Press Release

November 2004

Melatonin Improves Sleep for Asthmatics

Treatment with melatonin significantly improved subjective sleep quality in 12 women with mild to moderate asthma, as compared with 10 asthmatic women who took placebo, according to a study in the first issue for November 2004 of the American Thoracic Society’s peer-reviewed journal.

Writing in the American Journal of Respiratory and Critical Care Medicine, Pedro F. C. de Bruin, M.D., Ph.D., of the Department of Medicine, Universidade Federal do Cear?, Fortaleza, Brazil, along with 3 associates, found improved sleep quality in the treated women as measured with the Pittsburgh Sleep Quality Index. Yet, test results showed no change in asthma symptoms, use of relief medication or daily peak expiratory flow rate as compared with the 10 patients on placebo.

Melatonin is a hormone secreted by the human pineal gland, a tiny endocrine gland situated near the center of the brain. Discovered in 1958, the hormone is a derivative of the amino acid trytophan, and is believed to play an important role in the regulation of sleep cycles.

“Disturbed sleep and its daytime consequences are relevant problems in the management of asthma,” said Dr. de Bruin. “Nocturnal exacerbations usually indicate inadequate disease control and cause sleep disruption, but poor sleep quality has been reported even in individuals with well-controlled stable asthma. Drugs used for the disease, such as methylxantines and oral steroids, have also been shown to disrupt sleep. Failure to deal with sleep problems may lead to impaired disease control and have a great negative impact on quality of life in patients with asthma.”

The study subjects were 22 consecutive female patients aged 18 to 60 years who had mild to moderate asthma. Those who were excluded from the study had a history of: asthma exacerbations within the prior 4 weeks, respiratory disease other than asthma, sleep disorders, use of hypnotic or sedative drugs, smoking, shift-work or were pregnant or breastfeeding. The study was conducted as a randomized, double blind, parallel-group, placebo-controlled study with a 2-week run-in and a 4-week treatment period. Throughout the active phase, treated patients and controls were asked to record their morning and evening peak expiratory flow rate, the presence of asthma symptoms and the frequency of their beta2-agonist inhalation use.

“On initial assessment, we found that despite having mild or moderate asthma, and being in a well-controlled stable condition, most of our subjects were poor sleepers and almost half of them showed increased subjective daytime somnolence, when compared with a normal population,” said Dr. de Bruin.

According to the authors, no adverse effects were reported by participants who took melatonin.

Although they concluded that melatonin can improve the sleep of asthmatics, the researchers said that further studies looking at long-term effects of using the hormone were needed before they could safely recommend its use for all asthmatics.

Accident Risk Factors Associated with Sleepy Truck Drivers

In a large study, Australian researchers found a high prevalence of sleep- disordered breathing and excessive sleepiness among drivers of commercial vehicles in their country, according to an investigation published in the first issue for November 2004 of the American Thoracic Society’s peer-reviewed journal.

Writing in the American Journal of Respiratory and Critical Care Medicine, Mark E. Howard, M.D., of the Institute of Breathing and Sleep, Austin Health and the University of Melbourne, Melbourne, Australia, along with 8 associates, measured excessive sleepiness and sleep-disordered breathing and assessed accident risk factors in 2,342 respondents who were Australian commercial truck drivers. In addition, another 161 from a group of selected professional truck drivers underwent a polysomnographic sleep test.

According to the investigators, about 60 percent of the drivers had sleep disordered breathing and 16 percent had obstructive sleep apnea syndrome. These figures contrasted sharply with those in the normal civilian population who showed a 24 percent sleep-disordered breathing rate and a 4 percent sleep apnea level.

For the study, sleep-disordered breathing was defined as five short pauses (apneas) or more in breathing per hour during sleep. Obstructive sleep apnea was characterized as five breathing pauses or more per hour, plus a high Epworth Sleepiness Scale score.

“Increasing sleepiness was related to increased accident risk,” said Dr. Howard. “The sleepiest 5 percent of drivers on the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire had an increased risk of accident and multiple accidents, even after adjustment for other risk factors. Also, there was increased accident risk with narcotic analgesic and antihistamine use.”

Altogether, 4 percent used narcotic analgesics, antihistamines, and benzodiapines, which raised their risk of multiple accidents.

According to the authors, between 20 to 30 percent of all accidents involving commercial truck drivers are sleep-related.

Among the 2,342 respondents who answered the study questionnaire, 739 drivers (35.5 percent) had a total of 1,407 accidents in the prior 3 years, with almost half of these drivers (48.3 percent) having had more than one accident.

“Having more sleep on days off, working night shift, and country or interstate driving were related to a lower accident risk,” said Dr. Howard.

In an editorial on the study in the same issue, Charles F.P. George, M.D., of the University of Western Ontario, London, Ontario, Canada, noted that subjective accident reporting such as in this study was more likely to lead to underestimation rather than overestimation of accident rates, which strengthened the overall results.

Dr. George said: “There are two new findings from this study. The first is the increased accident risk in association with analgesic use or antihistamine use. Although the number of drivers taking these medications was not high, it does highlight another potential risk factor for accidents for which the clinician should be aware. Due to the rigors of the job, musculoskeletal injury is common and the potential for increasing analgesic use may exist. The second is the use of a quality of life measure, the Functional Outcomes of Sleep Questionnaire (FOSQ), where impact of sleepiness is clearly an accident risk factor. Other studies have examined the relationship between the Epworth Sleepiness Scale (ESS) and accidents. Using both the ESS and the FOSQ in this study, the sleepiest drivers had at least a two-fold increase in accidents, supporting the previously recognized relationship between accident risk and chronic sleepiness.”

Huge Study Reveals Critical Care Use in Serious Illness

In results from a huge study of Medicare patients who were seriously ill, researchers found that use of critical care was less likely the older an individual got; yet, regardless of age, 3 percent of the patients who repeatedly entered intensive care accounted for 23 percent of the hospitalizations, comprising almost $3 billion in costs.

Writing in the first issue for November 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Theodore J. Iwashyna, M.D., Ph.D., of the Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, analyzed the records of 1,108,060 Medicare beneficiaries in a large database. These persons were at least 68 years old and newly diagnosed with serious illnesses. Their health problems included 1 of 9 listed malignancies, stroke, congestive heart failure, hip fracture or heart attack.

“Of this cohort, almost 55 percent used critical care at some time after diagnosis,” said Dr. Iwashyna. “Older patients were much less likely to ever use critical care. We compared those more than 90 years of age with those 68 to 70 years. The older patients had one-third the odds of using critical care. In addition, a total of 31,348 patients (2.8 percent) were repeated users of critical care. They accounted for $3.6 billion in hospital charges and $1.4 billion in Medicare reimbursement.”

Dr. Iwashyna used the “Care after Onset of Serious Illness” (COSI) data set. It consists of a population-based cohort of 1,164,790 elderly patients identified with a serious illness in 1993. The illnesses were chosen to represent diverse conditions that account for the majority of deaths in the United States. For this study, the patients in the COSI data set were followed through the end of 1997. The study design allowed the researcher to track patients across multiple hospitals or states to assess their frequency of repeated intensive care unit (ICU) use.

The median age of the 1,108,060 patients involved was 79. Of the group, almost 42 percent were male, 88.3 percent were white, and 15.8 percent also received Medicaid benefits given to those who have either low or no income.

The repeated users of critical care were defined as those who had 5 or more distinct hospitalizations in which the ICU was used between diagnosis and death. Cardiac patients were disproportionately represented. Reimbursement for the multiple users represented 15 percent of all critical care hospitalization charges, and accounted for 23 percent of all critical care hospitalization by cohort members.

“We conclude that critical care use is common in serious chronic illness and is not associated with preterminal hospitalization,” said Dr. Iwashyna. “Use is uneven, however, and a minority of patients who repeatedly use critical care account for disproportionate costs.

Risk Factors for Early Relapse of Tuberculosis

In a large study of pulmonary tuberculosis patients, researchers found that disease relapse was associated with thrice weekly versus daily drug therapy and with the presence of cavitation (cavities) on the individual’s chest X-ray at diagnosis, according to an article in the second issue for November 2004 of the American Thoracic Society’s peer-reviewed journal.

Writing in the American Journal of Respiratory and Critical Care Medicine, Kwok C. Chang, M.B., B.S., M.Sc., of the Yaumatei Chest Clinic in Hong Kong, China, along with 4 associates, studied 12,183 patients who completed antituberculosis treatment between January 1, 1998, and December 31, 2000. Of this group, more than 105 cases relapsed within 30 months after commencement of treatment. The mean time to relapse was almost 15 months.

A total of 226 matched controls were selected from the 12,070 patients who did not relapse. Of the 226 controls, 166 completed 30 months of follow-up at clinics.

“A total of 100 cases and 209 control subjects were given the standard regimen or its extension,” said Dr. Chang. “The standard regimen referred to treatment with 6 months of isoniazid and rifampin supplemented by pyrazinamide in the initial 8 weeks. A total of 61 cases and 140 control subjects were given daily treatment throughout, whereas 44 cases and 56 control subjects were given thrice weekly treatment throughout.”

According to the authors, the definition of relapse refers to the situation in which

a patient becomes and remains culture negative while receiving antituberculosis drugs but develops active tuberculosis after completion of treatment.

Of the relapse cases, all were under the care of 17 chest clinics. In this group, 84 cases (almost 75 percent) were male, and were, on average, at diagnosis almost 48 years old.

“A better therapeutic efficacy for daily therapy is not surprising for two reasons,” said Dr. Chang. “First, most of the risk factors of relapse are ultimately related to the bacterial load of the lesions. Second, M. tuberculosis replicates approximately once daily, when it is actively dividing. Faster sterilization is expected when actively dividing bacteria are killed daily, even though post-antibiotic effects of intermittent treatment may continue to inhibit bacteria.”

Based on their estimates of 30-month relapse rates, the authors point out that the standard thrice-weekly regimen with fewer administrative medication doses could still be cost- effective in the absence of cavitation on the initial chest X-ray. However, they advise that daily therapy and prolonged therapy are necessary if cavitation is present.

In an editorial on the paper in the same issue of the journal, Andrew A. Vernon, M.D., M.H.S., and Michael F. Iademarco, M.D., M.P.H., of the U.S. Centers for Disease Control and Prevention in Atlanta, Georgia, noted that Dr. Chang and his colleagues had presented a well-executed case-control study of risk factors for the early relapse after treatment for tuberculosis. The study should lead to important reflection on the topic.

The editorialists wrote: “What should we conclude? First, more is more and less is less. That is, for regimens with the same drugs, more treatment means more cures, and vice versa. Second programs need to consider some individualization of therapy—not for the routine patient, but rather for the rarer patient with very extensive disease or cavitation who is slow to respond to therapy. Third, these considerations need not discourage us from intermittent therapy, but should remind us that sophisticated management based on case-specific circumstances is still needed. We should not be surprised in an era in which we are learning weekly about advances of host and bacterial genomics, that individuals may differ in the response to therapy, and that these differences may sometimes have implications for treatment. Programs must evaluate the values of reduction in relapse and transmission relative to the costs of directly observed therapy and drugs. We should be cautious about dogma, and always eager to evaluate our programmatic and clinical experience. . .”

Effects of Ozone on Mortality in 23 European Cities

In their analysis of the effects of ozone on mortality in 23 European cities, investigators found that death from respiratory disease was more strongly associated with ozone exposure that was either the total or cardiovascular rate, according to a study in the second issue for November 2004 of the American Thoracic Society’s peer-reviewed journal.

Writing in the American Journal of Respiratory and Critical Care Medicine, Klea Katsouyanni, M.Sc., D.M.Sc., of the Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece, along with 15 associates, found that the ozone effects on mortality occurred almost exclusively during the warm months.

Ozone is a toxic gas that irritates tissue. It occurs naturally in small amounts in the earth’s stratosphere, where it absorbs solar ultraviolet radiation. Under certain conditions in the lower atmosphere, photochemical reactions produce ozone concentrations high enough to the irritate eyes, mucous membranes and lung tissue. Ozone is considered one of the most toxic compounds in the photochemical air pollution mixture.

Data on mortality, including natural, cardiovascular, and respiratory death, was obtained from 23 European cities covering at least a three-year period. Information was also collected on daily ozone concentrations and potential confounders.

According to the authors, in 19 of 23 cities, ozone was found to be associated with an increase in mortality during the warmer months. No significant effects were found during the cold half of the year.

“The seasonal pattern of ozone is in direct contrast to the annual cycle of daily mortality which usually peaks during the winter,” said Dr. Katsouyanni. “Turin, Prague, Budapest, and Athens had the highest median ozone concentrations, whereas Tel-Aviv, London, and Paris had the lowest.”

The research was conducted for a project entitled “Air Pollution and Health: A European Approach.”

“The magnitude of ozone effects according to the causes of mortality indicates that a major part of the excess mortality related to elevated ozone levels is classified as cardiovascular and respiratory deaths,” said Dr. Katsouyanni. “These cases probably occur among cardiopulmonary-compromised individuals. There are several potential underlying mechanisms: inflammation of pulmonary tissues, which can induce a spectrum of mediators that may also alter cardiac function, or irritant receptor-mediated stimulation of parasympathetic pathways.”

The authors said that the ozone effects were larger on average in southern European cities where the concentrations of the pollutant were higher.

They said that they did not have enough data to investigate what modifications might have to be made if the various populations were taking antioxidant vitamins.

A Shorter, Stable Cure for Murine Tuberculosis

In a study employing a mouse model of tuberculosis (TB), researchers used a combination of rifampin, moxifloxacin and pyrazinamide to shorten the time to negative cultures in the rodents by up to 2 months. Their improved results with moxifloxacin use at 4 months were in direct contrast to the standard regimen of rifampin, isoniazid and pyrazinamide which took 6 months to accomplish the same goal.

Writing in the second issue for November 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Eric L. Nuermberger, M.D., of the Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, along with 9 associates, said that their results suggest the use of rifampin, moxifloxacin and pyrazinamide could substantially shorten the duration of therapy needed to cure human TB. They noted that the full value of pyrazinamide in this regimen could be realized after just 1 month of treatment.

“The development of an efficacious ultra-short course of 4 months for the treatment of TB in humans is expected to promote treatment completion rates and facilitate the worldwide implementation of directly observed treatment programs,” said Dr. Nuermberger. “The rifampin, moxifloxacin, pyrazinamide-based regimens have the potential to achieve this goal. The TB Trials Consortium of the Centers for Disease Control and Prevention is currently enrolling patients in a phase 2 clinical trial comparing a 2-month intensive regimen of rifampin, isoniazid, pyrazinamide and moxifloxacin versus the same combination with ethambutol substituted for moxifloxacin. The results should shed light on the additive activity and tolerability of moxifloxacin.”

The mice involved in the study were 7-week-old females. After they were infected with TB, they were placed randomly into 4 treatment groups. The control group received the standard 6-month therapy. The three experimental groups received a 5-month regimen of rifampin, pyrazinamide and moxifloxacin based on varying lengths of time and drug use.

According to the investigators, up to now, moxifloxacin has been used as a second-line drug for the treatment of patients with multidrug-resistant TB or with patients who were intolerant of first-line agents.