clearer scientific literacy is Gerd Gigerenzer of the Max Planck Institute for Human Development in Germany, who has written numerous tutorials for researchers suggesting how to clearly present written information. One such paper, addressing the theme of how doctors can “improve the presentation of statistical information so that patients can make well informed decisions,” is available on our website.(Gigerenzer and Edwards 2003)

Why is this important?
In the context of a clinical visit, a process of shared decision-making often leads to higher satisfaction with the visit.(Mathieu, Barratt et al. 2007; Nagle, Gunn et al. 2008) In order for that process to be effective, beneficial, and truly shared, it’s important that the information being used is understandable by both patient and practitioner alike.(Hoffrage, Lindsey et al. 2000; Gigerenzer and Edwards 2003)

Guidelines for evaluating research results for yourself
In evaluating the quality and reliability of medical research, the ideal is information that is objective and unbiased, so that we know the pros and cons of a particular test or treatment will be clear. Medical studies are reported first in the primary scientific literature (conferences or journals) and second in the general media. Most people will typically hear of a study first in the general media. Here are some pointers for weighing that information:

» Is the article’s headline or writing presented in a sensationalized way that might serve to discount essential weaknesses or disadvantages of the study results?

» Does the article provide background information that is helpful in evaluating whether the new finding is relevant or important? For example, does the article address what’s already known about the topic and whether this new study represents progress or provides new cautions?

» Does the article being presented relate in some way to advertisers associated with the show, publication, or website? Is the article identified as an advertisement?

» Is the news presented in a balanced way that also highlights the new treatment’s side effects? Are alternate points of view presented in interviews with other researchers or clinicians?

When reading the original results of a study, for example in a medical journal, here are some additional guidelines to assess the usefulness of that information:

» What type of study is it: laboratory or cell culture, animal, or human? The results of laboratory and animal research do not always translate into success in treating people.

» Was the article presented at a meeting or published in a peer-reviewed medical journal? Although meeting results are more current, treatments reported at conferences have not yet been subjected to as much scrutiny as would be done in a journal. If results are posted on the investigator’s web site or in a company’s brochure, the same caution is justified.

» Who conducted the study? Although researchers at well-known universities or research groups are typically considered to be more objective than individuals without institutional affiliations, this is by no means always the case. Many questionable relationships between university-based research programs and their funding sources have been reported. These relationships are often difficult to assess or clearly understand.

» How was the study funded? Funding from government, independent grant agencies, or foundations that rely on a peer-reviewed selection process to critically evaluate and select studies to be funded are preferred. Ideally, commercial sponsorship of research will be disclosed in the publication.

» How large was the study? Of the people originally recruited, how many completed the trial? Results of small studies do not always accurately predict how well the treatment or test will perform in larger groups of people.

» Who were the people who volunteered for the study, in terms of age, sex, ethnic group, medical history, etc.? This is important in extrapolating the results to a specific person.

» Is this a new treatment being first reported or has the approach been tested by other researchers as well? Results that are validated by repeat trials tend to be more reliable.

» In drug trials, were side effects mentioned and, if so, how do potential side effects compare to the potential benefits?

Other useful study details to consider
Components of study design that help research conform to these parameters include randomization and blinding. Typically, randomized trials will provide more reliable results. When participants are randomized to control groups (measuring the known medication or procedure) and treatment groups (comparing the know medication or procedure to either a new medication, a new procedure, an herbal formula, etc.), we are assured of a selection process that is not resulting from an individual’s or an institution’s biases. Similarly, when study volunteers (a “Single Blinded” study) or both the volunteers and the researchers themselves (“Double Blinded”) don’t know which group participants are assigned to, this further helps avoid bias and typically produces more useful results.

Some other types of studies you may be reviewing include cross-sectional studies, which take place at a single point in time (such as estimating how many people in the city of Seattle currently have ovarian cancer), versus a longitudinal study, which involves a series of measurements taken over a long period of time (such as following a group of smokers for 10 years to see who develops cancer). Cross-sectional studies examine the relationship between different variables at a fixed point in time. However, since exposure and disease status are measured at the same point in time, it may not always be possible to distinguish whether the exposure preceded or followed the disease. A “cohort study,” where a group is identified before the appearance of the disease that is under investigation, is often undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease. Results that are obtained from long-term cohort studies are considered to be higher quality studies than retrospective or cross-sectional studies.

Summary
As with any human endeavor, there is a wide range of quality and validity in the arena of medical research. Fortunately, in evaluating research results, the principles of what constitutes good research are easily accessible. We hope that the guidelines and perspectives raised in this article will be helpful to you in considering the veracity and relevance of medical information to your particular question.

References
Barden, J., S. Derry, et al. (2006). “Bias from industry trial funding? A framework, a suggested approach, and a negative result.” Pain 121(3): 207-18.

De Amici, D., C. Klersy, et al. (1997). “Graphic data representation in anaesthesiological journals: a proposed methodology for assessment of appropriateness.” Anaesth Intensive Care 25(6): 659-64.

Gaissmaier, W. and G. Gigerenzer (2008). “Statistical illiteracy undermines informed shared decision making.” Z Evid Fortbild Qual Gesundhwes 102(7): 411-3.

Gigerenzer, G. (2003). “Why does framing influence judgment?” J Gen Intern Med 18(11): 960-1.

Gigerenzer, G. and A. Edwards (2003). “Simple tools for understanding risks: from innumeracy to insight.” Bmj 327(7417): 741-4.

Hardon, A. (2003). “New WHO leader should aim for equity and confront undue commercial influences.” Lancet 361(9351): 6.

Hochman, M., S. Hochman, et al. (2008). “News media coverage of medication research: reporting pharmaceutical company funding and use of generic medication names.” Jama 300(13): 1544-50.

Hoffrage, U., S. Lindsey, et al. (2000). “Medicine. Communicating statistical information.” Science 290(5500): 2261-2.

Landefeld, C. S. (2004). “Commercial support and bias in pharmaceutical research.” Am J Med 117(11): 876-8.

Mathieu, E., A. Barratt, et al. (2007). “Informed choice in mammography screening: a randomized trial of a decision aid for 70-year-old women.” Arch Intern Med 167(19): 2039-46.

McMahon, B. J., R. Neubauer, et al. (2003). “Developing and implementing a program of grand rounds for internists that is free of commercial bias.” Ann Intern Med 139(1): 77-8.

Nagle, C., J. Gunn, et al. (2008). “Use of a decision aid for prenatal testing of fetal abnormalities to improve women’s informed decision making: a cluster randomised controlled trial [ISRCTN22532458].” Bjog 115(3): 339-47.

Pitkin, R. M., M. A. Branagan, et al. (1999). “Accuracy of data in abstracts of published research articles.” Jama 281(12): 1110-1.

Rutledge, P., D. Crookes, et al. (2003). “Do doctors rely on pharmaceutical industry funding to attend conferences and do they perceive that this creates a bias in their drug selection? Results from a questionnaire survey.” Pharmacoepidemiol Drug Saf 12(8): 663-7.

Saha, S. (2009). “Rectifying institutional bias in medical research.” Arch Pediatr Adolesc Med 163(2): 181-2.

Woloshin, S. and L. M. Schwartz (2006). “Media reporting on research presented at scientific meetings: more caution needed.” Med J Aust 184(11): 576-80.

Becoming Your Own Advocate

Simple Tools For Understanding Risks: From Innumeracy to Insight

Post author By PSFJA
Post date June 15, 2009
No Comments on Simple Tools For Understanding Risks: From Innumeracy to Insight

Bad presentation of medical statistics such as the risks associated with a particular intervention can lead to patients making poor decisions on treatment. Particularly confusing are single event probabilities, conditional probabilities (such as sensitivity and specificity), and relative risks. How can doctors improve the presentation of statistical information so that patients can make well informed decisions?

Becoming Your Own Advocate Chemotherapy & Antioxidants Featured

Lymphoma, Chemotherapy, & Antioxidants

Post author By PSFMM
Post date May 12, 2009
No Comments on Lymphoma, Chemotherapy, & Antioxidants

INTRODUCTION
Oxidative stress is defined as a type of physiological stress on the body caused by the damage done by free radicals inadequately neutralized by antioxidants. It has long been known that oxidative stress is an essential mechanism by which chemotherapy works to treat cancer. However, the question of whether this is always the case is seldom debated openly. Taking a deeper look into the research literature yields many examples where oxidative stress on cancer cells has been shown to be counterproductive. For example, a study using human Burkitt lymphoma cells found that oxidative stress actually interferes with the ability of the chemotherapy drugs doxorubicin, cisplatin, etoposide, and cytarabine to cause cancer cell death.

When oxidative stress levels are reduced in cancer cells, their growth is more easily controlled through a process called apoptosis. During apoptosis, cells are removed by the immune system before they lose their cell wall, thus avoiding an inflammatory response to the dying cells.
However, when oxidative stress levels go up, cancer cell death happens through a slower, messier, and less effective pathway called pyknosis or necrosis. Additionally, the ability of the body to “clean up” the resulting cellular debris from cancer cell death is also inhibited by oxidative stress. The body’s house-cleaning cells (called monocyte-derived macrophages) cannot function optimally under conditions of oxidative stress (i.e. low oxygen levels).

The authors of the above-mentioned study on Burkitt lymphoma cells and chemotherapy suggest that including antioxidants in the treatment protocol may enhance chemotherapy-induced apoptosis and phagocytosis. (Shacter, Williams et al. 2000) A second study, involving the chemotherapy drugs etoposide and calcimycin, confirms this finding: Human Burkitt’s lymphoma cells were unable to die quickly by apoptosis in the presence of oxidative stress and instead died using the slower and messier method of necrosis. In this study, it was found that oxidative stress inhibited apoptosis by depleting cells of their energy source, which is called adenosine triphosphate (ATP). (Lee and Shacter 1999)

Related to these observations about the relationship between cellular oxidative stress levels is the widely held view in medicine that the use of antioxidant dietary supplements diminishes chemotherapy’s effectiveness. However, when one looks more closely at the existing published science on how antioxidants and chemotherapy combine, the true answer is not so definitive. Many research studies, encompassing cell culture tests in the laboratory and also animal and some human studies, are coming to a conclusion often very different from the conventional perspective that chemotherapy and antioxidants should never be combined.

One example is a human study in which researchers discovered that higher levels of the antioxidant selenium in the blood of patients with aggressive B-cell non-Hodgkin’s lymphoma correlated with increased achievable doses of anthracycline based chemotherapy, better treatment response, achievement of long term remission, and longer overall survival. It is important to note that in this study, however, the level of selenium present in the blood of patients was from their diet; the study was not a test of supplemented selenium. (Last, Cornelius et al. 2003) As seen in this study, higher levels of natural antioxidants can help treatment outcomes.

On the other hand, the decreased levels of antioxidants (or oxidative stress) that are caused by many chemotherapy treatments correlates with increased side effects. In patients with Hodgkin’s lymphoma, chemotherapy with Adriamycin, bleomycin, vincristine, and dexamethasone significantly decreases antioxidant levels. (Kaya, Keskin et al. 2005) In children with acute lymphoblastic leukemia who received high-dose methotrexate, oxidative damage to proteins as well as other factors was related to toxic side effects. (Carmine, Evans et al. 1995)

Using antioxidants during chemotherapy is an important and controversial question among health care providers, patients, and their support teams. In previous issues of Avenues, we have researched this subject thoroughly for prostate, breast, lung, colon, and ovarian cancers. In this article, we turn our focus to lymphoma, conducting a systematic search for published research that would support or discourage the use of antioxidants in combination with chemotherapy. The overwhelming majority of studies find a favorable interaction between antioxidants and chemotherapy, providing evidence that antioxidants can decrease chemotherapy side effects, increase treatment effectiveness, and decrease resistance to chemotherapy.

For this paper, we searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities around the world. Some of these studies are still in early stages and include only laboratory or animal data while others have advanced to include human volunteers. We organized these data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. used cancer cell cultures), used animals, or involved human volunteers. As each antioxidant appears in the paper for the first time, we provide some introduction to the antioxidant including what food sources naturally contain it, other common applications in clinical use, and typical dosages. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

Bendamustine

CURCUMIN
Curcumin is a polyphenol and is an extract of the Indian curry spice plant turmeric. Curcumin is known for its anti-tumor, antioxidant, anti-amyloid, and anti-inflammatory properties. It also promotes healthy bile excretion and healthy platelet function.

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 2,000 mg daily. Take with meals, as curcumin can cause stomach upset when taken on an empty stomach. Bioavailability and potency are increased when combined with Bioperine, an extract from black pepper.

In non-Hodgkins lymphoma cells (not cell cultures, but rather cells taken directly from bone marrow of patients), curcumin increased bendamustine treatment effect, likely due to NF-KappaB inhibition by curcumin. (Alaikov, Konstantinov et al. 2007)

Cisplatin

TEMPOL & MNTBA
Tempol is an antioxidant drug that is used to prevent hair loss for cancer patients undergoing treatment. MnTBA is a synthetic antioxidant.

When combined with Tempol or MnTBA, cisplatin was found to induce cell death in human B lymphoma cells without any detectable oxidative stress. Furthermore, there was no inhibition of the ability of cisplatin to destroy cancer cells. (Senturker, Tschirret-Guth et al. 2002)

COMBINATIONS TO AVOID:
CISPLATIN WITH N-ACETYL CYSTEIN
In human B lymphoma cells, N-acetyl cysteine inhibited cisplatin induced cell death, but not because of interference with oxidative stress. (Senturker, Tschirret-Guth et al. 2002) N-acetyl cysteine is known to inactivate cisplatin and also decrease absorption of cisplatin into cancer cells cell. (Kroning, Lichtenstein et al. 2000)

Cyclophosphamide

METHYLSELENINIC ACID (MSA)
Methylseleninic Acid is an organic selenium compound, produced by the body’s metabolism of the mineral selenium found in foods. Brazil nuts are the single best food source of selenium. Selenium is as an antioxidant most widely known as a cancer preventive.

» Selenium (mineral): The US adult Tolerable Upper Intake Level (UL) is 400 micrograms a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 micrograms daily. There are several different forms of selenium. Se-Methylselenocysteine is a highly bioavailable form because it is not incorporated within a protein such as the form selenomethionine. We recommend getting selenium either in the organically bound forms, such as of Se-Methylselenocysteine, or a combination of selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione, and Se-methylselenocysteine.

MSA increased the chemotherapeutic effect of cyclophosphamide in human B-cell lymphoma cells. Cell lines were either sensitive or resistant to MSA. Treatment effect of cyclophosphamide was increased from 19% (cyclophosphamide alone) to 50% (cyclophosphamide with MSA) in sensitive cells and from 7% (alone) to 22% (with MSA) in resistant cells. (Juliger, Goenaga-Infante et al. 2007)

SULFOETHYL GLUCAN
Sulfoethyl-glucan is a beta-1,3-D-glucan derivative from the baker’s yeast Saccharomyces cerevisiae. Besides stimulating the immune system, it has high antioxidant and antimutagenic activity (reduces damage to DNA). (Krizkova, Durackova et al. 2003)

» Beta-1,3 D-glucan: Typical dosages range from 100 to 500 mg per day.

Sulfoethyl glucan derived from yeast polysaccharide enhanced the effect of cyclophosphamide in mice with lymphosarcoma both sensitive and resistant to chemotherapy. (Khalikova, Zhanaeva et al. 2005; G, M et al. 2008)

RETINOIDS & MELATONIN
Retinoids are vitamin A derivatives. Vitamin A (retinol) is a fat-soluble, antioxidant vitamin important for bone growth and vision. Vitamin A is ingested in a precursor form from animal foods and is especially plentiful in cod liver oil. Other good sources include butter and egg yolks as well as whole milk, cream, and yogurt.

» Vitamin A: Typical dosages range from 2500 IU to 25,000 IU.

Melatonin is a hormone that is released from the pineal gland in the evening and promotes normal sleep; its secretion diminishes significantly with age. It is known to help maintain cell health and many people take it to improve sleep. It is also known to reduce metastasis in cancer patients. In most published studies, melatonin shows a beneficial effect, although it has been reported that in a small proportion of people, melatonin can paradoxically cause sleep disturbance. In others, there can be residual daytime drowsiness, which is usually resolved by using a lower dose.

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3 to 7 days. The ideal is to achieve peak blood levels of melatonin at about 2 am. To do so, one can take the melatonin at bedtime, ideally between 9 pm and 10 pm.

Twenty patients with stage III or IV low-grade non-Hodgkin’s lymphomas received one month of treatment with cyclophosphamide, somatostatin, bromocriptine, retinoids, melatonin, and ACTH (Adrenocorticotropic hormone).

Somatostatin is a naturally occurring hormone (which may be given as a prescription drug) that inhibits the release of growth hormone (GH, somatotropin) and thyroid-stimulating hormone (TSH). Bromocriptine is a drug used in the treatment of pituitary tumors and Parkinson’s disease and is a dopamine agonist.

This treatment was continued if patients had stable or responding disease. After one month, 70% of patients had a partial response, 20% had stable disease, and 10% progressed during treatment. Of the 70% of patients who had a partial response, none had disease progression (average follow up time was 21 months) and 50% of these patients had a complete response. Of the 20% of patients who in the first month of treatment had stable disease, 25% had a partial response and 75% progressed on therapy. Toxicity was mild and included drowsiness, diarrhea, and hyperglycemia. (Todisco, Casaccia et al. 2001)

In a case report, a patient who experienced a relapse of high-grade non-Hodgkin lymphoma two years after autologous stem cell transplant was treated with cyclophosphamide, somatostatin, bromocriptine, retinoids, melatonin, and ACTH (Adrenocorticotropic hormone). Side effects were minimal and the patient was able to continue normal activities. After two months of treatment, the patient had a partial response and after five months, a complete response. At the time the case report was written, the patient was in complete remission 14 months after beginning treatment. (Todisco 2006)

In a second case report, a patient with stage IV low grade non-Hodgkin lymphoma was treated with cyclophosphamide, somatostatin, bromocriptine, retinoids, and melatonin. Side effects were minimal and the patient was able to continue normal activities. After two months of this treatment, he had a partial response and after five months a complete response. At the time of the case report, 18 months after beginning treatment, the patient was in complete remission. (Todisco 2007)

Doxorubicin

COENZYME Q10 (COQ10)
CoQ10 is naturally produced in the body and is necessary for the basic functioning of cells. CoQ10 is also found in dietary sources such as fish, meat, spinach, broccoli, peanuts, and whole grains. It is a vitamin-like substance that can also act as an antioxidant. Among other functions, it is incorporated into the mitochondria of cells throughout the body and facilitates and regulates the transformation of fats and sugars into energy. Patients with heart problems often use CoQ10.

» CoQ10: Dosages range from 15 mg to 600 mg per day.

Twenty children with acute lymphoblastic leukemia or non-Hodgkin lymphoma were treated with anthracycline chemotherapy (this family of drugs include doxorubicin and daunorubicin, among others). Heart related side effects are a major concern with anthracycline chemotherapy, so ten of these children also received CoQ10 to test the ability of CoQ10 to protect the heart. The children receiving CoQ10 experienced less cardiac effects than the children receiving no CoQ10. Percentage left ventricular fractional shortening decreased more in children not taking CoQ10. Interventricular septum wall thickness decreased only in children who did not take CoQ10 and abnormalities of the septum wall motion was similarly only detected in children not taking CoQ10. Overall this study found a protective effect of taking CoQ10 with anthracycline chemotherapy. (Iarussi, Auricchio et al. 1994)

METHYLSELENINIC ACID (MSA)
MSA increased the chemotherapeutic effect of doxorubicin in human B-cell lymphoma cells. Cell lines were either sensitive or resistant to MSA. Treatment effect of doxorubicin was increased from 21% (doxorubicin alone) to 49% (doxorubicin with MSA) in sensitive cells and from 8% (alone) to 44% (with MSA) in resistant cells. A 50% reduction of NF-kappaB activity was seen after exposure to MSA, perhaps one of the mechanisms by which MSA works synergistically with chemotherapy. (Juliger, Goenaga-Infante et al. 2007)

VITAMIN B6 (PYRIDOXINE)
Vitamin B6 comes from a variety of dietary sources, such as turkey, tuna, spinach, banana, lentils, and potatoes.

» Vitamin B6: Typical doses range between 10 mg and 200 mg per day. Individuals using more than 100 mg per day for more than two months should be supervised by a health care professional, as chronic overdose may lead to sensory neuropathy.

To test if vitamin B6 could help prevent palmar-plantar erythrodysesthesia (PPES) or hand-foot syndrome, an animal study (randomized, double-blinded clinical trial) included forty-one dogs with non-Hodgkin lymphoma that received Doxil chemotherapy. Doxil is a drug that is made by placing doxorubicin into a fat bubble called a liposome. The dogs were randomized to receive either oral vitamin B6 or placebo daily during Doxil chemotherapy (total of five Doxil treatments of 1 mg/kg i.v. every 3 weeks). Vitamin B6 did not completely prevent hand-foot syndrome in the dogs, however it decreased the risk of serious hand-foot syndrome and therefore prevented dose reduction or discontinuation of Doxil therapy. Dogs receiving vitamin B6 came close to the cumulative target dose of Doxil at a median dose of 4.7 mg/kg (compared to the target dose of 5 mg/kg). Dogs receiving placebo were only able to tolerate a median dose of 2.75 mg/kg. There was a trend toward longer remission length in the dogs receiving vitamin B6 likely because they were able to receive more Doxil without delays or discontinuation of treatment. (Vail, Chun et al. 1998)

Etoposide

N-ACETYL CYSTEINE, TEMPOL, & MNTBAP
N-acetyl cysteine is an efficiently absorbed and used form of the amino acid L-cysteine. L-cysteine, L-glutamic acid, and glycine are the three amino acids that form glutathione, which is one of the most important and powerful antioxidants in the body.

» N-acetyl cysteine: Typical dosages range between 600 mg and 1,800 mg per day.

Etoposide was found to induce cell death in human B lymphoma cells without any detectable oxidative stress. Furthermore, the antioxidants N-acetyl cysteine, Tempol, and MnTBAP did not inhibit Etoposide induced cell death. (Senturker, Tschirret-Guth et al. 2002)

GREEN TEA EXTRACT – EPIGALLOCATECHIN-3-GALLATE (EGCG)
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol (a group of antioxidants) found in green tea.

» EGCG: One cup of green tea contains between 10 mg and 400 mg of polyphenols depending on the source, amount of leaves used, and steeping time. EGCG may be conven2iently obtained from extracts. Among the green tea extract dietary supplement products, a desirable potency is standardized to 98% polyphenols, 45% of which is EGCG.

In a lymphoma cell line called B-lymphoblastoid Ramos, EGCG enhanced the chemotherapeutic effect of etoposide. (Noda, He et al. 2007)

METHYLSELENINIC ACID (MSA)
MSA increased the chemotherapeutic effect of etoposide in human B-cell lymphoma cells. Cell lines were either sensitive or resistant to MSA. Treatment effect of etoposide was increased from 32% (etoposide alone) to 60% (etoposide with MSA) in sensitive cells and from 4% (alone) to 22% (with MSA) in resistant cells. (Juliger, Goenaga-Infante et al. 2007)

Methotrexate

VITAMIN A
In a prospective randomized un-blinded clinical trial, vitamin A was given with high-dose-methotrexate to children with leukemia and lymphoma to see if vitamin A could protect against chemotherapy induced intestinal malabsorption. Thirty five children participated in the trial. Twenty-two patients received a single dose of 180,000 IU before methotrexate chemotherapy and thirteen patients received chemotherapy only. There was no difference in blood, skin, and organ toxicities. Intestinal absorption was significantly better in children receiving vitamin A. Absorption was decreased in only five of twenty-two (23%) children receiving vitamin A, compared to eight of thirteen (62%) children receiving chemotherapy only. Therefore, this study found some benefit to vitamin A treatment to prevent mucosal damage and therefore malabsorption in the intestines. (Dagdemir, Yildirim et al. 2004)

Rituximab

Rituximab is a newly-developed antibody therapy, not a traditional chemotherapy.

BETA-1,3 D-GLUCAN
Beta-1,3 D-glucan is derived from yeast and is a macrophage stimulator. Macrophages are an important part of the immune system.

» Beta-1,3 D-glucan: Typical dosages range from 100 mg to 500 mg per day.

In an animal study with mice, some of which had non-Hodgkin’s lymphoma and some Hodgkin’s lymphoma, the combination of rituximab and beta-1,3 D-glucan was significantly more effective than either rituximab or beta-glucan treatment alone. Mice with widespread lymphoma had significantly increased survival in the mice receiving the combination of rituximab and beta-glucan. No toxicity due to the combination was observed. (Modak, Koehne et al. 2005)

Cyclophosphamide, Vincristine, & Doxorubicin

L-CARNITINE
L-carnitine is an antioxidant that comes from protein-rich dietary sources such as red meat and dairy. L-carnitine helps convert fatty acids into energy; as a supplement, it is used among other things for increased energy, heart health, and age related memory loss (Acetyl-L-carnitine is preferred for memory). Although often used for weight loss, no clinical evidence has emerged that supports effectiveness for this application.

» L-carnitine: Typical doses range from 300 mg to 4000 mg. If using high doses, taking half the dose twice daily is beneficial.

In a clinical trial, L-carnitine was given to investigate if it could reduce cardiotoxicity from chemotherapy. Twenty patients received 3 g of L-carnitine intravenously before each chemotherapy cycle, followed by 1 g of L-carnitine orally per day for 21 days. Another twenty patients received placebo. Chemotherapy consisted of six CHOP cycles (cyclophosphamide 750 mg/m2 in 500 mL NaCl, vincristine 1.4 mg/m2, max. 2 mg absolute; doxorubicin 50 mg/m2 in 259 mL NaCl; days 2–5: prednisolone 100 mg p.o.). Cumulative doxorubicin doses of up to 600 mg/m2 were reached in this study. No cardiotoxicity occurred in either group. Survival, quality of life, and duration of remission was the same in both groups. Thus this study found no adverse effect of L-carnitine on effectiveness of chemotherapy. (Waldner, Laschan et al. 2006)

In a previous study, fifteen cancer patients receiving doxorubicin treatment had increased cardiac abnormalities with higher cumulative doses of doxorubicin. A trend towards lower serum carnitine levels was also observed with higher cumulative doses of doxorubicin, which was what led the study authors to consider investigating the role of carnitine in prevention of cardiac side effects. (Yaris, Ceviz et al. 2002)

GENISTEIN
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues. Isoflavones such as genistein also have anti-angiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

» Genistein: A good product will use organic non-GMO genistein. To achieve anti-tumor effects, the target daily dose, based on animal studies and calculations for similar human dosage, is 1,500 mg. The recommended dose for further research is between 100 mg and 1,100 mg. (Boik 2001) One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

In mice with large cell lymphoma, the CHOP chemotherapy regimen was given along with genistein (genistein was given for 5 days before CHOP). The combination of CHOP and genistein led to greater tumor growth inhibition than CHOP alone. The tumor growth was delayed 17 days in mice given the combination of genistein and CHOP and only 8 days in mice given CHOP alone. Genistein decreased NF-kappaB and increased the Bax/Bcl-2 ratio. (Mohammad, Al-Katib et al. 2003)

CONCLUSIONS
The 23 studies reviewed in this article provide compelling evidence suggesting that the question of chemotherapy in combination with antioxidants in the treatment of lymphoma deserves reconsideration, further discussion, and further research. We have reviewed cell culture, animal, and human clinical studies. It is important to note that 22 of these 23 studies identified either beneficial outcomes to combining antioxidants with chemotherapy or provided evidence dispelling the assumption that increased oxidative stress is required for chemotherapy to be effective. Although these studies are not conclusive, they nevertheless provide a basis for re-examining the long-held assumption that antioxidants are always contraindicated in the context of chemotherapy treatment for lymphoma.

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REFERENCES

Alaikov, T., S. M. Konstantinov, et al. (2007). “Antineoplastic and anticlastogenic properties of curcumin.” Ann N Y Acad Sci 1095: 355-70.

Carmine, T. C., P. Evans, et al. (1995). “Presence of iron catalytic for free radical reactions in patients undergoing chemotherapy: implications for therapeutic management.” Cancer Lett 94(2): 219-26.

Dagdemir, A., H. Yildirim, et al. (2004). “Does vitamin A prevent high-dose-methotrexate-induced D-xylose malabsorption in children with cancer?” Support Care Cancer 12(4): 263-7.

G, K., P. M, et al. (2008). “Yeast cell wall polysaccharides as antioxidants and antimutagens: Can they fight cancer?” Neoplasma 55(5): 387-93.

Iarussi, D., U. Auricchio, et al. (1994). “Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma.” Mol Aspects Med 15 Suppl: s207-12.

Juliger, S., H. Goenaga-Infante, et al. (2007). “Chemosensitization of B-cell lymphomas by methylseleninic acid involves nuclear factor-kappaB inhibition and the rapid generation of other selenium species.” Cancer Res 67(22): 10984-92.

Kaya, E., L. Keskin, et al. (2005). “Oxidant/antioxidant parameters and their relationship with chemotherapy in Hodgkin’s lymphoma.” J Int Med Res 33(6): 687-92.

Khalikova, T. A., S. Y. Zhanaeva, et al. (2005). “Regulation of activity of cathepsins B, L, and D in murine lymphosarcoma model at a combined treatment with cyclophosphamide and yeast polysaccharide.” Cancer Lett 223(1): 77-83.

Krizkova, L., Z. Durackova, et al. (2003). “Fungal beta-(1-3)-D-glucan derivatives exhibit high antioxidative and antimutagenic activity in vitro.” Anticancer Res 23(3B): 2751-6.

Kroning, R., A. K. Lichtenstein, et al. (2000). “Sulfur-containing amino acids decrease cisplatin cytotoxicity and uptake in renal tubule epithelial cell lines. ” Cancer Chemother Pharmacol 45(1): 43-9.

Last, K. W., V. Cornelius, et al. (2003). “Presentation serum selenium predicts for overall survival, dose delivery, and first treatment response in aggressive non-Hodgkin’s lymphoma.” J Clin Oncol 21(12): 2335-41.

Lee, Y. J. and E. Shacter (1999). “Oxidative stress inhibits apoptosis in human lymphoma cells.” J Biol Chem 274(28): 19792-8.

Modak, S., G. Koehne, et al. (2005). “Rituximab therapy of lymphoma is enhanced by orally administered (1–>3),(1–>4)-D-beta-glucan.” Leuk Res 29(6): 679-83.

Mohammad, R. M., A. Al-Katib, et al. (2003). “Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy.” Mol Cancer Ther 2(12): 1361-8.

Noda, C., J. He, et al. (2007). “Induction of apoptosis by epigallocatechin-3-gallate in human lymphoblastoid B cells.” Biochem Biophys Res Commun 362(4): 951-7.

Senturker, S., R. Tschirret-Guth, et al. (2002). “Induction of apoptosis by chemotherapeutic drugs without generation of reactive oxygen species.” Arch Biochem Biophys 397(2): 262-72.

Shacter, E., J. A. Williams, et al. (2000). “Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis.” Blood 96(1): 307-13.

Todisco, M. (2006). “Relapse of high-grade non-Hodgkin’s lymphoma after autologous stem cell transplantation: a case successfully treated with cyclophosphamide plus somatostatin, bromocriptine, melatonin, retinoids, and ACT H.” Am J Ther 13(6): 556-7.

Todisco, M. (2007). “Low-grade non-Hodgkin lymphoma at advanced stage: a case successfully treated with cyclophosphamide plus somatostatin, bromocriptine, retinoids, and melatonin.” Am J Ther 14(1): 113-5.

Todisco, M., P. Casaccia, et al. (2001). “Cyclophosphamide plus somatostatin, bromocriptin, retinoids, melatonin and ACT H in the treatment of low-grade non-Hodgkin’s lymphomas at advanced stage: results of a phase II trial.” Cancer Biother Radiopharm 16(2): 171-7.

Vail, D. M., R. Chun, et al. (1998). “Efficacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: a randomized, double-blind clinical trial using a canine model.” Clin Cancer Res 4(6): 1567-71.

Waldner, R., C. Laschan, et al. (2006). “Effects of doxorubicin-containing chemotherapy and a combination with L-carnitine on oxidative metabolism in patients with non-Hodgkin lymphoma.” J Cancer Res Clin Oncol 132(2): 121-8.

Yaris, N., N. Ceviz, et al. (2002). “Serum carnitine levels during the doxorubicin therapy. Its role in cardiotoxicity.” J Exp Clin Cancer Res 21(2): 165-70.

Tags Antioxidants, Becoming Your Own Advocate, Chemotherapy & Antioxidants, Lymphoma

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Cómo dormir bien: Para comprender la importancia del descanso y la salud optima

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Post date January 1, 2009
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Adaptado de: How to Sleep Well [Cómo dormir bien]

Durante los últimos 25 años, los estadounidenses han estado durmiendo cada vez menos. [1] Los resultados de encuestas realizadas por la Fundación Nacional del Sueño [Nacional Sleep Foundation] muestran que el 69% de los adultos responden que tienen problemas para dormirse por lo menos varias veces a la semana, si no más.

Becoming Your Own Advocate Chemotherapy & Antioxidants

Ovarian Cancer, Chemotherapy, & Antioxidants

Post author By PSFJA
Post date September 22, 2008
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INTRODUCTION

Oxidative stress is a condition in animal cells where increased free radicals are produced, or when the cell doesn’t have enough antioxidants. Oxidative stress happens in inflammation and infection, and can lead to cellular degeneration. Oxidative stress also helps cause many types of cancer, including ovarian cancer. One of the most important cancer journals, the Journal of National Cancer Institute, said that ovarian cancer is caused by inflammation. (Ness and Cottreau 1999) It is also now known that ovarian cancer patients have increased levels of oxidative stress and decreased levels of antioxidants, such as vitamins C and E, in comparison to healthy controls. (Senthil, Aranganathan et al. 2004)

Chemotherapy drugs used in the treatment of ovarian cancer work, in part, by inducing even higher levels of oxidative stress to attack cancer cells. This increased oxidative stress also causes chemotherapy related side effects. Oncologists have been concerned that antioxidants, which can decrease oxidative stress, can therefore also decrease chemotherapy treatment effectiveness or increase resistance to chemotherapy.

Using antioxidants during chemotherapy is an important and controversial question among health care providers, patients, and their support teams and we have previously researched this subject thoroughly for prostate, breast, lung, and colon cancers. In this article, we turn our focus to ovarian cancer and have searched for published research that would support or discourage the use of antioxidants in combination with chemotherapy. The overwhelming majority of studies find a favorable interaction between antioxidants and chemotherapy because antioxidants can decrease chemotherapy side effects, increase treatment effectiveness, and decrease resistance to chemotherapy.

No substantial clinical research has emerged to support the assertion that antioxidants are contraindicated during chemotherapy. The research that supports the concern about the use of antioxidants during chemotherapy treatment does not directly combine antioxidants and chemotherapy in human, animal, or cell culture studies. Rather, the studies that support this view simply show that ovarian cancer cells that are resistant to chemotherapy often have naturally higher levels of glutathione, which is one of the body’s most important and natural antioxidants. (Zeller, Fruhauf et al. 1991; Kudoh, Kita et al. 1994; Chen, Hutter et al. 1995; Parekh and Simpkins 1996; Akcay, Dincer et al. 2005; Das, Bacsi et al. 2006) Glutathione can facilitate the detoxification and excretion of many chemotherapy agents. (Akcay, Dincer et al. 2005; Das, Bacsi et al. 2006) Buthionine sulfoximine is a chemical that lowers glutathione levels and numerous studies also find that adding buthionine sulfoximine sensitizes ovarian cancer cells to chemotherapy drugs. (Zeller, Fruhauf et al. 1991; Kudoh, Kita et al. 1994; Parekh and Simpkins 1996; Sharp, Smith et al. 1998; Lewandowicz, Britt et al. 2002) Beyond the references provided here, many other studies have also explored this topic with similar findings.

5-Fluorouracil

LENTINAN

Lentinan is a polysaccharide derived from the edible Japanese shiitake mushroom (Lentinula edodes). It possesses immunostimulating antitumor properties.

» Shiitake mushroom extracts: Typical doses range from 100 to 400 mg per day.

A patient with recurrent ovarian cancer in the pelvis had a partial response to cisplatin and 5-fluorouracil. She then received an operation but the tumor could not be completely removed. Following the operation, cisplatin no longer produced any effect against the remaining tumor. She was then treated with lentinan (2 mg per week) and 5-fluorouracil. Four months after the start of this therapy, the tumor, which had become resistant to cisplatin, disappeared completely. At the time this case report was written in 1989, the patient had resumed normal activities and had been free of disease for six months, confirmed by physical exam, cytologic examination, CT, scintigraphy, and B scope. (Shimizu, Hasumi et al. 1989)

Cisplatin

ACETYL-L-CARNITINE

Acetyl-L-carnitine is an antioxidant that comes from dietary sources, such as dairy and meat. As a supplement, it is used for Alzheimer’s, age related memory loss, cognitive deficits, and neuropathies.

» Acetyl-L-carnitine: Typical doses range from 500 to 4000 mg. If using high doses, taking half the dose twice daily is beneficial.

In an animal study with rats, cisplatin or paclitaxel was combined with Acetyl-L-carnitine. Acetyl-L-carnitine significantly reduced toxicity to the nerves of both cisplatin and paclitaxel. In two different ovarian cancer cell lines, Acetyl-L-carnitine did not change the anti-tumor activity of cisplatin or paclitaxel. (Pisano, Pratesi et al. 2003)

CAFFEINE

Caffeine is one of the most consumed drugs in the world and sources include coffee, black tea, green tea, oolong tea, guarana, mate, and kola nut. Caffeine in combination with pain medication can be used in treating headaches.

» Caffeine: Typical doses range from 150 mg to 600 mg. Six ounces of drip coffee typically contains between 80 mg and 130 mg of caffeine. A double shot of espresso typically contains between 60 mg and 100 mg of caffeine.

Caffeine was found to significantly enhance cisplatin cytotoxicity in human ovarian cancer cells in two different laboratory studies. (Boike, Petru et al. 1990; Schiano, Sevin et al. 1991)

CURCUMIN

Curcumin is a polyphenol and is an extract of the Indian curry spice plant turmeric. Curcumin is known for its anti-tumor, antioxidant, anti-amyloid, and anti-inflammatory properties. It also promotes healthy bile excretion and healthy platelet function.

In two different ovarian cancer cell types, curcumin increased cisplatin effectiveness. Curcumin was effective when added at the same time as cisplatin, or 24 hours prior to cisplatin treatment. One of the ovarian cancer cell lines had a high level of IL-6 (a cytokine linked to cancer, poor prognosis, and cisplatin resistance). Curcumin inhibited the production of IL-6 in these cells. (Chan, Fong et al. 2003)

ETHYLENEDIAMINETETRAACETIC ACID (EDTA)

EDTA is a chelating agent that binds to metals and assists in their removal from the body.

» EDTA: The dose when used for lead poisoning is typically administered intravenously at 50 mg per kilogram of body weight to a maximum dose of 3 g diluted with 5% dextrose or 9% sodium chloride. Intravenously, EDTA commonly causes abdominal cramps, anorexia, nausea, vomiting, diarrhea, headache hypotension, exfoliative dermatitis, and a burning sensation and pain at the site of infusion. EDTA must be administered by a qualified health care practitioner.

When EDTA was combined with one of the chelatable elements, such as bismuth, calcium, cadmium, copper, iron, magnesium, selenium, vanadium, or zinc in cisplatin sensitive and resistant human ovarian cancer cells, together with the chemotherapy drug cisplatin, the treatment effect of cisplatin was enhanced as compared to cisplatin treatment alone. (Maier, Purser et al. 1997)

EGCG

Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea.

» EGCG: One cup of green tea contains between 10 mg and 400 mg of polyphenols depending on the source, amount of leaves used, and steeping time. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.

In ovarian cancer cells, EGCG increased cisplatin treatment effect. In three different types of ovarian cancer cells (SKOV3, CAOV3, and C200), EGCG increased the potency of cisplatin by three to six fold. (Chan, Soprano et al. 2006)

GENISTEIN

Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues. Isoflavones, such as genistein, also have anti-angiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

When genistein and daidzein were used in combination with cisplatin and topotecan in five different ovarian cancer cell lines, the treatment effect was enhanced. In combination with paclitaxel, genistein and daidzein did not interfere with the treatment, but also did not increase the effect of the treatment. (Gercel-Taylor, Feitelson et al. 2004)

GINSENOSIDE RH2 FROM PANAX GINSENG

Ginsenosides are active ingredients derived from ginseng, one of the most widely known herbal medicines in the world and commonly used for its immune stimulating and anti-tumor properties. (Boik 2001)

» White American Ginseng Extract: Commonly used dosage levels

of ginseng extract range between 200 mg and 1,000 mg.

In three animal studies, ginsenoside administered together with cisplatin significantly inhibited ovarian tumor growth and prolonged survival beyond that of cisplatin treatment given alone. Ginsenoside did not cause any side effects. (Kikuchi, Sasa et al. 1991; Tode, Kikuchi et al. 1992; Nakata, Kikuchi et al. 1998) One of these studies found that oral (but not intraperitoneal) treatment with Rh2 resulted in apoptosis in tumor cells and an increase in natural killer activity in spleen cells. (Nakata, Kikuchi et al. 1998)

GINGER

Ginger, also known as sheng jiang or gan jiang in Chinese, is a spice and dietary ingredient that can also be obtained as a supplement. It is often used for motion sickness and nausea.

» Ginger: Typical dosage levels of ginger range between 2 g to 4 g daily.

In a randomized controlled crossover study, researchers at the Gynecologic Oncology Unit of Bangkok Medical College investigated whether a daily dose of 1,000 mg of ginger could reduce vomiting in women with ovarian cancer receiving cisplatin chemotherapy. At the first cycle of chemotherapy, women were randomized to either ginger or placebo, in addition to standard anti-nausea medication. For the second cycle, women then crossed over to the other group, so the group which first received ginger then received placebo, and the group first on placebo switched to ginger. There was no reduction in either nausea or vomiting with ginger treatment, however there was less restlessness. (Manusirivithaya, Sripramote et al. 2004)

GLUTATHIONE

Glutathione is one of the most powerful and important natural antioxidants produced in the body.

» Glutathione: Typical dosage ranges between 50 mg and 600 mg daily. N-acetyl cysteine is the pre-cursor of glutathione and is more efficiently absorbed. When taking glutathione or N-acetyl cysteine, combine with three times as much vitamin C to prevent these amino acids from being oxidized in the body and to ensure their ability to act as antioxidants.

In a double-blind, randomized trial from England, 151 patients with ovarian cancer (stages I to IV) were given either cisplatin alone (100 mg per m2) or cisplatin combined with intravenous glutathione (3 g per m2). The researchers’ goal was to see whether the addition of glutathione could help patients complete the planned six cycles of cisplatin chemotherapy. They found that 58% of patients receiving additional glutathione completed six cycles of treatment, while only 39% of patients receiving cisplatin alone were able to complete all six cycles. Patients in the glutathione plus cisplatin group also had significantly less depression, vomiting, neuropathy, hair loss, shortness of breath, difficulty concentrating, and kidney side effects. They were also better able to continue their ordinary daytime activities. (Smyth, Bowman et al. 1997)

In a randomized controlled trial from Italy, 31 patients with recurrent ovarian cancer who had been in remission for at least one year were given either cisplatin alone (50 mg per m2) or cisplatin and glutathione (2.5 g). Researchers found that 56% of patients in the glutathione group were able to complete the full dose of chemotherapy, compared to only 27% in the cisplatin only group. The glutathione plus cisplatin group also experienced lower levels of neuropathy, without decreasing the anti-tumor activity. (Colombo, Bini et al. 1995)

In a prospective, randomized study, 33 women with recurrent ovarian cancer were given cisplatin alone or cisplatin combined with glutathione. The patients experienced minimal neurotoxicity with no reduction in treatment effectiveness by the addition of glutathione to cisplatin therapy. (Bogliun, Marzorati et al. 1992)

MELATONIN

In cisplatin-sensitive and resistant ovarian cancer cells, melatonin enhanced cisplatin treatment effectiveness. (Futagami, Sato et al. 2001)

PROTEIN-BOUND POLYSACCHARIDE-K (PSK)

Polysaccharide-K (PSK) is extracted from a mushroom called turkey tail. Other names include Trametes versicolor and Coriolus versicolor (Latin), yun zhi (Chinese), and kawaratake (Japanese). It is commonly used to boost immune health and often used with cancer patients.

» PSK: Typical doses for cancer patients range between 2 g and 6 g.

In human ovarian cancer cells, PSK was found to enhance the treatment effect of cisplatin in a laboratory study. (Kobayashi, Kariya et al. 1994)

QUERCETIN

Quercetin is a flavonoid found in capers, apples, tea, onions, red grapes, citrus fruits, leafy green vegetables, cherries, and raspberries. Quercetin has anti-inflammatory activity, inhibits allergic and inflammatory reactions, and has strong antioxidant activity.

» Quercetin: Typical dosages range from 200 mg to 1,200 mg daily.

Quercetin increased the treatment effect of cisplatin in ovarian cancer cells. (Scambia, Ranelletti et al. 1990) In another laboratory study, when quercetin and genistein were combined, their anticancer effect was greater than either antioxidant used alone. (Shen and Weber 1997)

RESVERATROL

Resveratrol is an antioxidant derived from the red pigment of grape skins.

» Resveratrol: Typical doses range from 25 mg to 250 mg per day.

Resveratrol in combination with either cisplatin or doxorubicin increased the treatment effect in ovarian and uterine cancer cells. In addition, resveratrol protected rats from doxorubicininduced heart toxicity. (Rezk, Balulad et al. 2006)

RUTIN AND HESPERIDIN

The flavonoid rutin can be obtained from sources such as buckwheat, the buds of the Chinese herb Sophora japonica, and propolis. Hesperidin is a flavonoid found in citrus fruits, such as lemons and oranges.

» Rutin: Typical doses range from 500 mg to 1,000 mg daily.

» Hesperidin: Typical doses range from 10 mg to 100 mg.

Rutin and hesperidin had no effect on ovarian cancer cells, either alone or in combination with cisplatin. (Scambia, Ranelletti et al. 1990)

SELENIUM

Selenium is an essential trace mineral found in variable amounts in food depending on the soil content of selenium. Brazil nuts are the single best food source of selenium. One of its roles in the body is as an antioxidant and it is most widely known as a cancer preventive.

Mice with ovarian tumors did not develop drug resistance to cisplatin treatment when they were also treated with selenite or selenomethionine. In contrast, when mice did not receive supplements, and only received cisplatin treatment, they quickly developed drug resistance. Selenite was found to enhance cisplatin treatment in ovarian tumors. Treatment with sulfite or methionine did not affect resistance to cisplatin. (Caffrey and Frenkel 2000; Frenkel and Caffrey 2001)

SILYBIN

Silybin (also called silibinin) is an important active compound found in silymarin, extracted from blessed milk thistle (Silybum marianum).

» Silymarin: Silibinin is the most biologically active constituent found in silymarin and isosilybin B complex is the most efficient constituent of silymarin in maintaining healthy cell division. Typical dosages range from 100 mg to 900 mg daily. An example of a good product is one containing 900 mg, standardized to 80% silymarin (720 mg), 30% silibinin (270 mg), and 4.5% isosilybin B complex (40.5 mg).

When silybin was used together with cisplatin in human ovarian cancer cells, there was a statistically significant increase in treatment effectiveness. In mice with ovarian cancer, tumor weight inhibition increased from 80% in mice treated with cisplatin alone to 90% in mice treated with a combination of silybin and cisplatin. Mice receiving a combination of silybin and cisplatin also recovered earlier in regards to weight loss compared to mice treated with cisplatin alone. Antiangiogenic (reduction in blood supply to the tumor) effect of silybin was also demonstrated. (Giacomelli, Gallo et al. 2002) In a second study, silybin was found to increase the effect of cisplatin in ovarian cancer cells resistant to cisplatin. (Scambia, De Vincenzo et al. 1996)

VITAMIN B3

Niacin (nicotinic acid) and niacinamide (nicotinamide) are two forms of vitamin B3. Dietary sources include poultry, fish, eggs, peanuts, brewers yeast, rice bran, wheat bran, legumes, mushrooms, and nuts.

» Vitamin B3: Typical doses can range between 100 mg and 1200 mg per day. Slow dose escalation is essential to acclimate the body to the “niacin flush.” Some people find that the niacinamide version does not cause flush.

In a laboratory study using cisplatin-resistant rat ovarian tumor cells, vitamin B3 significantly enhanced the treatment effect of cisplatin. However, this same treatment had no substantial effect on the cisplatin-sensitive rat ovarian tumor cells. In the live animal part of the same study, cisplatin given alone had no antitumor activity in the resistant tumor. When vitamin B3 was added, the survival time increased almost 50% in the group receiving both cisplatin and vitamin B3. (Chen and Zeller 1993)

VITAMIN E

Vitamin E includes several related compounds: Tocopherols and tocotrienols, each of which have four subtypes of alpha, beta, gamma, and delta. Previously, only alpha-tocopherol was considered important, however each type has unique contributions to health. The best dietary sources of vitamin E are considered to be unrefined, cold-pressed vegetable oils (such as wheat germ, sunflower seed, and olive oils) and raw or sprouted seeds, nuts, and grains.

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, including tocopherols and tocotrienols. Typical dosage ranges from 50 IU to 800 IU daily.

Researchers from Italy’s National Cancer Institute conducted a study in which they randomized 47 patients to receive either vitamin E (alpha-tocopherol, 300 mg per day) during cisplatin chemotherapy or cisplatin alone. Vitamin E was given orally before cisplatin chemotherapy and continued for three months after completion of treatment. Twenty-seven patients completed six cycles of cisplatin chemotherapy. The vitamin E plus cisplatin group had significantly less neurotoxicity compared to the chemotherapy alone group. Severity of neurotoxicity was also significantly lower. Addition of vitamin E also did not reduce anti-tumor effectiveness of cisplatin or longevity. (Pace, Savarese et al. 2003)

Carboplatin and Cisplatin

GLUTATHIONE

Researchers at the National Institute for the Study and Cure of Cancer in Milan, Italy published a study in which they tested whether glutathione can reduce side effects and increase effectiveness of high-dose carboplatin and cisplatin chemotherapy. In this study, fifty consecutive eligible patients with previously untreated stage III or IV ovarian cancer received two cycles of cisplatin and carboplatin chemotherapy, followed by surgery, and again two cycles of chemotherapy. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin treatment. The toxicity was moderate with lack of significant kidney toxicity. In this group of patients, median survival was 48 months, better than would have been expected if treating with chemotherapy alone. (Bohm, Oriana et al. 1999)

Cisplatin and Paclitaxel

VITAMIN E

Peripheral neuropathy, or damage to the nerves in the hands and feet, can be a painful and sometimes long-lasting side effect of chemotherapy treatment, making walking and handling objects with the hands more difficult. Paclitaxel and the family of platinum chemotherapy drugs are the most likely to cause this often debilitating problem. In a randomized controlled trial, researchers at the University of Patras Medical Center in Greece tested the ability of vitamin E at a daily dose of 600 mg (900 IU) to prevent neuropathy caused by six courses of cisplatin and/or paclitaxel. The sixteen patients in the treatment group received vitamin E during chemotherapy and continuing for three months after that treatment ended, while the fifteen patients in the control group received no vitamin E. The risk of developing peripheral neuropathy was reduced by 66% in the group receiving vitamin E. It is important to add that the research team also did a pre-clinical animal study, which showed that in mice, vitamin E did not interfere with the ability of cisplatin to suppress tumor growth or increase life span. (Argyriou, Chroni et al. 2005)

Cyclophosphamide

GINSENOSIDE RG 3

In an animal study using mice with ovarian cancer, ginsenoside Rg3 was used in combination with cyclophosphamide. Mice treated with this combination lived longer and tumor inhibition was higher than mice receiving chemotherapy alone. The combination of ginsenoside Rg3 and cyclophosphamide decreased blood supply to the tumor more than cyclophosphamide alone. Mice receiving ginsenoside Rg3 alone had even greater decrease in blood supply to the tumor than mice receiving chemotherapy alone or a combination of chemotherapy and ginsenoside Rg3. (Xu, Xin et al. 2007)

Cisplatin and Cyclophosphamide

SELENIUM, VITAMIN E, VITAMIN C, BETA-CAROTENE, RIBOFLAVIN, AND NIACIN

In a pilot clinical study, the dietary supplement Protecton Zellactiv (Smith Kline Beecham, Germany), which contains selenium (200 mcg daily), vitamin E, beta-carotene, riboflavin, niacin, and vitamin C was used together with chemotherapy. Researchers from Pomeranian Academy of Medicine in Poland investigated whether the Protecton Zellactiv could influence oxidative stress, glutathione levels, or reduce side effects in women with ovarian cancer receiving cisplatin and cyclophosphamide chemotherapy. Women using this dietary supplement experienced significantly less nausea, vomiting, diarrhea, mouth sores, hair loss, flatulence, abdominal pain, weakness, malaise, or loss of appetite. Researchers also found an increase in glutathione peroxidase, which may have helped protect those women against chemotherapy toxicity. (Sieja and Talerczyk 2004)

GLUTATHIONE

In a phase II study from Italy, researchers gave 20 women with stage III or IV ovarian cancer a combination of cisplatin (45 mg per m2), cyclophosphamide (900 mg per m2), and intravenous glutathione (2,500 mg). Of these women, 55% achieved a complete response. Median survival was 26.5 months. At 35 month followup, five patients were still alive. There was little toxicity in general, and no kidney toxicity. (Locatelli, D’Antona et al. 1993)

In a clinical study from Italy, 79 women with stage III or IV ovarian cancer were treated with up to five courses of high-dose cisplatin (40 mg per m2 daily in normal saline, for four days) plus glutathione (2,500 mg as a short-term infusion before cisplatin), together with cyclophosphamide (600 mg per m2 as an i.v. bolus on day four). Of these women, 57% achieved a complete response and 25% achieved a partial response. These benefits were seen with only minimal toxicity, with severe neuropathy side effects occurring in only 4% of these women. (Di Re, Bohm et al. 1993)

In study of high-dose cisplatin (160 mg per m2) and cyclophosphamide (600 mg per m2) plus glutathione, 32 women with ovarian cancer were examined for neurotoxicity. After five courses of chemotherapy, no cases of disabling neuropathy were observed. (Pirovano, Balzarini et al. 1992)

In a pilot study, twelve patients with localized or stage III ovarian cancer were treated with cisplatin (90 mg per m2, i.v. in 250 ml of normal saline over 30 minutes), cyclophosphamide (600 mg per m2 i.v.) every 3 weeks, and glutathione (5 g in 200 ml of normal saline) prior to cisplatin. No cases of kidney toxicity or neurotoxicity were seen. Nine of 11 evaluable patients with stage III ovarian cancer achieved complete remission. (Bohm, Battista Spatti et al. 1991)

Forty consecutive patients with stage III and IV ovarian carcinoma were treated with cisplatin (40 mg per m2 daily for four consecutive days), cyclophosphamide (600 mg per m2 on day four) and glutathione (1,500 mg per m2, which is roughly equivalent to 37.5 mg per kg, based on a conversion using median height of 175 cm and median weight of 80 kg). Glutathione was administered over 15 minutes before each cisplatin treatment. This treatment was given every three to four weeks for five courses providing no severe toxicity or progression occurred. Surgery was performed on 18 patients prior to chemotherapy. After two to three courses of chemotherapy, 16 other patients received surgery. Surgery could not be carried out in six patients. Three patients were not evaluable for response because they discontinued treatment. Twenty-three patients (62%) achieved complete clinical remission. The overall (complete plus partial) response rate was 86%. Two patients achieved disease free status after a second surgery. Patients experienced some nausea and vomiting. Myelosuppression (a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets) was acceptable. There was no renal impairment (likely because of the protective effect from glutathione). Neurotoxicity was the most significant cumulative toxicity, however it was not associated with motor dysfunction. It occurred in 24 out of 32 patients who received four to five courses. (Di Re, Bohm et al. 1990)

In a non-randomized study, 15 consecutive patients with ovarian cancer were treated with cisplatin and cyclophosphamide or the same regimen in combination with reduced glutathione (1,500 mg per m2, which is roughly equivalent to 37.5 mg per kg, based on a conversion using median height of 175 cm and median weight of 80 kg). Glutathione was administered prior to each chemotherapy treatment to seven patients. The efficacy of chemotherapy treatment was equal in both groups and therefore it was not reduced by glutathione pretreatment. Severity of myelosupression was reduced with glutathione. Two patients who received chemotherapy alone developed transient nephrotoxicity (toxicity to the nerves) while no patients receiving glutathione developed nephrotoxicity. (Oriana, Bohm et al. 1987)

Cisplatin and Hexamethylmelamine

VITAMIN B6 (PYRIDOXINE)

Vitamin B6 comes from a variety of dietary sources, such as turkey, tuna, spinach, banana, lentils, and potatoes.

» Vitamin B6: Typical doses range between 10 mg and 200 mg per day. Individuals using more than 100 mg per day for more than two months should be supervised by a health care professional as chronic overdose may lead to sensory neuropathy.

A randomized clinical trial included 248 patients with stage III to IV ovarian epithelial cancer. Of these, 114 patients had prior chemotherapy and 134 did not. They were randomized to one of four cisplatin and hexamethylmelamine regimens. Hexamethylmelamine was given at 200 mg per m2 orally on days 8 to 21 of each 21 day cycle. Cisplatin was given at two doses of 37.5 mg per m2 or 75 mg per m2. Half of the patients were randomized to also receive vitamin B6 at a dose of 300 mg per m2 (which is roughly equivalent to 7.5 mg per kg, based on a conversion using median height of 175 cm and median weight of 80 kg) orally on days 1 to 21. The overall response rate was 54% and 25% achieved a complete response. Patients receiving the higher dose of cisplatin had a greater response rate of 61%, while patients receiving lower doses had a response rate of 47%. The median response duration was 8.3 months. Response duration was shortened in the vitamin B6 group of patients and thus had an unfavorable effect on treatment effectiveness. Patients treated with higher dose cisplatin had more nausea and vomiting as well as increased neurotoxicity. Vitamin B6 significantly reduced neurotoxicity.

Doxorubicin

7-MONOHYDROXYETHLRUTOSIDE (MONOHER)

Flavonoids are beneficial antioxidants found in fruits and vegetables, especially red grape juice, green tea, soy, and many other legumes. One potential useful example of a beneficial flavonoid is monoHER, one of the most powerfully active antioxidants in flavonoid products, such as Venoruton, which is used to treat varicose veins. (van Acker and Boven, 1997) MonoHER is a derivative of the flavonoid rutin, obtained from many sources, such as buckwheat and the buds of the Chinese herb Saphora japonica. It is also found in propolis.

» Rutin: Typical dosages range from 500 mg to 1,000 mg daily.

The flavonoid monohydroxyethylrutoside (monoHER) prevented heart cell damage from doxorubicin by 15 fold. However, monoHER may also protect ovarian cancer cells from being effectively treated by doxorubicin. Specifically, monoHER reduced doxorubicin effectiveness in one type of ovarian cancer cell culture (A2780) and did not interfere with doxorubicin treatment in another ovarian cancer cell line (OVCAR-3). In practical terms, this means that monoHER used at high concentrations as demonstrated in this study has the potential to decrease the effectiveness of doxorubicin treatment. The authors of this study note that lower concentrations of monoHER, which are more realistic in clinical use, do not influenced the antitumor activity of doxorubicin. (Bruynzeel, Abou El Hassan et al. 2007)

In a combined laboratory and animal study, monoHER protected mice against doxorubicin-induced cardiotoxicity. Furthermore, monoHER did not interfere with the treatment effect of doxorubicin in human ovarian cancer cells or in mice with ovarian cancer. (van Acker, Boven et al. 1997)

TOPICAL 99% DIMETHYL SULFOXIDE (DMSO)

Dimethyl sulfoxide (DMSO) is a natural substance derived from wood pulp.

» Dimethyl sulfoxide (DMSO): This product is used topically in small amounts such as 1/8 teaspoon. Thorough cleaning of the skin prior to use is essential. Drying of the skin can occur. This should be a practitioner-guided approach.

Two patients with recurrent ovarian cancer receiving pegylated liposomal doxorubicin chemotherapy at the University of Arizona developed the painfully debilitating side effect called hand-foot syndrome, at the severe intensity level of grade 3. Their symptoms resolved over a period of one to three weeks while receiving topical 99% DMSO four times daily for 14 days. (Lopez, Wallace et al. 1999)

SPIRULINA

Spirulina is blue green algae that grows in tropical and subtropical alkaline waters with high-salt content. It is a rich source of dietary protein, B-vitamins, and iron.

» Spirulina: Typical doses range from 250 mg to 5 grams per day.

Spirulina did not interfere with the treatment effect of cisplatin in ovarian cancer cells. Additionally, spirulina protected rats from cisplatin-induced toxicity to the kidneys. The spirulina was given four days prior to chemotherapy treatment, on the day of chemotherapy, and four days after. (Mohan, Khan et al. 2006)

When mice were treated with spirulina (orally) along with doxorubicin, they were significantly protected from doxorubicininduced damage to the heart. They also had lower mortality: only 26% compared to 53% in mice treated with doxorubicin alone. In the laboratory portion of the study, spirulina did not reduce the anti-tumor activity of doxorubicin in ovarian cancer cells. (Khan, Shobha et al. 2005)

THEANINE

Theanine is an amino acid that is used for its anti-anxiety calming effects. Dietary sources include green tea as well as the edible Bay Bolete mushroom (Boletus badius).

» Theanine: Typical doses range from 50 mg to 200 mg per day.

In an animal study, mice with ovarian cancer were treated with either adriamycin alone or with adriamycin in combination with theanine. Adriamycin alone did not inhibit tumor growth. In contrast, when the same dose of adriamycin was used with theanine, tumor weight was reduced to 62% of the control level. When combined with theanine, the concentration of adriamycin in the tumor increased by 2.7 fold, however adriamycin concentrations in normal tissue decreased. (Sugiyama and Sadzuka 1998)

In a second animal study with mice with ovarian sarcoma, theanine was used in combination with doxorubicin. The combination enhanced reduction of metastasis to the liver. In the laboratory portion of the study, theanine increased the concentration of doxorubicin in ovarian cancer cells. (Sugiyama and Sadzuka 1999)

VITAMIN E

In 2004, a group of clinicians at New York’s Memorial Sloan-Kettering Cancer Center reported on the case of a women with ovarian cancer receiving the new chemotherapy drug pegylated liposomal doxorubicin in combination with vitamin E. This patient was experiencing significant vaginal irritation and burning, which began several days after her first round of chemotherapy. She was advised to avoid intercourse for three to five days after chemotherapy and to use both intravaginal vitamin E suppositories three times per week and vaginal estrogen tablets (initial course of 14 days followed by twice weekly usage), use of lubricants (Astroglide) during intercourse, and counseling. This combination approach allowed her to resume intercourse throughout the rest of her chemotherapy treatment. (Krychman, Carter et al. 2004)

Docetaxel

CURCUMIN

In mice with ovarian cancer, the combination of curcumin and docetaxel was more effective than docetaxel alone. Tumor mass was reduced by 66% compared to docetaxel therapy alone . In mice with ovarian cancer (which had developed resistance to docetaxel), treatment with docetaxel did not reduce tumor growth. Treatment with a combination of docetaxel and curcumin resulted in 58% tumor reduction. Docetaxel alone did not reduce angiogenesis, but when combined with curcumin, angiogenesis was reduced. Interestingly, curcumin alone had the strongest effect in reducing angiogenesis. This study found that one of the mechanisms by which curcumin controls cancer cell growth is by inhibition of NF-kappaB. (Lin, Kunnumakkara et al. 2007) Activation of NF-kappaB, a protein complex, is not favorable in cancer treatment as it leads to cellular events that promote inflammation, cell proliferation, angiogenesis, metastasis, and discourages cell death. NF-kappaB is associated with cancer risk, poor prognosis, and contributes to chemotherapy resistance. (Lee, Jeon et al. 2007; Sethi, Sung et al. 2008)

Irinotecan and Topotecan

GENISTEIN

In a cell culture study, genistein was used in combination with either irinotecan or topotecan. Genistein enhanced the treatment effect of these two chemotherapy drugs in ovarian as well as cervical cancer cells. (Papazisis, Kalemi et al. 2006)

Melphalan

SELENITE

In an animal study using mice with ovarian tumors, intraperitoneal injection of selenite (another form of selenium) prevented the development of resistance to melphalan as well as cisplatin. Selenite injection prevented increase in cellular glutathione. The method of selenite administration was important. When administered in drinking water or injected subcutaneously, selenite had little effect on the development of resistance. (Caffrey, Zhu et al. 1998) In a laboratory study by the same authors, Selenite was found to completely prevent ovarian cancer cell resistance to melphalan. (Caffrey, Zhu et al. 1998)

Forty patients with ovarian cancer had significantly lower selenium levels than matched control subjects. Higher stage of disease was associated with lower selenium levels. Patients with progressive disease had lower selenium levels than patients in remission. (Sundstrom, Yrjanheikki et al. 1984)

COMBINATIONS TO AVOID :

GLUTAMINE, LEUCINE, METHIONINE, AND TYROSINE

In human ovarian cancer cells, the amino acids glutamine, tyrosine, methionine, and leucine significantly reduced uptake of melphalan thereby decreasing effectiveness of treatment. (Vistica, Von Hoff et al. 1981; Dufour, Panasci et al. 1985)

Paclitaxel

COMBINATIONS TO AVOID: N-ACETYLCYSTEINE

In ovarian cancer cells, the antioxidant N-acetylcysteine decreased paclitaxel-induced cell death. (Goto, Takano et al. 2008)

Paclitaxel and Carboplatin

VITAMIN C, VITAMIN E, AND COENZYME Q10

Vitamin C, also called ascorbic acid, is a nutrient that humans cannot synthesize and must obtain from food. Almost all fresh vegetables and fruits are sources of vitamin C. Broccoli, cauliflower, citrus fruits, and tomatoes are examples of food sources particularly high in vitamin C.

» Vitamin C: Typical doses range from 60 mg to 1000 mg a day or up to bowel tolerance.

Coenzyme Q10 (CoQ10) is naturally synthesized in the body and is also available from food sources such as meat, poultry, fish, nuts, vegetables, fruits, and dairy. The amount of CoQ10 obtained from food is quite small compared to taking a supplement. The average intake of CoQ10 from food is less than 10 mg per day.

» Coenzyme Q10: Oil softgels have higher absorption. Typical daily doses of CoQ10 range from 30 mg to 300 mg and is best taken with food. About three weeks of daily dosing are necessary to reach maximal serum concentrations of CoQ10. Bioavailability is increased when combined with piperine. The most advanced version of CoQ10 is the more highly absorbable version called Ubiquinol.

Researchers in the Department of Obstetrics and Gynecology at University of Kansas Medical Center published a remarkable case report of two women with stage III-C ovarian cancer being treated with carboplatin and paclitaxel. The first woman began high-dose antioxidant therapy during her first round of chemotherapy, consisting of vitamin C, vitamin E, beta-carotene, CoQ10, a multivitamin/mineral complex, and intravenous vitamin C at a total dose of 60 g given twice weekly at the end of her carboplatin chemotherapy and prior to paclitaxel. Her CA-125 levels normalized after her first cycle of chemotherapy and remained normal at the time of publication, three and a half years after diagnosis. She also had no evidence of disease on CT scans of her abdomen and pelvis.

The second woman added antioxidants just prior to beginning chemotherapy, including vitamin C, beta-carotene, vitamin E, coenzyme Q10, and a multivitamin/mineral complex. At the completion of her six cycles of paclitaxel/carboplatinum chemotherapy, even though scans showed she still had remaining tumors, she refused further chemotherapy. She switched to intravenous ascorbic acid at 60 g twice weekly. Three years after diagnosis, she has normal CA-125 and no evidence of recurrent disease on physical exam. (Drisko, Chapman et al. 2003) Based on the successful treatment with these two patients, this team at the University of Kansas has initiated a non-randomized trial in which vitamin C is being combined with chemotherapy. For information, contact Jeanne Drisko, MD, at (913) 588-6104.

VITAMIN E AND VITAMIN A

Vitamin A (retinol) is a fat-soluble, antioxidant vitamin important for bone growth and vision. Vitamin A is ingested in a precursor form from animal foods and is especially plentiful in cod liver oil. Other good sources include butter and egg yolks as well as whole milk, cream, and yogurt.

» Vitamin A: Typical dosages range from 2500 IU to 25,000 IU.

The natural levels of antioxidants in the body in 28 ovarian and breast cancer patients were measured in a study to determine if decreased antioxidants correlate with toxicity from paclitaxel and carboplatin chemotherapy. The antioxidants that were measured were vitamin E (alpha-tocopherol) and vitamin A (retinol). Note that these antioxidants were not given as supplements, rather the natural level of these antioxidants was measured before and after chemotherapy and the amount varied among patients. There was a significant increase in vitamin E and vitamin A during chemotherapy treatment. Patients who experienced significant side effects from chemotherapy had low levels of vitamins A and E. Patients who had significantly higher levels of these vitamins during chemotherapy did not experience serious toxicity. (Melichar, Kalabova et al. 2007)

Antioxidants Used Alone

QUECETIN

In a phase I clinical trial of the flavonoid quercetin, researchers from Birmingham, UK gave quercetin by intravenous infusion at escalating doses at three week intervals, starting at 60 mg per m2 and increasing to 1,700 mg per m2 (which is roughly equivalent to 1.5 and 42 mg per kg respectively, based on a conversion using median height of 175 cm and median weight of 80 kg). At the highest dose, dose-limiting kidney toxicity occurred but there was no suppression of blood-cell production in the bone marrow. Overall, two of ten patients had kidney toxicity at the highest dose. The dose with the optimum ratio of effectiveness and safety was 945 mg per m2 (23.6 mg per kg) (eight at three week intervals and six at weekly intervals). From among these patients, one was a woman with ovarian cancer resistant to cisplatin. Following two courses of quercetin (420 mg per m2 or 10.5 mg per kg), the CA 125 had fallen from 295 to 55 units per ml. The researchers concluded that quercetin can be safely administered by intravenous bolus. They also saw inhibition of lymphocyte tyrosine kinase activity and evidence of antitumor activity. (Ferry, Smith et al. 1996)

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REFERENCES

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INTRODUCTION

5-Fluorouracil

LENTINAN

Lentinan is a polysaccharide derived from the edible Japanese shiitake mushroom (Lentinula edodes). It possesses immunostimulating antitumor properties.

» Shiitake mushroom extracts: Typical doses range from 100 to 400 mg per day.

Cisplatin

ACETYL-L-CARNITINE

» Acetyl-L-carnitine: Typical doses range from 500 to 4000 mg. If using high doses, taking half the dose twice daily is beneficial.

CAFFEINE

» Caffeine: Typical doses range from 150 mg to 600 mg. Six ounces of drip coffee typically contains between 80 mg and 130 mg of caffeine. A double shot of espresso typically contains between 60 mg and 100 mg of caffeine.

Caffeine was found to significantly enhance cisplatin cytotoxicity in human ovarian cancer cells in two different laboratory studies. (Boike, Petru et al. 1990; Schiano, Sevin et al. 1991)

CURCUMIN

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 2,000 mg daily. Take with meals, as curcumin can cause stomach upset when taken on an empty stomach. Bioavailability and potency are increased when combined with Bioperine, an extract from black pepper.

ETHYLENEDIAMINETETRAACETIC ACID (EDTA)

EDTA is a chelating agent that binds to metals and assists in their removal from the body.

» EDTA: The dose when used for lead poisoning is typically administered intravenously at 50 mg per kilogram of body weight to a maximum dose of 3 g diluted with 5% dextrose or 9% sodium chloride. Intravenously, EDTA commonly causes abdominal cramps, anorexia, nausea, vomiting, diarrhea, headache hypotension, exfoliative dermatitis, and a burning sensation and pain at the site of infusion. EDTA must be administered by a qualified health care practitioner.

EGCG

Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea.

» EGCG: One cup of green tea contains between 10 mg and 400 mg of polyphenols depending on the source, amount of leaves used, and steeping time. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.

GENISTEIN

» Genistein: A good product will use organic non-GMO genistein. To achieve anti-tumor effects, the target daily dose, based on animal studies and calculations for similar human dosage, is 1,500 mg. The recommended dose for further research is between 100 mg and 1,100 mg. (Boik 2001) One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

GINSENOSIDE RH2 FROM PANAX GINSENG

» White American Ginseng Extract: Commonly used dosage levels

of ginseng extract range between 200 mg and 1,000 mg.

GINGER

Ginger, also known as sheng jiang or gan jiang in Chinese, is a spice and dietary ingredient that can also be obtained as a supplement. It is often used for motion sickness and nausea.

» Ginger: Typical dosage levels of ginger range between 2 g to 4 g daily.

GLUTATHIONE

Glutathione is one of the most powerful and important natural antioxidants produced in the body.

» Glutathione: Typical dosage ranges between 50 mg and 600 mg daily. N-acetyl cysteine is the pre-cursor of glutathione and is more efficiently absorbed. When taking glutathione or N-acetyl cysteine, combine with three times as much vitamin C to prevent these amino acids from being oxidized in the body and to ensure their ability to act as antioxidants.

MELATONIN

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3 to 7 days. The ideal is to achieve peak blood levels of melatonin at about 2 am. To do so, one can take the melatonin at bedtime, ideally between 9 pm and 10 pm.

In cisplatin-sensitive and resistant ovarian cancer cells, melatonin enhanced cisplatin treatment effectiveness. (Futagami, Sato et al. 2001)

PROTEIN-BOUND POLYSACCHARIDE-K (PSK)

» PSK: Typical doses for cancer patients range between 2 g and 6 g.

In human ovarian cancer cells, PSK was found to enhance the treatment effect of cisplatin in a laboratory study. (Kobayashi, Kariya et al. 1994)

QUERCETIN

» Quercetin: Typical dosages range from 200 mg to 1,200 mg daily.

RESVERATROL

Resveratrol is an antioxidant derived from the red pigment of grape skins.

» Resveratrol: Typical doses range from 25 mg to 250 mg per day.

RUTIN AND HESPERIDIN

» Rutin: Typical doses range from 500 mg to 1,000 mg daily.

» Hesperidin: Typical doses range from 10 mg to 100 mg.

Rutin and hesperidin had no effect on ovarian cancer cells, either alone or in combination with cisplatin. (Scambia, Ranelletti et al. 1990)

SELENIUM

» Selenium (mineral): The US adult Tolerable Upper Intake Level (UL) is 400 micrograms a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 micrograms daily. There are several different forms of selenium. Se-Methylselenocysteine is a highly bioavailable form because it is not incorporated within a protein such as the form selenomethionine. We recommend getting selenium either in the organically bound forms, such as of Se-Methylselenocysteine, or a combination of selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione, and Se-methylselenocysteine.

SILYBIN

Silybin (also called silibinin) is an important active compound found in silymarin, extracted from blessed milk thistle (Silybum marianum).

» Silymarin: Silibinin is the most biologically active constituent found in silymarin and isosilybin B complex is the most efficient constituent of silymarin in maintaining healthy cell division. Typical dosages range from 100 mg to 900 mg daily. An example of a good product is one containing 900 mg, standardized to 80% silymarin (720 mg), 30% silibinin (270 mg), and 4.5% isosilybin B complex (40.5 mg).

VITAMIN B3

» Vitamin B3: Typical doses can range between 100 mg and 1200 mg per day. Slow dose escalation is essential to acclimate the body to the “niacin flush.” Some people find that the niacinamide version does not cause flush.

VITAMIN E

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, including tocopherols and tocotrienols. Typical dosage ranges from 50 IU to 800 IU daily.

Carboplatin and Cisplatin

GLUTATHIONE

Cisplatin and Paclitaxel

VITAMIN E

Cyclophosphamide

GINSENOSIDE RG 3

Cisplatin and Cyclophosphamide

SELENIUM, VITAMIN E, VITAMIN C, BETA-CAROTENE, RIBOFLAVIN, AND NIACIN

GLUTATHIONE

Cisplatin and Hexamethylmelamine

VITAMIN B6 (PYRIDOXINE)

Vitamin B6 comes from a variety of dietary sources, such as turkey, tuna, spinach, banana, lentils, and potatoes.

» Vitamin B6: Typical doses range between 10 mg and 200 mg per day. Individuals using more than 100 mg per day for more than two months should be supervised by a health care professional as chronic overdose may lead to sensory neuropathy.

Doxorubicin

7-MONOHYDROXYETHLRUTOSIDE (MONOHER)

» Rutin: Typical dosages range from 500 mg to 1,000 mg daily.

TOPICAL 99% DIMETHYL SULFOXIDE (DMSO)

Dimethyl sulfoxide (DMSO) is a natural substance derived from wood pulp.

» Dimethyl sulfoxide (DMSO): This product is used topically in small amounts such as 1/8 teaspoon. Thorough cleaning of the skin prior to use is essential. Drying of the skin can occur. This should be a practitioner-guided approach.

SPIRULINA

Spirulina is blue green algae that grows in tropical and subtropical alkaline waters with high-salt content. It is a rich source of dietary protein, B-vitamins, and iron.

» Spirulina: Typical doses range from 250 mg to 5 grams per day.

THEANINE

Theanine is an amino acid that is used for its anti-anxiety calming effects. Dietary sources include green tea as well as the edible Bay Bolete mushroom (Boletus badius).

» Theanine: Typical doses range from 50 mg to 200 mg per day.

VITAMIN E

Docetaxel

CURCUMIN

Irinotecan and Topotecan

GENISTEIN

Melphalan

SELENITE

COMBINATIONS TO AVOID :

GLUTAMINE, LEUCINE, METHIONINE, AND TYROSINE

Paclitaxel

COMBINATIONS TO AVOID: N-ACETYLCYSTEINE

In ovarian cancer cells, the antioxidant N-acetylcysteine decreased paclitaxel-induced cell death. (Goto, Takano et al. 2008)

Paclitaxel and Carboplatin

VITAMIN C, VITAMIN E, AND COENZYME Q10

» Vitamin C: Typical doses range from 60 mg to 1000 mg a day or up to bowel tolerance.

» Coenzyme Q10: Oil softgels have higher absorption. Typical daily doses of CoQ10 range from 30 mg to 300 mg and is best taken with food. About three weeks of daily dosing are necessary to reach maximal serum concentrations of CoQ10. Bioavailability is increased when combined with piperine. The most advanced version of CoQ10 is the more highly absorbable version called Ubiquinol.

VITAMIN E AND VITAMIN A

» Vitamin A: Typical dosages range from 2500 IU to 25,000 IU.

Antioxidants Used Alone

QUECETIN

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