Jewish World Review August 9, 2004 / 22 Menachem-Av, 5764

Statin drugs & children; Gulf War Syndrome: no help from antibiotic therapy; briefly…

By Robert A. Wascher, M.D., F.A.C.S. | The statin drugs are highly effective in reducing cholesterol levels in adults, and have been shown by multiple research studies to reduce the risk of heart attacks and strokes. These drugs work by inhibiting a key enzyme in the liver, hydroxy-methylglutaryl-coenzyme-A reductase (HMG-CoA), thereby reducing the blood levels of the "bad cholesterol," LDL, and increasing levels of the "good cholesterol," HDL. Although statins have proven to be safe in the overwhelming majority of adult patients, serious side effects occasionally occur, including muscle and liver injury. For these reasons, and because elevated blood cholesterol levels occur primarily in adults, statins have not generally been recommended for use in the pediatric population.

However, children who are born with familial hypercholesterolemia (FH), a relatively common genetic disorder, develop accelerated onset of the same cardiovascular diseases seen in older adults with elevated blood cholesterol levels. In its most severe form, children afflicted with the FH mutation in the liver's LDL receptor genes rarely live beyond adolescence. One of the earliest findings in children with the severe form of FH is a progressive thickening of the walls of the carotid arteries (the large arteries in the neck that supply the brain with blood). This arterial wall thickening is a known precursor to the atherosclerotic disease that underlies the majority of heart attacks and strokes in FH patients, and in adults with elevated blood cholesterol levels. In view of these factors, the statin drugs may represent potentially effective new treatments for FH in children.

A new study reported in the Journal of the American Medical Association (JAMA) prospectively randomized 214 children, aged 8 to 18 years, to receive a statin drug or a placebo (sugar pill). All of the children were also placed on a low-fat diet, and were encouraged to exercise regularly during this 2-year study. Pravastatin, a popular statin drug, was given to 106 of the children, while the remaining 108 children received a placebo. (Neither the children nor their research physicians knew which pill each child received during the study.) All children were then followed with serial measurements of the thickness of their carotid arteries. Among the children receiving pravastatin, carotid artery thickness tended to decrease during the 2-year study period, while the carotid artery thickness of the children who received placebo pills gradually increased. At the conclusion of the study, there was a significant difference in average carotid artery thickness between the two groups of children with FH. The children taking pravastatin also experienced a 24 percent reduction in LDL blood levels when compared to the children who received the placebo pills.

The safety of pravastatin administration to children was also assessed in this study. Fortunately, no differences in growth, muscle or liver function, hormonal function, and onset of — and progression through — puberty were detected between the two study groups.

This study appears to show that a statin drug, pravastatin, is both safe and effective in causing regression of carotid artery atherosclerosis in children with FH. The next logical step, following this study, is a much larger version of the same study. More kids with FH will need to be studied, and over a longer period of time, before we will know if the long-term use of statin drugs in this population of children actually reduces the cardiovascular complications of FH in a clinically significant manner.

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The Gulf War Syndrome, also called Gulf War Veterans' Illnesses (GWVIs), refers to a constellation of symptoms experienced by 6 to 15 percent of veterans returning from the first Gulf War (1991). Chronic symptoms that have been associated with GWVIs include muscle aches, headaches, fatigue, memory loss, insomnia, skin rashes, hair loss, numbness, respiratory complaints, recurrent diarrhea and/or constipation, menstrual abnormalities, and various cardiovascular disorders.

There has been considerable debate within the medical community about the likelihood that a single syndrome could encompass such a variety of symptoms, both within single individuals and across a group of 30,000 to 100,000 Gulf War I veterans. Complicating the study of GWVIs further are the highly subjective nature of many of the symptoms attributed to GWVIs, and the widely divergent estimates of the number of Gulf War I veterans afflicted with presumptive GWVIs.

A variety of causes have been put forth to explain GWVIs, and at least one study, using chickens, has shown that exposure to the anti-nerve gas agent pyridostigmine, in combination with the common insect repellants DEET and permethrin, leads to neurological deficits similar to those seen in many patients with GWVIs. However, no single etiology has been proposed that would explain all of the myriad symptoms experienced by veterans diagnosed with GWVIs.

More recently, some scientists have suggested that at least some cases of GWVIs might be caused by a group of bacteria-like microbes called Mycoplasma. The theory that GWVIs might be caused by Mycoplasma arose from research into another somewhat controversial syndrome, seen primarily in women, and generally referred to as Chronic Fatigue Syndrome/Fibromyalgia Syndrome (CFS/FMS). In some studies, particularly in Europe, as many as 50 percent of patients with CFS/FMS have tested positive for Mycoplasma, compared to about 10 percent of the general population.

In view of the similarity of symptoms experienced by both veterans with GWVIs and non-veterans with CFS/FMS, extensive research has been conducted in an effort to identify evidence of Mycoplasma infection in patients diagnosed with GWVIs. In a few studies, veterans with GWVIs and symptoms similar to CFS/FMS do indeed appear to have a rather high incidence of latent Mycoplasma infection.

Following reports that at least some patients with CFS/FMS have improved following antibiotic therapy directed against Mycoplasma, some scientists have wondered if veterans with GWVIs should also be offered antibiotic treatment. A new randomized, double-blinded, placebo-controlled study in the Annals of Internal Medicine evaluated the impact of a 12-month course of doxycycline (versus placebo) in 491 Gulf War I veterans diagnosed with GWVIs. All GWVIs patients participating in this study had detectable Mycoplasma DNA in their blood.

Unfortunately, no significant differences in the persistence or severity of pain, fatigue, or Mycoplasma positivity were identified in the group of veterans taking the anti-Mycoplasma antibiotic doxycycline when compared to the group that received a placebo pill instead. On the other hand, the group that received doxycycline did experience a higher incidence of nausea and sensitivity to sunlight, both of which are well-known side effects of doxycycline. While this study did not answer the many controversial questions surrounding the etiology — or etiologies — of GWVIs, it does suggest, however, that long-term treatment with an antibiotic effective against Mycoplasma is not an effective treatment for the GWVIs syndrome.

Statins & Regression of Coronary Atherosclerosis: A new study in the journal Circulation has shown that 12 months of simvastatin therapy, following 3 months on a low-fat diet, significantly reduced atherosclerotic changes in the coronary arteries of 40 male patients with elevated cholesterol levels and coronary artery disease. However, the volume of the arterial lumen (the hollow interior of an artery through which blood flows), as measured by ultrasound, did not change significantly. The clinical relevance of this latter finding is unknown at this time.

Breast Cancer Genes, Breastfeeding & Breast Cancer Risk: Increasing cumulative durations of breastfeeding reduce a woman's risk of developing breast cancer. Among all cases of breast cancer diagnosed in the US, 5 to 10 percent are associated with mutations in either of the two known breast cancer genes: BRCA1 and BRCA2. (These gene mutations are also associated with an increased risk of ovarian, prostate and uterine cancer, and male breast cancer, as well.) A new study in the Journal of the National Cancer Institute takes a look at the protective effects, if any, of breastfeeding in women who are known to have BRCA1 or BRCA2 mutations.

The study evaluated almost 2,000 women with either of these gene mutations, half of whom had previously been diagnosed with breast cancer, and half of whom had not developed breast cancer. The women were then surveyed regarding their previous pregnancies and breastfeeding habits. The study determined that each month of breastfeeding was associated with a 2 percent reduction in the risk of developing breast cancer among women with the BRCA1 mutation. In the same group of women with the BRCA1 mutation, breastfeeding for more than 1 year resulted in a 45 percent reduction in the relative risk of developing breast cancer when compared to the women who had never breastfed their babies.

Unfortunately, there was no evidence of a reduction in the risk of breast cancer associated with breastfeeding among the women known to have the BRCA2 mutation.

Passive Smoking and the Risk of Heart Disease & Stroke: Smoking increases the risk of heart disease and stroke, as well as lung disease. Increasingly, many US cities are enacting anti-smoking ordinances that outlaw smoking in public buildings. Opponents of these measures often claim (falsely) that there is no evidence that secondhand smoke poses any significant health danger to nonsmokers.

A new study in the British Medical Journal prospectively evaluated almost 5,000 men who completed detailed smoking history surveys, and who regularly supplied blood samples between 1978 and 1980. These blood samples were tested for cotinine, a byproduct of nicotine metabolism. (Blood levels of cotinine reliably estimate a person's level of exposure to tobacco smoke.) The study volunteers were then followed for at least 20 years.

The nonsmokers who had the highest measured levels of cotinine in their blood, when compared to the nonsmokers with minimal detectable levels of cotinine, experienced a 57 percent increase in the relative risk of developing heart disease during their 20-year follow-up. Intermediate levels of elevated blood cotinine levels in nonsmokers were, not surprisingly, associated with lesser — but still significant — increases in the risk of coronary artery disease. Interestingly, elevated cotinine levels in nonsmokers were not, at least in this study, associated with an increased risk of stroke. This study, as with multiple other previous studies, confirms that chronic exposure to secondhand cigarette smoke is associated with adverse health effects in nonsmokers.

Secondhand Smoke & Infants: There is considerable evidence that childhood asthma, as well as other chronic pediatric ailments, may either be caused by, or exacerbated by, environmental factors, including exposure to secondhand tobacco smoke. A prospective study of more than 8,000 infants appears in the current issue of the Archives of Pediatric and Adolescent Medicine. Over the course of 18 months, the number of hospital admissions for these infants, and the reasons for their admissions, were monitored. A detailed smoking history was obtained for all members of the infants' households, as well. In particular, the study looked at whether or not adult smokers in the infants' households routinely smoked in close proximity to the babies or not. Not surprisingly, there was no difference in infant hospitalizations between the nonsmoking households and the households where the smokers lit up more than 10 feet away from the babies. Also not surprising was the finding that infants from households in which the smokers lit up within 10 feet of the babies had a 28 percent increased relative risk of being hospitalized during their first 18 months of life….

Prostate Cancer Radiation Therapy, Fatigue & Exercise: Patients undergoing radiation therapy for prostate cancer commonly complain of feeling fatigued. Many physicians advise such patients to rest, and to avoid strenuous activity until they have completed their radiation treatment. A new study in the journal Cancer, however, would appear to refute that advice. A total of 66 men were randomized to one of two groups prior to undergoing radiation therapy for early-stage prostate cancer. One group of 33 men was advised to "take it easy," while the other 33 men were placed on a monitored exercise program. At the end of their 4-week course of radiation therapy, all 66 men were tested to ascertain their levels of physical conditioning. The men who participated in the exercise program actually exhibited an improved level of physical conditioning at the end of the study period, compared to their pretreatment baseline, while the group who took it easy experienced a mild overall decline in their level of conditioning. The subjective levels of fatigue reported by the non-exercise group increased as their radiation therapy progressed, while the men in the exercise group reported no increase in fatigue from their pre-treatment baseline. This small study suggests that a program of moderate and regular aerobic exercise may effectively combat radiation treatment-induced fatigue in men with early prostate cancer.

JWR contributor Dr. Robert Wascher is an oncologic surgeon, professor of surgery, oncology research scientist, and author. He lives in Honolulu with his wife and two daughters. Comment by clicking here.



© 2004, Dr. Robert A. Wascher