Clinical Briefs with Comments from Russell H. Greenfield, MD
Clinical Briefs
With Comments from Russell H. Greenfield, MD. Dr. Greenfield is Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC; and Visiting Assistant Professor, University of Arizona, College of Medicine, Tucson, AZ.
Sweet Sleep Honey and Nighttime Cough
Source: Paul IM, et al. Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents. Arch Pediatr Adolesc Med. 2007;161:1140.
Goal: To compare the effects of a single nighttime dose of either buckwheat honey (BH) or dextromethorphan (DM) with no treatment (NT) for children with nighttime cough and sleep disturbances associated with uncomplicated upper respiratory tract infections (URIs).
Study Design: Prospective, partially double-blind clinical trial.
Subjects: Children (2-18 years) with viral URI and moderately disruptive nighttime cough for < 7 days' duration (n=131, with evaluable data on n=105) taken from a single university outpatient general pediatric practice.
Methods: Randomization occurred after stratification by age to assure proper dosing (ages 2-5, 6-11, and 12-18 years). Treatment consisted of either a single dose of honey-flavored DM (17 mg/5 cc and prepared by compounding pharmacist to approximate unique characteristics of BH, and in a dosage approximating typical recommendations by age) or a similar volume of BH given 30 minutes prior to bedtime with a non-caffeinated beverage. A survey was developed and completed by parents on the day of presentation and then the next day following treatment or NT by phone. Primary outcome measures included cough frequency and severity, and sleep quality for both children and parents.
Results: All outcomes measured as rated by parents favored the use of BH, followed by DM and NT. With respect to cough frequency, those receiving BH had a 1.89-point improvement compared with 1.39- and 0.92-point improvements for DM and NT, respectively, with similar findings for cough severity. Parents also rated their children's sleep, as well as their own, as better with BH. Only BH was superior to NT for combined nocturnal symptoms score associated with childhood URI, but direct comparison between BH and DM in this regard revealed no statistically significant difference. Mild adverse reactions (n=5) were more common with honey (combination of insomnia, hyperactivity and nervousness).
Conclusion: In this brief intervention trial, parents rated BH better than DM or NT for management of nocturnal cough associated with uncomplicated URI.
Study strengths: Use of trained study coordinators to administer surveys; compounding pharmacist prepared the DM.
Study weaknesses: Non-blinding of NT group; inability to guarantee compliance with protocol; subjective nature of survey.
Of note: These authors previously showed that neither DM nor diphenhydramine was better than placebo for children with URI, cough and disturbed sleep (part of the reason why a NT arm was employed rather than a placebo arm); cough is the primary complaint behind almost 3% of all US outpatient visits; the World Health Organization cites honey as a potential treatment for cough and cold symptoms though there is a relative lack of research in this area; only 81% of subjects completed the one-night study; in this study, potential subjects who had taken DM or an antihistamine the night prior to presentation were excluded from the trial (which significantly impacted recruitment).
We knew that: Billions of dollars each year continue to be spent on cough and cold remedies for children, even though safety of such products for those aged 2-11 years is in doubt, and products marketed to infants and toddlers for URI have been voluntarily removed from the market; numerous studies have suggested that DM is not effective for the treatment of childhood URI symptoms, and is associated with significant side effects; honey is generally regarded as safe for use in children except for infants, where botulism remains a concern; honey has demulcent actions that may soothe the throat, but also possesses antioxidant and antimicrobial effects; BH and other dark honeys reportedly have higher amounts of phenolic compounds.
Comments: It's enjoyable to review data on studies evaluating interventions to help parents relieve childhood symptoms of illness, especially for such a ubiquitous problem as URIs. Though warnings have become widespread regarding the use of OTC aids like DM for relief of cough and cold symptoms, many children continue to be exposed to them by well-meaning caregivers. This study shows that a simple, inexpensive dose of honey may be both safer and more effective.
The methodology employed was relatively straightforward, but it is understood that symptoms like nighttime cough may improve simply with the natural course of the illness. And even though the trial's duration was only 2 days, almost 20% of subjects did not complete the protocol.
The symptom improvements noted by parents were mild to moderate, so some readers may minimize the import of such findings. For those of us with young children, however, administering a small dose of tasty BH that may safely help our children sleep through the night as they recover from their URI allows us to place our heads on our pillows with some added comfort (and might even let us stay there through the night).
What to do with this article: Keep a copy on your computer.
In vino veritas Resveratrol and Aging
Source: Barger JL, et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PloS ONE. 2008;3(6): e2264.
Goal: To examine the role of resveratrol (R) in gene expression profiles associated with mammalian aging, and the specific effects of R and a calorie restricted diet (CRD) on gene expression patterns in multiple tissues, as well as endocrine and other factors possibly related to the aging process.
Study Design: Prospective intervention trial using mice.
Subjects: Long-lived male hybrid (F1) mice.
Methods: Individually-housed, middle-aged to elderly mice (14-30 months) were fed either a control diet, a CRD, or a control diet supplemented by a low dose of R. Echocardiography and specific blood testing was performed on young (5 months) control mice and older (25 months) control, CRD- and R-fed mice. Animals were sacrificed at 30-31 months, tissues collected, and gene expression analysis performed with a focus on heart, skeletal muscle, and brain tissue.
Results: Long-term feeding of the CRD resulted in reduced body weight not seen in the R group. When young and old mice on the control diet were compared, there were over 1,000 heart genetic expression changes identified with aging. When older control mice were compared with older mice on the CRD, a significant positive effect of CRD was seen on age-related gene expression in the heart. When the hearts of older control mice were compared with those of older mice supplemented with R, similar beneficial changes were seen with R as with the CRD group. Lesser benefits of both CRD and R were identified in skeletal muscle and brain tissue. A striking transcriptional overlap of CRD and R was identified for both changes related to and not associated with aging. Following 2 months of dietary intervention, decreases in IGF-1 were seen for those mice on the CRD, but not for those receiving R. R also mimicked the CRD's effects regarding insulin-mediated glucose uptake in muscle, though the mechanism of action appears to be different.
Conclusion: Both CRD and R may retard aspects of aging, perhaps through alterations in chromatin structure and transcription. R, as obtained through low-dose supplementation of the diet, may help prevent age-related cardiac dysfunction.
Study strengths: Degree of genetic profiling and wide variety of parameters measured.
Study weaknesses: Methodology did not permit evaluation of effects of CRD or R on average or maximum lifespan; most of us are not mice.
Of note: R is commonly found in grapes and red wine, and is known to possess antioxidant activity; global gene expression profiling can be used to assess biological, as opposed to chronological, age of various tissues.
We knew that: CRD appears to slow different aspects of the aging process in mammals, including tumorigenesis, and creates significant metabolic and hormonal shifts, including decreases in circulating IGF-1; in some studies, but not all, R has been shown to extend the lifespan of invertebrates; in at least one study, R prevented early death in mice fed a high-fat diet.
Comments: Animal data serve mainly to direct future trials in humans, and this study is no exception. The trial is called to the attention of AMA readers because there is growing interest in "anti-aging medicine," in the potential benefits of calorie restriction on health, and of late on the therapeutic possibilities associated with R.
Perhaps most notable are the effects of R on age-related cardiac dysfunction. R has previously been shown to possess cardioprotective effects in select circumstances in the lab, but the dearth of human clinical data in this regard is yet to be addressed. The authors of the current study also point out that a thorough "anti-aging" approach might also include means to lower IGF-1, as seen with CRDs.
These are heady results that warrant excitement, though not necessarily active implementation. With contradictory findings in abundance, it is unclear how best to proceed. The effects of R, and even some of the effects of CRD on the body, remain unclear, and very little human data yet exist. As is all too often true, we await further study to help guide us. The majority of bench and animal-focused research suggests a potential benefit from either of these interventions, and human trials may help bolster the argument for the enjoyment, in moderation, of both food and drink. Remember, however, that grape juice contains R, too.
What to do with this article: Keep a copy on your computer.
Get MovingExercise and Breast Cancer Risk
Source: Maruti SS, et al. A prospective study of age-specific physical activity and premenopausal breast cancer. J Natl Cancer Inst. 2008;100:728-737.
Goal: To determine whether or not exercise has an impact on breast cancer risk for premenopausal women, and if so to identify which age periods of what types of intensity of exercise are most important.
Study Design: Large prospective cohort trial.
Subjects: A total of 64,777 premenopausal women participating in the Nurses' Health Study II who responded to questions about leisure-time physical activity from age 12 to current age, starting with the 1997 questionnaire.
Methods: The Nurses' Health Study II is an ongoing cohort trial that began in 1989 with > 100,000 participants aged 25-42 years. Subjects completed a questionnaire about cancer risk factors, including aspects of lifestyle. For this study, subjects were followed for 6 years starting in 1997 when they answered questions about past and present physical activity, and were between 33-51 years of age. Information was obtained through responses regarding activity during 5 age periods (12-13, 14-17, 18-22, 23-29, and 30-34 years) as well as different categories of activity (strenuous, moderate and walking).
Results: Physically active women were found to be more likely to be nulliparous, to drink more alcohol, and to be current smokers. They also had lower BMI and ate less animal protein. Total activity declined considerably as they aged. A total of 550 cases of premenopausal breast cancer were diagnosed in the cohort over 6 years of follow-up. In separate analyses of average lifetime physical activity as divided into strenuous, moderate, walking and total activities, it was in total activities that the greatest risk reduction was found. Further analysis again suggested that total activity, rather than level of intensity, was more important with respect to reduced risk of breast cancer. Women who engaged in approximately 3.25 hours/week of running or 13 hours/week of walking from age 12 years onward experienced a 23% decrease in breast cancer risk. When evaluating the importance of fitness activities during specific times of life, activities during the ages of 12-22 were associated with the strongest protective effect (25%). Sub-analysis revealed a significant benefit of regular physical activity amongst women with a BMI < 25, but no statistically significant benefit with respect to breast cancer risk for women with BMI > 25.
Conclusion: Leisure-time physical activity is associated with reduced premenopausal breast cancer risk. Premenopausal women who engage in regular fitness activities from adolescence through adulthood are likely to obtain the greatest risk health benefits.
Study strengths: Large sample size; prospective nature of trial; self-reported diagnoses of breast cancer were confirmed by study physicians; multivariate analysis.
Study weaknesses: BMI and age at menarche were not included as core covariates (though they were included in other aspects of assessment by the researchers); data not widely generalizable (mainly white women); linear interpolation of data in between reporting cycles.
Of note: Premenopausal breast cancer comprises 25% of all breast cancer diagnoses, and is often more aggressive and difficult to treat than when the disease occurs in older women; few modifiable risk factors have been identified in the premenopausal population; some experts believe that the manner in which exercise helps reduced cancer risk varies over time, such that fitness activities during adolescence, when there are significant increases in sex hormones and rapid proliferation of breast tissue, may be of singular importance; response rates for participants in the Nurses' Health Study II approach 90%; in this trial occupational physical activity was not examined because there was little variation amongst participants in the cohort.
We knew that: Exercise is associated with a lowered risk for postmenopausal breast cancer, but little is known about the effects of fitness activities on premenopausal breast cancer risk; adolescent girls who regularly exercise vigorously experience later menarche and a delayed establishment of regular menses, while older women who exercise are more apt to have anovulatory cycles or amenorrhea, in either case there being essentially a decreased lifetime exposure to hormones tied to an increased risk of breast cancer; physical activity may reduce the risk for breast cancer through a variety of processes including decreased production of estrogen, insulin and IGF-1, all of which may act as mitogens; insulin and IGF-1 increase cellular proliferation and survival, and thus may raise the risk for cancer.
Comments: All practitioners and the majority of our patients understand that regular physical activity can translate into significant health benefits. Most patients focus on heart health and body weight in this context, with a minority aware of the potential anti-cancer benefits of fitness activities. Even so, information has been inconsistent with respect to when, how much, how long, and for whom. The data offered in this excellent paper provide healthcare practitioners with at least some clarity.
As has been posited for dietary interventions, fitness activities may have their most significant health benefit when started early in life and continued forever more. Even for the person who has never exercised consistently, the sooner they start the better off they may be in many ways, including a lowered risk of breast cancer for premenopausal women.
Cancer is frightening for many reasons, not the least of which being that many of our patients feel there may be little any of us can do to prevent the illness. As data accumulate, that appears to be not true at all. One of the ways we can best help our patients is by defeating fear with good information that they can then act upon. The results of this paper should be shared with every woman and child, and the men who love them.
What to do with this article: Make copies to hand out to your peers.
Greenfield, RH. Sweet Sleep – Honey and Nighttime Cough. Alter Med Alert. 2008:11;81. Greenfield, RH. In Vino Veritas – Resveratrol and Aging. Alter Med Alert. 2008:11;82. Greenfield, RH. Get Moving – Exercise and Breast Cancer Risk. Alter Med Alert. 2008:11;83.Subscribe Now for Access
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