Lopid

HELSINKI, Finland, April 10 - Deaths from coronary heart disease were significantly reduced among patients with dyslipidemia who were given early treatment with Lopid (gemfibrozil), according to an 18-year follow-up of patients in the Helsinki Heart Study.

The reduction in cardiac deaths was greatest among patients who started therapy between ages 40 to 47 and in a subgroup of patients who were overweight (BMI ≥ 27.5) and whose lipid disorder was related to the metabolic syndrome, according to a report in the April 10 issue of Archives of Internal Medicine.

In an accompanying editorial, Hanna Bloomfield, M.D., of the Minneapolis VA Medical Center, discussed the role of fibrates in a world now dominated by statins. "The fibrates may be down," she wrote, "but they are not yet out."

The Helsinki Heart Study was a double-blind, controlled primary prevention study of 4,081 dyslipidemic middle-aged men given Lopid or placebo in 1982. After five years, the men were invited to continue Lopid therapy through 1995, and about two-thirds of the subjects in both groups chose to do so.

In the year 2000, the researchers compared coronary heart disease, cancer, and all-cause mortality among subjects in the original study. By 1995, subjects in the original Lopid group had a 32% lower relative risk of coronary heart disease mortality (P=.03) compared with the original placebo group, according to Leena Tenkanen, Ph.D., of the Helsinki Heart Study group here and Tampere University in Tampere, Finland, and colleagues.

Early treatment, the researchers found, was most significant. According to Kaplan Meier plots, the differences between the two groups decreased when follow-up was extended beyond 1995. Followed to the year 2000, the relative risk was only 23% lower (P= .05), Dr. Tenkanen said.

Moreover, in 1995 a significant age split appeared, she said. Among men ages 40 to 47 years at the beginning of the study, the relative risk of coronary heart disease mortality was 42% lower in the treated group compared with the controls (P=.07), but it was only 24% lower among those 48 to 57 years at the start. By the 18-year follow-up, the corresponding figures were 31% (P=.08) and 17%, Dr. Tenkanen said.

Overall, trends for all-cause and cancer mortality were not statistically significant, the researchers wrote.

However, prompt treatment was of most benefit for a subgroup of Lopid patients. Those patients in the highest tertiles for BMI (≥27.5) and triglycerides (≥184 mg/dL) had a 71% lower relative risk of coronary heart disease mortality (P<.001) and a 33% lower risk of all-cause mortality (P=.03) compared with the placebo patients, the researchers reported.

Patients with low levels of high density lipoprotein-cholesterol (HDL-C) at baseline also had similar benefits from starting treatment promptly. However, low density lipoprotein levels (LDL-C) were unchanged, the researchers said.

The Helsinki finding that Lopid reduced the risk of coronary events mainly in overweight patients with additional metabolic-syndrome risk factors predicts good treatment effects with the drug, Dr. Tenkanen said. Recent reports that Lopid therapy was most effective in patients with insulin resistance suggest that although the Helsinki study did not measure insulin resistance, BMI does play a central role in the metabolic syndrome, she said.

Studies on the action of fibrates at the molecular levels may provide a broader understanding of the various beneficial effects of Lopid on coronary heart disease risk factors, the researchers said. Fibrates, they said, have been found to activate the peroxisome proliferator-activated receptors (PPARs) that control lipoprotein metabolism and atherosclerotic plaque thrombogenicity.

One of the limitations of the study, Dr. Tenkanen pointed out, is that there was no placebo group after the double-blind phase, and after 1995 the researchers had no information on the subjects' choice of medications and therefore the effect of Lopid, although they assumed that the study groups did not differ in their choice of treatment.

In conclusion, the researchers said, their study lends support to the hypothesis that an early and a young-age start of treatment with Lopid may be important, especially for those whose dyslipidemia is related to the metabolic syndrome.

In her editorial, Dr. Bloomfield said that recently, for several reasons there has been a resurgence of interest in fibrates, despite the dominance of statins.


First, is fibrates' capacity to raise HDL cholesterol levels and lower triglyceride levels, which brought about significant reductions in cardiovascular events even in the absence of lower LDL cholesterol levels.

Second, she noted, was the discovery that fibrates are ligands for PPARs, nuclear receptors that regulate expression of genes involved in glucose and lipid metabolism. New uses for fibrates may emerge as their potential is more fully explored, she suggested.

Third, Dr. Bloomfield said, is the fact that statins prevent only 20% to 30% of cardiac events, so combination therapy with fibrates might further reduce coronary heart disease, provided the combination proves safe. Finally, she said, the high rates of obesity, diabetes, and metabolic syndrome in the U.S. offer a profile for which fibrates might be ideally suited.

For patients similar to those in both the Helsinki and the 1999 VA-HDL Intervention Trial (which found similar benefits for Lopid), and especially for those with features of metabolic syndrome, Dr. Bloomfield wrote that "gemfibrozil is a very reasonable and less expensive alternative to statins." (A generic fibrate might cost less than $20 a month vs. $62 for a generic statin.)

Nevertheless, Dr. Bloomfield added, the evidence for statins is more robust owing to the huge number of patients who have been studied and the fact that the Lopid trials have not shown a convincing effect on all-cause mortality.

In an interview, cardiologist Homeyar Dinshaw, MBBS, of the Ochsner Clinic in New Orleans, said that fibrates could be useful in selected patients, those overweight and with triglyceride levels of 184 mg/dL, somewhat above the normal of 150 mg/dL. But, he said, "it remains to be seen whether it is safe and effective to routinely add fibrates to statin therapy, thereby increasing the risks of combination therapy." The benefits, he suggested, should outweigh the increase in risks.

Dr. Dinshaw also noted that at the time of the study, women were significantly underrepresented in all such studies and that there might be some differences in findings for female patients.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

health alert to physicians and wearers of soft contact lenses

ROCKVILLE, Md., April 11 - An outbreak of Fusarium keratitis in 17 states has prompted the FDA to issue a public health alert to physicians and wearers of soft contact lenses.

The alert reminded wearers of soft contacts to "practice good basic hygiene and follow manufacturers' instructions for proper use, cleaning and storage of their lenses."


The infections have been linked to both soft lenses and the solution used to clean and store them. The CDC reported that eight patients required corneal transplantation.


At the same time, Bausch & Lomb announced that it had voluntarily stopped shipment of its ReNu Moisture Loc contact lens solution while it continued its own investigation of the cause of the infections. The company did not pull products from store shelves, although it advised consumers to use ReNu Moisture Loc "with caution" and to report any signs or symptoms of eye infection to doctors.


Symptoms include redness, pain, tearing, increased light sensitivity, blurry vision, and discharge or swelling. The FDA warned that contact lens users who experience any of these symptoms should immediately remove the lenses and call a doctor.


The CDC said that as of April 9 it was investigating 109 suspected cases of Fusarium keratitis. Twenty-six of 30 fully investigated cases occurred in patients who used Bausch & Lomb ReNu brand contact lens solution or generic brands manufactured by Bausch & Lomb.


Nine of the 30 patients reported wearing lenses overnight, which is a known risk factor for microbial keratitis.


Infections have been reported in California, Connecticut, Florida, Georgia, Iowa, Maryland, Massachusetts, Michigan, Missouri, New Jersey, New York, North Dakota, Ohio, Pennsylvania, Tennessee, Texas, and Vermont.


According to the CDC, risk factors for infection include "trauma (usually with plant material), chronic ocular surface diseases, immnodeficiencies, and, rarely, contact lens use." There are an estimated 30 million contact lens users in the United States and the rate of microbial keratitis is estimated at four to 21 cases per 10,000 soft contact lens users, but the risk increases if users wear the lenses overnight.


Moreover, fungal keratitis is more common in warmer climates and the proportion of fungal infections confirmed as Fusarium keratitis ranges from 25% to 62%. The infection is not transmitted person to person.


First-line treatment of the infection includes topical and oral antifungal medications.


The FDA public health advisory recommended these preventive strategies:

Wash hands with soap and water. Dry hands using a lint-free method before handling lenses.
Wear and replace lenses according to the schedule prescribed by the doctor.
Follow the specific lens-cleaning and storage guidelines from the doctor and solution manufacturer.
Keep lenses clean and replace every three to four months.



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Blood Transfusions Could Transmit Variant Creutzfeldt-Jakob

Bovine spongiform encephalopathy (BSE), better known as mad cow disease, is apparently not easily transmitted From cattle to humans. That's the good News.

The bad News is that once BSE makes the jump into people in the form of variant Creutzfeldt-Jakob disease, or vCJD, it may readily spread From one person to the next through the British blood supply, reported researchers in an early Online release From The Lancet Neurology.


Studies of transgenic mice bred to express the human prion protein gene in its most common human variants indicate that while there appears to be good protection against BSE transmission to humans, human-to-human transmission of vCJD may readily occur in all but about 10% of the population, according to Jean C. Manson, Ph.D., and colleagues of the Institute for Animal Health here.


Variant CJD may also have a very long incubation period, and there may be a significant level of subclinical disease, the investigators suggested.


"Although the cattle BSE epidemic in the United Kingdom has amounted to more than 180,000 cases since the 1980s, the extent of the human vCJD epidemic has so far remained limited, with the total number of cases worldwide currently at 190," Dr. Manson and colleagues wrote.


"One explanation for this apparent discrepancy is that there exists a significant species barrier between cattle and human beings, which limits the susceptibility of the human population to BSE…," they added. "However, once BSE has passed through human beings in the form of vCJD, the transmissibility of this transmissible spongiform encephalopathy strain is altered for the human population."


A specific polymorphism, or variant, in the prion protein gene in humans has been shown to be a major determinant of susceptibility to prion diseases. The polymorphism, which occurs at codon 129 of the gene, determines whether the amino acids methionine or valine are present at that location.


About 40% of Caucasians are homozygous for methionine, and an additional 50% of Caucasians are heterozygous (I.e., have one valine and one methionine allele), and another 10% are homozygous for valine.


"All cases of human vCJD have been in patients with the methionine-methionine genotype, which suggests that the methionine-valine and valine-valine genotypes are protective," wrote Corinne Ida Lasmezas, Ph.D., a professor of biomedical Research at the Scripps Research Institute in Jupiter, Fla., in an accompanying editorial.


But as Dr. Manson and colleagues found in their Study, "all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion."


They determined this by using transgenic mice as surrogates for humans. The mice were bred to express either the human or bovine forms of the prion protein gene. For the mice with the human gene, the investigators bred three genetically identical populations that expressed the gene in the three human variants (methionine homozygous, heterozygous, or valine homozygous).


The mice were then inoculated with either BSE or vCJD delivered directly into the brain, and all mice were assessed for Clinical and pathological signs of prion disease.


They found that while BSE was transmitted via inoculation to those mice expressing the bovine form of the prion protein gene, the mice with the human forms of the gene did not develop transmissible spongiform encephalopathies.


In contrast, vCJD was transmitted to all three mouse lines expressing the human gene variants, with different pathological characteristics for each genotype. For example, mice with the methionine-methionine polymorphism had evidence of disease at a relatively early stage, 370 days after inoculation, whereas as the heterozygous animals had evidence of disease that was restricted to only a few brain areas beginning at around 581 days, and remained limited at least 700 days after inoculation.


In addition, the authors found that there was a gradation of transmission efficiency, with the methionine-methionine genotype being the most susceptible (11 of 17 mice infected) to methionine-valine (11 or 16 infected) to valine-valine (1 of 16 infected).


There findings suggest that "transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there seems to be a substantially reduced barrier for human-to-human transmission of vCJD," the authors wrote.


"Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant Public-Health issue," they concluded.


Saludos Cordiales

Dr. José Manuel Ferrer Guerra

Seizure Disorder in Amish Children Points to Autism

A Study of Old Order Amish Children has identified the genetic mutation that causes a previously unknown disorder, with seizures that progress to autism and retardation.
The recessive disorder, dubbed cortical dysplasia-focal epilepsy syndrome, or CDFE, is marked by relatively normal infancy followed by onset at about 14 to 16 months of age of frequent seizures -- 50 to 90 per week.


The seizure onset is followed by language regression and the Development of hyperactivity, aggressive and impulsive behaviors, and mental retardation, reported Kevin A. Strauss, M.D., of the Clinic for Special Children here, and colleagues, The Old Order Amish is a close-knit, genetically homogenous population.


The finding points to a genetic variation in the gene encoding for contactin-associated protein-like 2 (CASPR2) as a possible cause of both epilepsy and autism in the affected Children, the investigators wrote in the March 30 issue of the New England Journal of Medicine.


"We were able to unequivocally map the disease gene to chromosome 7 and identify a pathogenic sequence variant in the gene CNTNAP2, which codes for the CASPR2 protein," said co-author Erik G. Puffenberger, Ph.D., laboratory director at the Center for Special Children.


"Although these patients were From an isolated population, we anticipate that CASPR2 mutations will be found in Children From other populations with mental retardation, seizures, and autism," he added.


Genetics researchers often find insights into the origins of Developmental Disorders by studying populations such as the Amish, Mennonites, and Hasidic Jews. Members of these groups tend to have ancestors who came From the same geographic region, live in isolated populations, and intermarry, allowing recessive genetic traits to emerge in their offspring.

Dr. Strauss and colleagues at his Center and at the Translational Genomics Research Institute in Phoenix and Center for Human Genetics in Marshfield, Wis., studied nine patients with CDFE to see whether they could narrow in on a specific cause of the epilepsy.

The Clinical course in the Children consisted of "mild gross motor delay and subtle limitations in skills that required imitation, concentration, or motor planning," the investigators wrote.

The Children generally had good language comprehension and eight of the nine had age-appropriate cognitive and social Development before the onset of seizures.

The seizures, including simple, partial, and complex partial types, began at a median age of 16 months (range 14-20) and were frequent and intractable when the Children were between the ages of two and seven. The seizures did not resolve following resective surgery, but tended to abate spontaneously several years after onset, the authors noted

The seizure onset was followed by deterioration in learning ability and social Development, and by age three all patients with CDFE were found to have "language regression, aberrant social interactions, and a restricted behavioral repertoire."

The investigators took DNA samples From four of the Children and their six parents, and used DNA microarray analysis to screen for genetic variations.

After narrowing the field of candidates, they then tested all of the Children with CDFE, and found that they were homozygous for a single-base deletion at nucleotide 3709 in exon 22 of the CNTNAP2 gene.

An analysis of an additional 105 healthy Old Order Amish controls showed that none was homozygous for the mutation, but that four were carriers. The authors then sequenced the gene in an additional 18 Amish patients with complex partial seizures, and found that nine of these patients were homozygous for the deletion. These patients were all siblings of seven of the Children with CDFE.

Their findings provide important insights into a previously unknown Developmental role for CASPR2, a protein known to be important for neuronal and glial connections in the mature central nervous system.

"Previous studies on CASPR2 in isolated cell cultures and genetic 'knockout' mice did not predict its fundamental role in human brain Development or cortical electrical activity," Dr. Krauss said. "The present findings are compelling evidence for such roles, and open new directions for epilepsy and autism Research beyond the index population."

His colleague, D. Holmes Morton, M.D., co-founder and Medical director of the Center for Special Children, added that "the identification of the mutation in CASPR2 in our Amish patients has already allowed us to recognize affected newborns before they become symptomatic. Our hope is that early treatment and prevention of prolonged seizures in these infants will lessen the effects of the disorder upon the lives of Children and their families."




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ADDS NEW RESOURCES ON HEART HEALTH

U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH
NIH News
National Heart, Lung, and Blood Institute (NHLBI)
http://www.nhlbi.nih.gov/

FOR IMMEDIATE RELEASE: Wednesday, April 12, 2006

CONTACT: NHLBI Communications Office, 301-496-4236,
nhlbi_news@nhlbi.nih.gov

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ADDS NEW RESOURCES ON HEART
HEALTH

A recent national survey shows that only 3 percent of U.S. adults
practice all of the "big four" habits to help prevent heart disease:
eating a healthy diet, getting regular physical activity, maintaining a
healthy weight, and not smoking. The National Heart, Lung, and Blood
Institute (NHLBI) of the National Institutes of Health has combined the
latest information and guidance on all of the factors that increase risk
for heart disease -- or may contribute to worsening heart disease --
into two new heart health guidebooks for men and women.

"In the United States, heart disease is the number one killer of both
women and men," says NHLBI Director Elizabeth G. Nabel, M.D. "But the
good news is that there are many things individuals can do to reduce
their risks of heart disease."

"Your Guide to a Healthy Heart" includes a detailed action plan for
heart health. "Your Guide to Living Well With Heart Disease," is
designed to help those with heart disease make decisions to protect and
improve their heart health. Both guides provide specific information on
lifestyle changes and treatments that can lessen a person's chances of
having a heart attack -- either a first attack or a repeat one.

Heart disease prevention advice in "Your Guide to a Healthy Heart"
includes tips on choosing health foods, starting and sticking to an
exercise program, and breaking the smoking habit. Features include how
to eat healthy while dining out, reading food labels and making
substitutions for limiting saturated fat, trans fat and cholesterol,
basics on the DASH eating plan, and a 12-week walking program.

In addition to the guidebooks, two fact sheets titled "In Brief: Your
Guide to a Healthy Heart" and "In Brief: Your Guide to Living Well with
Heart Disease" highlight the basics for heart health. There are many
things men and women can do to reduce their risk for heart disease.

-- Don't smoke, and if you do, quit. People who smoke are up to six
times more likely to suffer a heart attack than non-smokers.

-- Aim for a healthy weight. It's important for a long, vigorous life.
Overweight and obesity cause many preventable deaths.

-- Get moving. Make a commitment to be more physically active. Aim for
30 minutes of moderate-intensity activity on most, preferably all, days
of the week.

-- Eat for heart health. Choose a diet that is low in saturated fat,
"trans" fat, and cholesterol. Be sure to include whole grains,
vegetables, and fruits.

-- Know your numbers. Ask your doctor to check your blood pressure,
cholesterol (total, HDL, LDL, triglycerides), and blood glucose. Work
with your doctor to improve any numbers that are not normal.

The guides are available for ordering through the NHLBI Information
Center, (301) 301-592-8573 or 240-629-3255 (TTY) or online at
http://emall.nhlbihin.net/.

Part of the National Institutes of Health, the National Heart, Lung, and
Blood Institute (NHLBI) plans, conducts, and supports research related
to the causes, prevention, diagnosis, and treatment of heart, blood
vessel, lung, and blood diseases; and sleep disorders. The Institute
also administers national health education campaigns on women and heart
disease, healthy weight for children, and other topics. NHLBI press
releases and other materials are available online at: www.nhlbi.nih.gov.

The National Institutes of Health (NIH) -- "The Nation's Medical
Research Agency" -- includes 27 Institutes and Centers and is a
component of the U.S. Department of Health and Human Services. It is the
primary federal agency for conducting and supporting basic, clinical and
translational medical research, and it investigates the causes,
treatments, and cures for both common and rare diseases. For more
information about NIH and its programs, visit http://www.nih.gov.



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Improving Asthma Diagnosis and Assessment

David A. Stempel, MD


The annual meeting of the American Academy of Allergy, Asthma & Immunology was held in San Antonio, Texas, from March 18-22, 2005. One of the topics that was addressed frequently throughout the meeting was how to improve the diagnosis and assessment of patients with asthma. Enhancing diagnostic skills in asthma allows for improved and more appropriate therapy for patients. Since the first National Institutes of Health guideline for the treatment of asthma in 1991, asthma therapy has been based on disease severity. Three important topics were discussed. First, is "asthma control" rather than "disease severity" a more important issue in determining who warrants therapy or adjustment to treatment? Second, are there clinical markers that offer guidance to selecting patients who require treatment and specifically predicting who will respond to a certain medication? Third, do these measures of asthma control correlate with disease activity?

Managing Asthma

At the plenary session, Sonia Buist, MD, from Oregon Health and Science University, addressed "Asthma Control as a Practical Outcome for Managing Asthma." The first part of her presentation addressed the availability of 3 questionnaires that assess asthma disease control. These 3 tools, the Asthma Control Test (ACT),[1] the Asthma Therapy Assessment Questionnaire (ATAQ),[2] and the Asthma Control Questionnaire (ACQ),[3] all focus on patient-oriented features of the disease. All 3 describe the impact of asthma on daily activities, sleep disrupted by asthma, and the need for rescue albuterol.

Disease severity, on the other hand, is not a patient-focused measure. Disease severity is limited by the requirement that it should be assessed prior to the use of medication. It includes measures of lung function that are a point in time and unfortunately are not performed regularly. In contrast, these 3 survey tools can be assessed in the presence of controller medications, are not dependent on the availability of a spirometer, and report on asthma control over a longer period of time -- 1-4 weeks depending on the questionnaire used. Disease control and disease severity have the inherent disconnect of the patient with mild disease that is not well controlled and the patient with severe disease who has good control.[4]

Dr. Buist added that the use of control measures allows for the establishment of "red flags." Use of short-acting bronchodilators (SABA) more than 1 canister a month, unscheduled asthma care, and missed school or work are all warning signs that a patient's asthma is not well controlled. Alternatively, good control is use of SABA less than twice a week, no nighttime symptoms, no emergency department or hospital use, no missed school or work, and no exacerbations. The level of control is an outcome of asthma that can be quantitated; the level of severity is a variable to the achievement of control.

Dr. Buist reported that a significant proportion of patients assessed with the ATAQ were not in good control. In this survey that was mailed to members of a large Northwest managed care organization, 52% identified 1 or more aspects of their asthma that was not in control. In addition, in a follow-up of this population, there was a correlation between asthma control and the risk of an exacerbation.

Next, Dr. Buist turned her attention to the recently reported GOAL study[5] that was designed to assess whether total or well control status was achievable. This study demonstrated that well or total control of asthma could be attained in the majority of patients treated with a salmeterol/fluticasone combination. Control was established at a high threshold; even at this level, it was achieved and sustained for the majority of patients. Total control includes the absence of exacerbations. This allows for the establishment of a new goal for assessing asthma outcomes; however, this study still leaves unanswered how to step down therapy once control is achieved.

Dr. Buist concluded by pointing out the significance and simplicity of using the Baylor "Rules of Two" as a quick and easy-to-remember survey: daytime symptoms twice a week or nighttime symptoms twice a month correlate with asthma that is not adequately controlled. Using the patient-oriented concept of control raises the question of whether this algorithm would lead to better adherence with controller medications and, ultimately, better control. Will asthma control alter disease inflammation and potentially disease progression? Will the change to disease control measures change the natural history of the disease, and will it be cost-effective? These are still unanswered questions requiring further research.

Biomarkers in Asthma

The next talk in this plenary session was presented by Dr. John Hunt, from the University of Virginia. His talk centered on the use of biomarkers in the assessment and treatment of asthma. Biomarkers of asthma are both measurable and informative. He defined them as noninvasive measures of lung metabolism. But he also gave the warning that they could be inappropriately applied and then be a random piece of "goo." He discussed the use of exhaled breath condensates and specifically the use of exhaled nitric oxide (eNO) and pH.[6]

Potentially, these markers could be used to help in the diagnosis of disease and to select and optimize therapy. It is clear that spirometry is not by itself an adequate physiologic measure on which to base all clinical decision making. In a later presentation discussed later in this article, Dr. Joseph Spahn pointed out that, in children, lung function is frequently normal although there is clinical evidence of disease as well as evidence of elevated eNO. Dr. Hunt continued that there is no simple way to measure and quantitate inflammation at present.

In a clinical example of the use of exhaled breath condensates, Dr. Hunt presented how exhaled pH could be used in the treatment of a child with a history of chronic cough. The child in Dr. Hunt's case report had multiple exhaled breath condensates collected for measurement of pH. When the child was actively coughing, his breath pH declined.. When he was without symptoms, his pH was normal. The child was then treated with a proton pump inhibitor, and within 10 days his cough resolved and his exhaled breath condensates all revealed a normal pH. This case illustrates how this research tool is now clinically applicable.

Markers of Inflammation

Dr. Joseph Spahn, from National Jewish Medical and Research Center, followed up on this topic in his presentation entitled, "Markers of Inflammation: The Future is Now." He established 6 criteria for the ideal marker of inflammation. It should be disease- specific, sensitive, easy to perform and inexpensive, easily quantitated, levels should correlate with airway inflammation, and, finally, there should be an association with disease severity. Sputum eosinophils appear to correlate with disease severity, lung function, and bronchial hyperreactivity.[7] There is evidence in the literature that they may be useful as a guide to treatment. In the Childhood Asthma Management Program,[8] there is evidence that those children treated with budesonide had decreased sputum eosinophils and that the presence of increased sputum eosinophils correlated with an increased likelihood of a relapse requiring oral corticosteroids. The difficulty with sputum eosinophils is the cost, time needed to perform the assay, and all patients may not be able to produce an adequate sample.

Next, Dr. Spahn turned the discussion over to the use of eNO, which is easily measured even in young children. eNO correlates with airway inflammation,[9] is elevated in untreated children with asthma, and is decreased after treatment with inhaled corticosteroids. There is evidence that eNO and sputum eosinophils correlate. Dr. Spahn also discussed reports that demonstrated that eNO may be a more sensitive tool in diagnosing asthma in children than spirometry because of the frequent finding of normal lung functions in children with asthma. This technique may be used more often in the future as the availability and cost of this test improve.

Asthma Control

This theme of asthma control was also the topic of a symposium at a forum on Sunday afternoon. Dr. Homer Boushey, from the University of California, San Francisco, started the session by describing the patient who is seen without symptoms but on spirometry has significant evidence of airflow limitation. This patient is then started on treatment and identifies significant improvement in quality of life. The failure to perform spirometry suggests that a significant cohort of patients with uncontrolled asthma based on clinical history alone will fail to be identified in the absence of this physiologic measure. Dr Boushey also identified that a significant emphasis needs to focus on the attainment of clinical outcome parameters to identify control.

Dr. Paul O'Byrne, from McMaster University, Hamilton Ontario, next discussed the importance of physiologic assessment in the determination of control. Success in management correlated with improvements in both spirometry and decreases in bronchial hyperreactivity. He used the early intervention study with budesonide published in The Lancet as an illustration of both clinical and pulmonary function improvement.[10] He pointed out the importance of trying to understand the significance of the population that appears to have a limited response or no change with therapy.

The final presentation in this session was by Dr. Reynold Panettieri, from the University of Pennsylvania. His topic focused on whether one could assess control based on the pathologic evidence of asthma. He started by defining airway remodeling as part of the injury repair process. He pointed out that many of the features associated with airway remodeling, including thickening of the lamina reticularis, smooth muscle hyperplasia and hypertrophy, and angiogenesis, may not correlate with disease severity.[11] Whether these changes are evidence of presence of persistent disease or just evidence of duration of asthma is unclear. He pointed out the need for continued research to identify changes that correlate with disease activity.

Two abstracts[12,13] were presented at the conference that discussed using the ACT at community health screenings. Approximately 2800 subjects who reported a physician diagnosis of asthma or use of asthma medications were studied. These subjects answered all 5 of the ACT questions and performed spirometry that met American Thoracic Society (ATS) criteria. Thirty-one percent of patients had an ACT score of 19 or less, indicating that their asthma was not well controlled. (This study cohort differs from the subjects in the report discussed by Dr. Buist who were identified with the presence of a medical claim for asthma.) Of those patients whose asthma was not well controlled, 64% used asthma medications, and 36% of the controlled patients used asthma medications. Use of SABA was significantly more common in the patients who were not well controlled. Additionally, there was a strong correlation between asthma control and a global assessment of general health status. Eighty-five percent of the controlled subjects stated that their overall health was good to excellent, while this was reduced to 58% of those not well controlled.

The second part of their research focused on patients who completed both ACT and a spirometry that met ATS criteria. This study demonstrated that ACT was able to identify the largest number of patients with uncontrolled asthma. Spirometry also identified a significant cohort with abnormal measure of forced expiratory volume in 1 second (FEV1). Although some of this population overlapped, there was a significant cohort that had an ACT score less than or equal to 19 with a normal FEV1, a similar cohort with an abnormal FEV1, and a normal cohort. Abnormal lung function tended to be in study subjects who were older and from minority groups. These findings point to a need to use both assessment measures to achieve the highest predictive value of asthma control. These results echo the patient reporting by Dr. Boushey in his presentation of the patient who failed to report symptoms of disease but was identified with abnormal spirometry. In addition, there are many patients with normal lung function, especially children and young adults with active symptoms and yet normal lung function. These 2 abstracts demonstrate that ACT by itself is a simple, inexpensive test that has been validated to determine asthma control and can be administered to large populations with asthma. Stanford and colleagues, in their second abstract, point to the need to increase the sensitivity of determining asthma that is not well controlled by performing both ACT and spirometry.

Conclusions

In summary, it appears from these presentations that there is a desire to move from the present asthma paradigm of disease severity to disease control as the tool for assessment of asthma status. In turn, disease control measures can be used as a means for determining patients who warrant controller therapy as well as to assess the success of asthma therapy. Spirometry remains an essential diagnostic tool in increasing the sensitivity of determining which patients have not achieved adequate control. These measures of lung function are limited in children, however, because of the frequent findings of normal spirometry in the presence of symptoms. The use of exhaled breath condensates and specifically eNO may prove to be of significant benefit in properly diagnosing patients with asthma.

Supported by an independent educational grant from GlaxoSmithKline.

References

1. Nathan R, Sorkness C, Kosinski M, et al. Development of the Asthma Control Test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113:59-65. Abstract
   
2. Vollmer W, Markson L, O'Connor E, et al. Association of asthma control with health care utilization and quality of life. Am J Respir Crit Care Med. 1999;160:1647-1652. Abstract
   
3. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14:902-907. Abstract
   
4. Cockcroft DW, Swystun VA. Asthma control versus asthma severity. J Allergy Clin Immunol. 1996;98(6 Pt 1):1016-1018.
   
5. Bateman ED, Boushey HA, Bousquet J, et al; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control Study. Am J Respir Crit Care Med. 2004;170:836-844. Abstract
   
6. Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med. 2001;163:1693-1722. Abstract
   
7. Green RH, Brightling CE, McKenna S, et al.. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360:1715-1721. Abstract
   
8. Covar RA, Spahn JD, Martin RJ, et al. Safety and application of induced sputum analysis in childhood asthma. J Allergy Clin Immunol. 2004;114:575.
   
9. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet. 1994;343:133-135. Abstract
   
10. Pauwels RA, Pedersen S, Busse WW, et al; START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361:1071-1076. Abstract
    
11. Lazaar AL, Panettieri RA Jr. Is airway remodeling clinically relevant in asthma? Am J Med. 2003;115:652-659.
    
12. Stanford R, Williamson A, Stemple D. Evaluation of asthma control in subjects. J Allergy Clin Immunol. 2005;115:S147.. Abstract #585.
    
13. Stemple D, Williamson A, Stanford R. Comparative assessment of asthma control with both ACT and spirometry in subjects attending community events. J Allergy Clin Immunol. 2005;115:S216. Abstract #858.
    
    
    
    Saludos Cordiales
    Dr. José Manuel Ferrer Guerra
    

Sustained-Release Bupropion or Buspirone May Augment Citalopram Response

Patients with depression not responding adequately to citalopram may respond to the addition of either bupropion or buspirone, with the former having certain advantages, according to the results of a randomized study reported in the March 23 issue of The New England Journal of Medicine..

"Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach," write Madhukar H. Trivedi, MD, from the University of Texas Southwestern Medical Center in Dallas, and colleagues from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study Team. "Buspirone, a partial agonist at the postsynaptic 5-hydroxytryptamine1A (5-HT1A) receptor, enhances the activity of SSRIs [selective serotonin reuptake inhibitors] through the 5-HT1A receptors. In contrast, sustained-release bupropion appears to produce antidepressant effects by blocking the reuptake of dopamine and norepinephrine. Buspirone is not viewed as an antidepressant monotherapeutic agent, whereas sustained-release bupropion is."

STAR*D enrolled adult outpatients who had nonpsychotic major depressive disorder without remission despite a mean of 11.9 weeks of citalopram therapy at a mean final dose of 55 mg/day. Participants were randomized to receive augmentation with sustained-release bupropion at a dose of up to 400 mg/day (n = 565) or buspirone at a dose of up to 60 mg/day (n = 286).

The primary outcome was remission of symptoms at the end of the study, defined as a score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17). Raters blinded to treatment assignment obtained HRSD-17 scores by telephone. Secondary outcomes were remission at the end of the study, defined as a score of less than 6 on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16), and response, defined as a reduction in baseline QIDS-SR-16 scores of at least 50%.

The sustained-release bupropion and buspirone groups had similar rates for HRSD-17 remission (39.0% vs 32.9%), QIDS-SR-16 remission (39.0% vs 32.9%), and QIDS-SR-16 (31.8% vs 26.9%) response. Compared with buspirone, however, sustained-release bupropion was associated with a greater reduction from baseline in QIDS-SR-16 scores (25.3% vs 17.1%; P < .04), a lower QIDS-SR-16 score at the end of the study (8.0 vs 9.1; P < .02), and a lower dropout rate due to intolerance (12.5% vs 20.6%; P < .009).

"Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical settings," the authors write. "Augmentation with sustained-release bupropion does have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects and adverse events."

Study limitations include lack of placebo, unblinded delivery of treatment, and inability to exclude spontaneous remission, the nonspecific effects of treatment, or the extended use of citalopram alone as the likely explanation for these findings.

"Factors to be considered when selecting augmentation treatments include efficacy, tolerability, burden of side effects, interactions among drugs, dosing convenience, adherence, and cost," the authors conclude. "These results do raise the question of whether to use augmentation agents (or other treatment combinations) as first-line treatment in an attempt to achieve greater remission rates sooner in more patients than with SSRIs alone."

The National Institute of Mental Health supported this study. Bristol-Myers Squibb, the maker of buspirone; Forest Pharmaceuticals; GlaxoSmithKline, the maker of bupropion; King Pharmaceuticals; Organon; Pfizer; and Wyeth-Ayerst Laboratories provided medications at no cost. Some of the authors have disclosed various financial relationships with Advanced Neuronetic Systems, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, HealthCare Technology Systems, Merck, Neuronetics, Organon, Ono Pharmaceuticals, Wyeth-Ayerst Laboratories, Guilford Press, Health Technology Systems, Pfizer, Johnson & Johnson, Sepracor, Cephalon, Corcept Therapeutics, Janssen Pharmaceutica, Predix Pharmaceuticals, Shire, Somerset, Genaissance, Innapharma, Cederroth, Lichtwer Pharma, Novartis, Abbott Laboratories, Lorex Pharmaceuticals, Bayer AG, Biovail, BrainCells, Compellis, Cypress Pharmaceutical, Dov Pharmaceutical, Grunenthal, Lundbeck, Pamlab, Aspect Medical Systems, AstraZeneca, Pharmavite, Roche, Sanofi-Synthelabo, and/or Solvay Pharmaceuticals.

In an accompanying editorial, David R. Rubinow, MD, from the University of North Carolina, Chapel Hill, states that these findings are simultaneously illuminating and disconcerting: the former because they provide real-world data on real-world outcomes in real-world patients.

However, they are discouraging because the results suggest that at least half of patients with depression do not have a remission.

"Affective neuroscience and effectiveness trials such as STAR*D should help us identify new targets for treatment and patients for whom the treatments will be the most effective and best tolerated," Dr. Rubinow writes. "However, if we fail to make health care accessible, to make the treatments for depression available, and to destigmatize depression, we will guarantee the continued and unnecessary suffering of millions of our friends and neighbors."

Dr Rubinow has disclosed no relevant financial relationships.

N Engl J Med. 2006;354:1243-1252, 1305-1307

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Describe the use of bupropion and buspirone in depression.
  
• Compare bupropion vs buspirone as augmentation therapy for patients with depression and an incomplete response to an SSRI.
  

Clinical Context

The lifetime prevalence of depression is approximately 15% to 20%, and many patients may not respond to therapy with an SSRI. While little large-scale research examining the benefits of augmentation therapy for such patients exists, smaller reports have suggested a role for bupropion and buspirone in such treatment. Buspirone may increase the effectiveness of SSRIs through its action as a postsynaptic 5-HT1A agonist, although it is not considered an antidepressant when used as monotherapy. Bupropion is indicated as monotherapy for depression and may also augment the effects of SSRIs by increasing central levels of dopamine and norepinephrine.

In the current trial, the authors compare bupropion vs buspirone among patients with depression who failed to achieve remission with citalopram.

Study Highlights

• Study subjects had nonpsychotic major depressive disorder and a HRSD score of 14 or more. All participants had failed to achieve remission with citalopram monotherapy, with remission defined by a score of 7 or less on the HRSD.
  
• Participants were randomized to receive augmentation of their stable dose of citalopram with either sustained-release bupropion or buspirone. For a 6-week period, these agents were titrated to maximum daily dosages of 400 and 60 mg, respectively.
  
• The primary study outcome was the remission from depression as measured by a score of 7 or less on the HRSD. Secondary outcomes included remission or response on the QIDS-SR-16, defined by a total score of 5 or less or a reduction of at least 50% from the baseline score, respectively. The study period was 12 weeks. No placebo control was used.
  
• 565 subjects underwent randomization to buspirone or bupropion therapy. The mean age of participants was 41 years old, and 58.8% were female. The average duration of the depressive episode was 16 years, and 79.3% of subjects reported a history of recurrent depression. 17.9% of the cohort had attempted suicide.
  
• Baseline data were similar between groups with the exception that the mean duration of illness among subjects in the bupropion group was 15 years vs a mean duration of 17 years in the buspirone group.
  
• The mean dose of citalopram was 54 mg. The mean daily dosages at the end of the study of bupropion and buspirone were 267.5 and 40.9 mg, respectively.
  
• Subjects receiving bupropion had a significantly longer mean duration of treatment vs those receiving buspirone (10.2 vs 9.2 weeks, respectively). 60% of subjects in the buspirone group received less than 4 weeks of treatment vs only 39% of the bupropion group.
  
• Overall rates of remission were similar between groups. Based on HRSD scores, rates of remission were 29.7% and 30.1% in the bupropion and buspirone groups, respectively. Based on the QIDS-SR-16 survey, the respective remission rates were 39.0% and 32.9%, and the respective response rates were 31.8% and 26.9%. However, QIDS-SR-16 scores at the end of the study were significantly lower in the bupropion vs buspirone groups.
  
• The mean time to remission was about 6 weeks in both treatment groups.
  
• Bupropion was better tolerated than buspirone, with study dropout rates due to adverse events of 12.5% and 20.6% in the bupropion and buspirone groups, respectively. However, rates of serious adverse events were similar between groups.

Pearls for Practice

• Buspirone can increase the serotonin-related action of SSRIs in the brain but is not considered an antidepressant when used in monotherapy. Bupropion may augment the effects of SSRIs by increasing central levels of norepinephrine and dopamine and can be used as monotherapy for depression.
  
• Augmentation of SSRI therapy for treatment-resistant depression may be equally effective with buspirone or bupropion, but bupropion may be better tolerated.
  
  
  
  Saludos Cordiales
  Dr. José Manuel Ferrer Guerra
  

Cigarette smoke linked to diabetes?

In another blow for tobacco smoke, a recent study shows that it could lead to diabetes.

A 15-year multicenter study called CARDIA (Coronary Artery Risk Development in Young Adults) looked at the impact of tobacco use in the evolution of glucose intolerance, a precursor to diabetes. Results from the study were published in the April 8 issue of the British Medical Journal.

Diabetes is a condition in which the pancreas is unable to produce the amount of insulin needed to regulate the body's blood sugar. According to the American Diabetes Association (ADA), it claims the lives of more than 224,000 Americans annually.

For the study, researchers enrolled 4,572 men and women from four states (Alabama, Minnesota, Illinois and California) and divided them into four groups: smokers, those who had stopped smoking, people who never smoked but were exposed to environmental tobacco smoke (ETS), and those who had never smoked and who weren't exposed to ETS.

Researchers found a direct correlation between tobacco exposure and the development of glucose intolerance, with 22 percent of smokers developing the condition.

Only 12 percent of nonsmoking, non-ETS-exposed individuals developed the condition. The other two groups fared somewhere in between.

Since the toxins emanating from cigarette smoke are produced at varying temperatures and under varying chemical conditions, those present in exhaled smoke may be more numerous and more harmful than those in directly inhaled smoke.

Apparently, there is something in both the inhaled and exhaled smoke that damages the pancreas.

The Environmental Protection Agency (EPA) has classified tobacco smoke as a known human carcinogen. It contains over 4,000 chemical compounds, more than 60 of which are suspected or known to cause cancer. Should you worry if you aren't a smoker?

According to the American Cancer Society, each year in the United States, secondhand smoke is responsible for:

• An estimated 35,000 to 40,000 deaths from heart disease in people who are not current smokers
  
• About 3,000 lung cancer deaths in nonsmoking adults
  
• Other respiratory problems in nonsmokers, including coughing, excess phlegm, chest discomfort and reduced lung function
  
• Between 150,000 to 300,000 lower respiratory tract infections (such as pneumonia and bronchitis) in children younger than 18 months of age, which result in 7,500 to 15,000 hospitalizations
  
• Increases in the number and severity of asthma attacks in about 200,000 to 1 million asthmatic children
  
• Increases in the risk of sudden infant death syndrome (SIDS) and middle-ear infections in young children
  
• Low birth weight in babies whose mothers are exposed to ETS
  

There is even some evidence now linking ETS to breast cancer, especially in younger women.

The colleges and institutions involved in the study included the University of Alabama at Birmingham, University of Minnesota, Northwestern University, Kaiser Foundation, University of California (Irvine and Los Angeles campuses) and the National Heart, Lung and Blood Institute






Saludos Cordiales
Dr. José Manuel Ferrer Guerra

High Cholesterol May Be Prostate Cancer Risk

MILAN, Italy, April 13 - Men who self-reported hypercholesterolemia had about a 50% greater risk for prostate cancer than men with normal cholesterol levels, and if they were older than 65 the extra risk climbed to 80%, researchers here reported.

The finding, if borne out by additional research, is sure to warm statin-makers' hearts, because it suggests that medications to control cholesterol could be protective against prostate cancer, noted Francesca Bravi, M.D., and colleagues, of the Istituto di Ricerche Farmacologiche Mario Negri in Milan, in the online edition of Annals of Oncology.


"Androgens -- hormones that have a role in prostate tissue and cancer -- are synthesized from cholesterol, suggesting a possible biological relationship between high cholesterol and prostate cancer," said Cristina Bosetti, Ph.D., a co-author and senior epidemiologist and biostatistician.


"Gallstones are related to high cholesterol levels as well and are often composed of cholesterol," she added. "So the direct relationship we found between gallstones and prostate cancer, while it was not statistically significant, suggests a similar biological mechanism may explain the link."


The investigators used the admittedly imprecise method of self-reporting to assess possible associations between high cholesterol levels, gallstones, and prostate cancer.


They conducted a case-control study using data on men from four geographic regions spanning the Italian peninsula. The cases were 1,294 men younger than 75 (median age 66, range 46-74) with incident histologically confirmed prostate cancer who had been diagnosed less than a year before being interviewed for the study. They had been admitted to major teaching and general hospitals in the study areas.


Controls were 1,451 men 75 or younger (median age 63, range 46-74) who had been admitted to the same hospitals for a variety of acute non-cancerous conditions that were not related to known or potential risk factors for prostate cancer or other chronic conditions. Controls included patients admitted for trauma, orthopedic problems, acute surgical conditions, and other illnesses.


All participants were interviewed in the hospital by trained interviewers using a structured questionnaire that included information on demographic factors, body measures, lifestyle habits (such as smoking and drinking), food frequency, and family history of cancer.


Patients were also asked whether they had ever suffered from one or more of several non-malignant conditions, including hypercholesterolemia and gallstones, and their age at first diagnosis or treatment of those conditions.


The authors found that after controlling for major confounding factors there was a direct association between prostate cancer and hypercholesterolemia (odds ratio 1.51, 95% confidence interval, 1.23-1.85, P < 0.0001).


Gallstones were not statistically significantly associated with excess risk for prostate cancer (OR 1.26, 95% CI 0.93-1.70, P value not shown).


Among men 65 and older the association between elevated cholesterol and prostate cancer was particularly strong (OR 1.80, 95% CI 1.32-2.40) compared with younger men.


The authors did not specify the definition of hypercholesterolemia they used for the study, and they acknowledged that the study was subject to recall bias and that the information provided by the cases could not be checked against medical records.


"Although the study relied on participants' self-reported medical conditions, the absence of an association between prostate cancer and about 10 other medical conditions we investigated indicates that the relationship we found between prostate cancer and high cholesterol appears to be a real one," Dr. Bravi said in defense of the findings.

Primary source: Annals of Oncology
Source reference:
Bravi F et al. "Self-reported history of hypercholesterolaemia and gallstones and the risk of prostate cancer." Annals of Oncology doi:10.1093/annonc/mdl080

Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Sibutramine May Help Control Weight Gain Associated With Olanzapine Treatment

Sibutramine may be effective in controlling the weight gain associated with olanzapine, according to the results of a randomized trial published in the May issue of the American Journal of Psychiatry.

"Weight gain is commonly observed with olanzapine treatment and can increase the risk for obesity, cardiovascular disease, hypertension, and diabetes mellitus," write David C. Henderson, MD, from the Massachusetts General Hospital in Boston, and colleagues. "Sibutramine hydrochloride, a weight loss agent affecting both serotonin and norepinephrine reuptake, was introduced into the U.S. Market in 1997. The hypophagic effect of sibutramine is thought to be mediated, in part, through activation of the serotonin 5-HT2C receptor."

In this 12-week, double-blind trial, 37 persons were randomized to receive placebo or sibutramine, up to 15 mg per day. All study subjects had schizophrenia or schizoaffective disorder meeting criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, treated with a stable dose of olanzapine for at least four months, and had a body mass index (BMI) of at least 30 kg/m2 or at least 27 kg/m2 plus at least one cardiovascular risk factor. During the first eight weeks, all study subjects participated in weekly group sessions dealing with nutrition and behavior modification.

At baseline, both groups were similar in age, sex, education, ethnicity, diagnosis, weight, BMI, and blood pressure. Although the difference between groups was not significant at weeks 4 and 8, by week 12, the sibutramine group fared significantly better than the placebo group in terms of reductions in weight (mean, 8.3 ± 2.4 lb vs 1.8 ± 1.6 lb), waist circumference, BMI, and hemoglobin A1C. These reductions were not sustained at three months after study completion; the study subjects who had received sibutramine gained weight and returned to near their baseline weight.

Most adverse effects were similar in both groups. However, the sibutramine group had a mean increase in systolic blood pressure of 2.1 ± 8.5 mm Hg, and anticholinergic adverse effects and sleep disturbances were at least twice as frequent in the sibutramine group.

"Sibutramine was an effective and well-tolerated adjunct to behavior modification for weight loss in patients with schizophrenia and schizoaffective disorder being treated with olanzapine," the authors write. "As expected, the benefits of sibutramine do not continue after discontinuation of the drug."

Study limitations may include lack of generalizability to other populations, particularly in the absence of a nutritional counseling program, such as patients taking serotonergic agents, selective serotonin reuptake inhibitors, or other medications that cause significant weight gain (e.g., clozapine). Other limitations include short duration and inability to determine whether the observed weight reductions could be maintained with long-term use of sibutramine.

"Sibutramine treatment improved several health status markers that are predictive of cardiovascular disease," the authors conclude. "This degree of weight loss in obese schizophrenia patients could, if sustained, substantially reduce morbidity and mortality.... "Additional studies are necessary to establish the long-term weight loss effectiveness and safety in schizophrenia patients whose weight gain from antipsychotic medications jeopardizes their cardiovascular health."

The National Alliance for Research on Schizophrenia and Depression and an investigator-initiated independent research grant from Eli Lilly and Co., maker of Zyprexa, supported this study. Knoll Pharmaceuticals (Abbott Laboratories) provided the study drug and placebo.

Am J Psychiatry. 2005;162:954-962

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Describe the relationship between antipsychotic agents and weight gain.
  
• Identify outcomes improved with the use of sibutramine in the management of olanzapine-associated weight gain.
  

Clinical Context

Although all antipsychotic agents may produce weight gain, newer unconventional agents may increase the risk of weight gain to a greater extent than do older drugs. Patients who are underweight at the initiation of therapy appear to carry the biggest risk of weight gain related to antipsychotic therapy, but patients who are overweight at baseline are most likely to experience the consequences of antipsychotic-associated weight gain, including diabetes.

Because improved response to antipsychotics has been associated with higher amounts of weight gain, treatment discontinuation or dosage reduction is less attractive for many patients and physicians who can witness the positive psychotropic effects of the medication. The authors of the current study examined the efficacy of sibutramine, which can reduce weight through activation of central serotonin receptors, in the management of weight gain associated with the newer antipsychotic olanzapine.

Study Highlights

• Patients who were receiving olanzapine for schizophrenia or schizoaffective disorder at stable doses for at least 4 months were eligible for study participation. All study subjects had experienced weight gain associated with olanzapine and had a BMI of at least 30 kg/m2 or 27 kg/m2 plus 1 or more cardiovascular risk factors. Patients with significant medical problems or substance abuse were excluded from study participation.
  
• The study intervention consisted of two to three 5-mg sibutramine tablets daily or matching placebo. The research was double-blinded. All participants attended 8 weekly sessions focused on weight education.
  
• The main study outcome was weight loss during the 12-week treatment period. Subjects were also followed for BMI, waist-to-hip ratio, and percentage of body fat, which was assessed using skinfold measurements. Psychiatric disease activity was monitored, as were lipid profiles and glycosylated hemoglobin.
  
• 37 study subjects participated in the trial. Baseline characteristics were similar between the sibutramine and placebo groups. The mean ages of participants were 43.2 and 40.7 years, respectively, and the mean baseline BMIs were 34.3 and 38.4 kg/m2, respectively. Estimated body fat was 38.4% in the sibutramine group and 34% in the placebo group.
  
• Both groups exhibited nonsignificant decreases in total calories consumed during the study period. Intake of polyunsaturated fats was lower in the sibutramine group at 12 weeks compared with baseline intake.
  
• There was no significant difference in weight loss between the 2 groups at weeks 4 and 8, but at week 12 a growing difference became statistically relevant. The average weight loss was 2 pounds in the placebo group at 12 weeks compared with 8 pounds in the sibutramine group.
  
• Both BMI and waist-to-hip ratio were improved in the sibutramine group compared with the placebo group at 12 weeks. However, the percentage of body fat did not differ between groups.
  
• Glycosylated hemoglobin values decreased from 5.6% at baseline to 5.3% at 12 weeks in the sibutramine group; the respective values for the placebo cohort were 5.7% and 6.0%. The difference in these values at 12 weeks between groups was statistically significant.
  
• Lipid profiles were not significantly different between groups at 12 weeks. Compared with baseline values, levels of low-density lipoprotein cholesterol decreased in the sibutramine group, but triglyceride levels increased.
  
• Sibutramine was associated with a mean increase in systolic blood pressure of 2.1 mm Hg. Anticholinergic adverse effects were also more common with sibutramine. Rates of study discontinuation were similar between the 2 treatment groups.
  
• In a follow-up of 22 study subjects 3 months after study termination, the benefits of sibutramine were no longer evident; patients from the 2 treatment groups exhibited similar weights, BMIs, and waist-to-hip ratios.
  

Pearls for Practice

• Newer antipsychotic agents may be more likely to increase patients' weight than are older agents, particularly for underweight patients and patients whose psychiatric symptoms respond well to treatment. Patients who are overweight at baseline, however, are more likely to experience negative health consequences as a result of antipsychotic-associated weight gain.
  
• Sibutramine can reduce weight, BMI, and waist-to-hip ratio after 12 weeks in patients with weight gain related to olanzapine. However, these benefits do not seem to persist after cessation of treatment with sibutramine.
  

Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Blood Transfusions Could Transmit Variant Creutzfeldt-Jakob

Bovine spongiform encephalopathy (BSE), better known as mad cow disease, is apparently not easily transmitted From cattle to humans. That's the good News.

The bad News is that once BSE makes the jump into people in the form of variant Creutzfeldt-Jakob disease, or vCJD, it may readily spread From one person to the next through the British blood supply, reported researchers in an early Online release From The Lancet Neurology.

Studies of transgenic mice bred to express the human prion protein gene in its most common human variants indicate that while there appears to be good protection against BSE transmission to humans, human-to-human transmission of vCJD may readily occur in all but about 10% of the population, according to Jean C. Manson, Ph.D., and colleagues of the Institute for Animal Health here.

Variant CJD may also have a very long incubation period, and there may be a significant level of subclinical disease, the investigators suggested.

"Although the cattle BSE epidemic in the United Kingdom has amounted to more than 180,000 cases since the 1980s, the extent of the human vCJD epidemic has so far remained limited, with the total number of cases worldwide currently at 190," Dr. Manson and colleagues wrote.

"One explanation for this apparent discrepancy is that there exists a significant species barrier between cattle and human beings, which limits the susceptibility of the human population to BSE…," they added. "However, once BSE has passed through human beings in the form of vCJD, the transmissibility of this transmissible spongiform encephalopathy strain is altered for the human population."

A specific polymorphism, or variant, in the prion protein gene in humans has been shown to be a major determinant of susceptibility to prion diseases. The polymorphism, which occurs at codon 129 of the gene, determines whether the amino acids methionine or valine are present at that location.

About 40% of Caucasians are homozygous for methionine, and an additional 50% of Caucasians are heterozygous (I.e., have one valine and one methionine allele), and another 10% are homozygous for valine.

"All cases of human vCJD have been in patients with the methionine-methionine genotype, which suggests that the methionine-valine and valine-valine genotypes are protective," wrote Corinne Ida Lasmezas, Ph.D., a professor of biomedical Research at the Scripps Research Institute in Jupiter, Fla., in an accompanying editorial.

But as Dr. Manson and colleagues found in their Study, "all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion."

They determined this by using transgenic mice as surrogates for humans. The mice were bred to express either the human or bovine forms of the prion protein gene. For the mice with the human gene, the investigators bred three genetically identical populations that expressed the gene in the three human variants (methionine homozygous, heterozygous, or valine homozygous).

The mice were then inoculated with either BSE or vCJD delivered directly into the brain, and all mice were assessed for Clinical and pathological signs of prion disease.

They found that while BSE was transmitted via inoculation to those mice expressing the bovine form of the prion protein gene, the mice with the human forms of the gene did not develop transmissible spongiform encephalopathies.

In contrast, vCJD was transmitted to all three mouse lines expressing the human gene variants, with different pathological characteristics for each genotype. For example, mice with the methionine-methionine polymorphism had evidence of disease at a relatively early stage, 370 days after inoculation, whereas as the heterozygous animals had evidence of disease that was restricted to only a few brain areas beginning at around 581 days, and remained limited at least 700 days after inoculation.

In addition, the authors found that there was a gradation of transmission efficiency, with the methionine-methionine genotype being the most susceptible (11 of 17 mice infected) to methionine-valine (11 or 16 infected) to valine-valine (1 of 16 infected).

There findings suggest that "transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there seems to be a substantially reduced barrier for human-to-human transmission of vCJD," the authors wrote.

"Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant Public-Health issue," they concluded.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

MRI May Not Be Necessary in Cervical Spine Trauma if CT Is Normal

Patients with cervical spine injuries can be cleared on the basis of normal computed tomography (CT) alone without also undergoing magnetic resonance imaging (MRI) if they are alert and have normal motor examination results, according to investigators whose findings were published in the August 2005 issue of the Archives of Surgery.
"This study evaluated all cervical MRIs in trauma patients without motor deficits and with normal CT results of the cervical spine," Rob Schuster, MD, and colleagues wrote. "We found that none of these patients had clinically significant injuries diagnosed by MRI. We also observed these patients clinically and found that no patient experienced neurologic deterioration." Even among comatose patients, "movement of the extremities ... Is sufficient motor activity to rule out spinal cord injury when the CT scan result is normal."

Dr. Schuster is affiliated with the department of surgery at the Santa Barbara Cottage Hospital in Santa Barbara, California.

The investigative team determined if cervical spine injuries could be ruled out with a normal CT alone in patients who have had sustained blunt trauma. Therefore, they prospectively gathered data on 2,854 trauma patients who were admitted to the hospital. Among these patients, 91.2% had blunt trauma, and among blunt trauma patients, 56.2% sustained a closed head injury. Among those admitted, 100 patients had a cervical spine injury, a spinal cord injury, or both. The treating physicians diagnosed 85 of the cervical spine injuries on the basis of CT results. Within the group of cervical spine injury, 15 had neurologic deficits that were not detected on CT, and among these, seven had soft-tissue abnormalities that were detected on MRI.

The investigators also assessed the MRIs of 93 patients who had a normal admission motor examination result, a negative CT result for trauma, and persistent cervical spine pain. Among these patients, all had MRI findings that were negative for clinically significant injury. The MRI showed degenerative disc disease in 17 and spinal canal stenosis secondary to ossification in six.

Among the 12 comatose patients, defined as a Glasgow Coma Scale (GCS) score of less than 9, all were able to move all four extremities when they were admitted. All had normal CT results of the cervical spine. These patients' subsequent MRI results were all negative for injury.

Among the patients with normal CT results, none had neurologic deterioration, and none required surgery for spinal injury, the authors wrote.

Arch Surg. 2005;140:762-766

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Describe the criteria for clearing the cervical spine in trauma patients.
  
• Explain why trauma patients with normal motor examination results and normal cervical CT scan do not need additional MRI studies to clear the cervical spine.
  

Clinical Context

Cervical spine injuries can lead to devastating neurologic deficits; therefore, accurate and rapid diagnosis and treatment is essential in trauma situations. To clinically clear the cervical spine, the physician must make certain the patient is awake, alert, and lucid and has a normal neurologic examination and no neck pain. All other patients who do not meet these criteria must undergo radiologic examination before the spine is cleared. Studies have found that plain radiographs alone miss 46% of injuries and are not adequate in clearing the spine.

CT of the cervical spine has increased the rate of injury detection and decreased the rate of missed injury. One study demonstrated that CT with sagittal reconstructions showed a sensitivity of 99% and specificity of 100% in detecting cervical spine injury. Therefore, cervical CT scans have become the mainstay in clearing the spine.

However, there are two populations of patients that may challenge the use of CT-based protocol, requiring a more extensive imaging study such as a MRI. There are concerns that patients with persistent neck pain and comatose patients may have a ligamentous injury. The current authors of this prospective study show that this type of injury is unlikely and would manifest as a neurologic deficit at the time of initial trauma. Further, in this study population, the authors note that clinically significant injuries would not be found. Hence, additional studies beyond a CT scan would not be needed to clear the cervical spine.

Study Highlights

• Between January 1999 to December 2003, 2,854 trauma patients at Santa Barbara Cottage Hospital were evaluated in this prospective study.
  
• 91.2% had blunt trauma, and of these, 56.2% had a closed head injury.
  
• The mean age was 37 years, and the Male-female proportion was 69.4% to 30.6%.
  
• Cervical spine protocol was implemented in all patients with evidence of blunt trauma. The cervical spine was clinically cleared with negative findings from the physical examination. However, for those who could not be cleared clinically, helical CT scanning was performed, and of those, selected patients had a MRI done.
  
• To measure neurologic outcomes, all patients had frequent neurologic examinations and outpatient follow-up in the clinic 1 to 2 weeks after discharge.
  
• 100 patients (3.8%) of all blunt trauma admissions had cervical spine and/or spinal cord injuries as evidenced by fracture and/or peripheral neurologic deficits. 85 patients had a cervical spine injury diagnosed by CT, and 15 patients had neurologic deficits without CT findings.
  
• 93 patients had a normal motor examination result, a negative CT result for trauma, and severe persistent cervical spine pain. They were all examined with MRI, and all results were negative for clinically significant injury.
  
• 12 comatose patients with a GCS score of less than 9, ability to move all 4 extremities on arrival, and with normal CT results of the cervical spine had negative MRI examination results.
  
• None of the patients experienced neurologic deterioration, and no patient required operative management of spinal injury.
  
• Blunt trauma patients with normal motor examination results and normal CT results of the cervical spine do not need further radiologic examination such as a MRI before clearing the spine.

Pearls for Practice

• To clinically clear the spine, the physician must make certain that the patient is awake, alert, and lucid and has a normal neurologic examination and no neck pain.
  
• There was no additional benefit or information gained in using MRI in blunt trauma patients with normal motor examination and normal CT results before clearing the spine.
  

Saludos Cordiales
Dr. José Manuel Ferrer

Pfizer Expands Commitment to Urology With Agreement to Acquire Worldwide Rights to New Drug Candidate Fesoterodine

Pfizer Expands Commitment to Urology With Agreement to Acquire Worldwide Rights to New Drug Candidate Fesoterodine


New Treatment Expected to Provide Additional Choice for Overactive Bladder Patients

NEW YORK, April 13, 2006 /PRNewswire-FirstCall/ -- Pfizer Inc said today that it has entered into an agreement with Schwarz Pharma AG under which Pfizer will acquire exclusive worldwide rights to fesoterodine, a new drug candidate for treatment for overactive bladder.


Earlier this year, Schwarz submitted new drug applications for fesoterodine with both the US Food and Drug Administration and the European Medicines Evaluation Agency (EMEA).

"Overactive bladder is a debilitating condition that affects up to 100 million people around the world," said Karen Katen, vice chairman of Pfizer Inc and president, Pfizer Human Health. "We are excited about the potential of this new medicine to offer patients and their doctors a new alternative to existing therapies for managing the symptoms of overactive bladder."

Under the terms of the agreement, Pfizer will make an initial payment of $100 million to Schwarz Pharma plus additional payments based on certain milestones. Schwarz Pharma will also be entitled to royalties on sales of both fesoterodine and Pfizer's Detrol product line for treatment of overactive bladder. The agreement settles all existing and potential fesoterodine patent litigation between the parties worldwide. The agreement is subject to clearance by U.S. Federal Trade Commission.

Pfizer is a leader in the field of urology with significant experience in meeting the needs of patients with overactive bladder. The company's once daily medicine Detrol LA helps control involuntary bladder contractions and reduce symptoms of urgency with or without frequency and incontinence. Since its introduction in 2001, Detrol LA has been prescribed for more than 11 million patients worldwide.

PFIZER DISCLOSURE NOTICE: The information contained in this document is as of April 13, 2006. Pfizer assumes no obligation to update any forward-looking statements contained in this document as a result of new information or future events or developments.

This release contains forward-looking information about an agreement by Pfizer to acquire the rights to a drug candidate that is under review by the United States Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) as well as the potential efficacy of such drug candidate. Such information involves substantial risks and uncertainties including, among other things, obtaining clearance of the agreement by the United States Federal Trade Commission; whether and when the FDA and the EMEA will approve the drug candidate and their decisions regarding labeling and other matters that could affect its availability or commercial potential; and competitive developments.

A further list and description of risks and uncertainties can be found in the Company's Annual Report on Form 10-K for the fiscal year ended December 31, 2005, and in its reports on Form 10-Q and Form 8-K.

CONTACT: Paul Fitzhenry, +1-212-733-4637 for Pfizer Inc

Web site: http://www.pfizer.com/

Company News On-Call: Pfizer's press releases are available through PR Newswire's Company News On-Call service on PRN's Web Site. Visit http://www.prnewswire.com/comp/688250.html/

Ticker Symbol: (:PFE)

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Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Acupressure May Be More Effective Than Physical Therapy at Relieving Low Back Pain

Acupressure is more effective than physical therapy at relieving low back pain, according to the results of a randomized Study reported in the February 17 Online First issue of the BMJ.
"The efficacy of acupressure in relieving pain associated with low back pain has been shown by a randomized controlled trial," write Lisa Li-Chen Hsieh, MD, From National Taiwan University in Taipei, and colleagues. However, the outcomes in that Study were assessed by description of pain character and failed to take into account functional status and disability as recommended by most low back pain researchers. Although trials have investigated the efficacy of physical therapy, acupuncture, and acupressure in reducing low back pain, the type of outcome measurement has varied From Study to Study."

At an orthopedic Clinic in Kaohsiung, Taiwan, 129 patients with chronic low back pain were randomized to receive acupressure or physical therapy for 1 month. Primary endpoints were self-administered Chinese versions of standard outcome measures for low back pain (Roland and Morris disability questionnaire) at baseline, after treatment, and at 6-month follow-up.

After treatment, the mean total Roland and Morris disability questionnaire score was significantly lower in the acupressure group than in the physical therapy group regardless of the difference in absolute score (-3.8; 95% confidence interval [CI], -5.7 to -1.9) or mean change From baseline (-4.64; 95% CI, -6.39 to -2.89).

Compared with physical therapy, acupressure was associated with an 89% reduction in significant disability (95% CI, 61% - 97%), and that improvement was maintained at 6-month follow-up. There were statistically significant differences between the groups for all 6 domains of the core outcome, pain visual Scale, and modified Oswestry disability questionnaire after treatment, and at 6-month follow-up.

Study limitations include a confounding psychological effect of therapy; loss of 15.5% of patients to follow-up at 6 months; and effectiveness of any manipulation therapy dependent on the therapist's technique and experience.

"Acupressure was effective in reducing low back pain in terms of disability, pain scores, and functional status," the authors write. "The benefit was sustained for six months."

The authors have disclosed no relevant financial relationships.

BMJ. Posted Online February 13, 2006.

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Compare the effect of acupressure vs physical therapy on disability in low back pain.
  
• Compare the effect of acupressure vs physical therapy on pain and functional status 6 months after treatment.
  

Clinical Context

Low back pain is a common condition worldwide, and the efficacy of acupuncture in alleviating low back pain remains uncertain. However, acupressure, using finger rather than needles for acupoints has been used to treat various pain Disorders and may be useful for low back pain, according to the authors. The current Study is an open randomized controlled trial using Chinese versions of validated standard outcome measures to compare the efficacy of acupressure with that of physical therapy in alleviating the pain and disability associated with low back pain in the short term and for 6 months in patients presenting to an outpatient specialist orthopedic Clinic in Taiwan.

Study Highlights

• Inclusion criteria were aged 18 to 81 years, chronic low back pain for 4 months diagnosed by a senior orthopedic specialist and absence of organic disease, cancer, psychiatric disease, or acute severe pain.
  
• Exclusion criteria were pregnancy and contraindication to acupressure.
  
• 64 patients were randomized to acupressure and 65 to physical therapy.
  
• Each participant received 6 treatment sessions within a 1-month period.
  
• Acupressure was delivered by 1 experienced therapist. Technique and acupoints used were not described.
  
• Physical therapy was provided by therapists in the orthopedic Clinic and included pelvic manual traction, spinal manipulation, thermotherapy, infrared light therapy, electrical stimulation, and exercise therapy as recommended by the physical therapist.
  
• Primary outcome was the Roland and Morris disability score administered in Chinese to participants.
  
• Secondary outcomes were core outcome measures, including a visual analog pain Scale and Oswestry disability score also administered in Chinese.
  
• The Roland and Morris disability score defined minimal disability as a score of 0 to 12 and significant disability as a score of 13 to 24.
  
• The modified Oswestry Scale was used and defined degree of disability as "minimal" (0 - 11), "moderate" (12 - 22), "severe" (23 - 32), "crippled" (33 - 43), and "bed bound" (>/= 44).
  
• Questionnaires were administered at baseline, posttreatment at 1 month, and at 6 months' posttreatment.
  
• Therapists were blinded to participant baseline assessments.
  
• Mean age was 51 years, 30% were men, 84% were married, 12% to 27% were office workers, and 13% were heavy laborers.
  
• Median time since onset of low back pain was 3.3 years in the acupressure and 1.6 years in the physical therapy group.
  
• The mean total Roland and Morris score after treatment was significantly lower in the acupressure group regardless of the difference in absolute score (-3.8; 95% CI, -5.7 to -1.9) and mean change from baseline (-4.64; 95% CI, -6.39 to -2.89).
  
• Acupressure conferred an 89% reduction in significant disability with a number needed to treat of 5.98.
  
• After adjustment for pretreatment score, mean scores were lower for the acupressure group for "low back pain," "leg pain," "pain interferes with normal work," "days cut down on doing things," and "days off from work/school."
  
• Mean scores after treatment were higher in the acupressure group for "satisfaction of life with the symptoms" and "satisfaction with previous treatment."
  
• Mean scores for the pain visual scale and sleeping with back pain were lower in the acupressure group after treatment.
  
• The statistically significant improvements in all these areas remained for the 6-month follow-up questionnaire.
  
• The mean total Oswestry disability questionnaire score after treatment was significantly lower in the acupressure group than in the physical therapy group regardless of the difference in absolute score or mean change from baseline.
  
• The odds ratio of increasing 1 grade of disability was 0.22 (95% CI, 0.11 - 0.48, P = .0001) for the acupressure group, and the difference remained significant after adjustment for pretreatment score and other baseline characteristics.
  
• The estimated number needed to treat for acupressure to reduce the disability by 1 grade was 6.15.
  
• The improvement in Oswestry score in the acupressure group vs the physical therapy group remained at 6 months with a number needed to treat of 4.58.
  

Pearls for Practice

• Acupressure compared with physical therapy for 1 month is associated with an 89% reduction in significant disability in patients with low back pain.
  
• The beneficial effects of acupressure compared with physical therapy for low back pain on disability, function, and pain for 1 month persist at 6 months' posttreatment.
  

Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Yoga May Be More Effective Than Self-Care for Chronic Back Pain

Yoga is more effective than use of a self-Care book for improving function and reducing pain in patients with chronic back pain, according to the results of a randomized trial reported in the December 20 issue of the Annals of Internal Medicine.

"Chronic low back pain is a common problem that has only modestly effective treatment options," write Karen J. Sherman, MD, From the Group Health Cooperative and University of Washington in Seattle, and colleagues. "Yoga may benefit patients with back pain simply because it involves exercise or because of its effects on mental focus. We found no published studies in western biomedical literature that evaluated yoga for chronic low back pain; therefore, we designed a Clinical trial to evaluate its effectiveness and safety for this condition."

At a nonprofit, integrated healthcare system, 101 adults with chronic low back pain were randomized to receive 12-week sessions of yoga or conventional therapeutic exercise classes or a self-Care book. The main endpoints, both determined at 12 weeks, were back-related functional status, measured with the modified 24-point Roland Disability Scale, and "bothersomeness" of pain on an 11-point numerical Scale. Clinically significant change was defined as 2.5 points on the functional status Scale and 1.5 points on the bothersomeness Scale. Secondary endpoints were days of restricted activity, general Health status, and medication use.

After adjustment for baseline values, back-related function at 12 weeks was better in the yoga group than in the book and exercise groups (yoga vs book: mean difference, -3.4; 95% confidence interval [CI], -5.1 to -1.6; P < .001; yoga vs exercise: mean difference, -1.8; 95% CI, -3.5 to -0.1; P = .034]).

At 12 weeks, no significant differences in symptom bothersomeness were detected between any 2 groups, but at 26 weeks, this measure was better in the yoga group than in the book group (mean difference, -2.2; 95% CI, -3.2 to -1.2; P < .001). At 26 weeks, back-related function in the yoga group was also better than in the book group (mean difference, -3.6; 95% CI, -5.4 to -1.8; P < .001).

"Yoga was more effective than a self-Care book for improving function and reducing chronic low back pain, and the benefits persisted for at least several months," the authors write. "It is important to note that some styles, such as Bikram and vinyasa, may be too vigorous for patients with back pain who are unfamiliar with yoga whereas other styles (for example, Iyengar) may need modification From normal practice to be appropriate for patients with back pain."

Study limitations include follow-up limited to 26 weeks; modest sample sizes; inclusion of relatively well-educated, functional participants; lack of blinding; and use of only 1 instructor to deliver each intervention.

"Physicians should encourage their patients to choose instructors who have experience working with individuals who have back pain and who can help them manage the symptom flare-ups that may occur as a result of physical activity," the authors conclude. "Future Research evaluating yoga for chronic back pain should investigate its mechanisms of action and whether similar results are seen in more diverse populations and in patients with more severe back pain."

The National Center for Complementary and Alternative Medicine and the National Institute for Arthritis and Musculoskeletal and Skin Diseases supported this Study. The authors have disclosed no relevant financial relationships.

Ann Intern Med. 2005;143:849-856

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Describe previous Research evaluating the use of yoga for back pain.
  
• Identify outcomes for back pain improved with yoga vs standard exercise therapy.
  

Clinical Context

Back pain is one of the most common complaints that patients describe to clinicians, and yoga offers some hope for patients with this difficult condition. In a Study by Williams and colleagues, published in the May 2005 issue of Pain, Iyengar yoga proved superior to an educational program in terms of pain intensity, functional disability, and pain medication usage among a cohort of patients with chronic back pain. However, yoga did not improve psychological or behavioral outcomes when compared with the control treatment.

Only 42 subjects completed the Study by Williams and colleagues. The authors of the current Study perform a randomized, controlled trial of yoga in a larger cohort of patients with back pain.

Study Highlights

• Patients eligible for Study participation had visited their physician for treatment of back pain in the 3 to 15 months prior to the Study. All subjects had back pain of at least 12 weeks' duration. Patients with a history of spinal complications, back pain secondary to other systemic disease, or who had received yoga or exercise therapy in the year prior to the Study were excluded From participation.
  
• Study participants were randomized to groups receiving yoga, a standard exercise program, or recommendations for self-management of back pain from a book. The yoga and standard exercise groups attended weekly 75-minute classes for 12 weeks and were instructed on home exercises as well. The yoga classes emphasized viniyoga, which was relatively easy to learn and implement. The standard exercise classes emphasized aerobic exercise and increasing strength.
  
• Outcomes were measured at 6, 12, and 26 weeks. The main study outcome was back dysfunction and symptoms, as measured by validated scales. The authors also measured general health status, limitations on activity, and the use of analgesic medications. Analysis of outcomes was by intent-to-treat.
  
• 101 subjects were enrolled in the study. The mean age of subjects was 44 years, and 66% of the cohort was female. 83% of subjects reported that their pain began for more than 1 year prior to the study, but most participants had not experienced a significant limitation at work secondary to pain. In general, disease characteristics were similar at baseline between groups, although leg pain below the knee was more common in the standard exercise and yoga groups than the book group.
  
• Compliance with all study treatments was good, and the rates of "connecting" with the exercise and yoga instructors were similar among these patient cohorts.
  
• Disability and symptoms of back pain improved with time in all treatment groups during the trial.
  
• The yoga group experienced significantly better evaluations of disability at all follow-up points compared with the book group, but the improvement in disability in the yoga group over the standard exercise cohort was judged not to be clinically significant. Back-related symptoms were also improved in the yoga vs the book group at 6 and 26 weeks, but there was not difference in back-related symptoms between the yoga and standard exercise groups.
  
• Medication use decreased in the yoga groups vs both the standard exercise and book groups. There was no difference between treatment groups in terms of limitation of activity secondary to back pain or overall quality of life.

Pearls for Practice

• Previous research has demonstrated that yoga can improve pain intensity, functional disability, and pain medication usage among patients with chronic back pain, but it was less successful in improving behavioral or psychological outcomes.
  
• The current study demonstrates that yoga and standard exercise are both effective in the management of chronic back pain, although patients receiving yoga used less medication for back pain than those randomized to standard exercise.
  

Saludos Cordiales


Dr. José Manuel Ferrer Guerra

Acupressure May Be More Effective Than Physical Therapy at Relieving Low Back Pain

Acupressure is more effective than physical therapy at relieving low back pain, according to the results of a randomized Study reported in the February 17 Online First issue of the BMJ.
"The efficacy of acupressure in relieving pain associated with low back pain has been shown by a randomized controlled trial," write Lisa Li-Chen Hsieh, MD, From National Taiwan University in Taipei, and colleagues. However, the outcomes in that Study were assessed by description of pain character and failed to take into account functional status and disability as recommended by most low back pain researchers. Although trials have investigated the efficacy of physical therapy, acupuncture, and acupressure in reducing low back pain, the type of outcome measurement has varied From Study to Study."

At an orthopedic Clinic in Kaohsiung, Taiwan, 129 patients with chronic low back pain were randomized to receive acupressure or physical therapy for 1 month. Primary endpoints were self-administered Chinese versions of standard outcome measures for low back pain (Roland and Morris disability questionnaire) at baseline, after treatment, and at 6-month follow-up.

After treatment, the mean total Roland and Morris disability questionnaire score was significantly lower in the acupressure group than in the physical therapy group regardless of the difference in absolute score (-3.8; 95% confidence interval [CI], -5.7 to -1.9) or mean change From baseline (-4.64; 95% CI, -6.39 to -2.89).

Compared with physical therapy, acupressure was associated with an 89% reduction in significant disability (95% CI, 61% - 97%), and that improvement was maintained at 6-month follow-up. There were statistically significant differences between the groups for all 6 domains of the core outcome, pain visual Scale, and modified Oswestry disability questionnaire after treatment, and at 6-month follow-up.

Study limitations include a confounding psychological effect of therapy; loss of 15.5% of patients to follow-up at 6 months; and effectiveness of any manipulation therapy dependent on the therapist's technique and experience.

"Acupressure was effective in reducing low back pain in terms of disability, pain scores, and functional status," the authors write. "The benefit was sustained for six months."

The authors have disclosed no relevant financial relationships.

BMJ. Posted Online February 13, 2006.

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Compare the effect of acupressure vs physical therapy on disability in low back pain.
  
• Compare the effect of acupressure vs physical therapy on pain and functional status 6 months after treatment.

Clinical Context

Low back pain is a common condition worldwide, and the efficacy of acupuncture in alleviating low back pain remains uncertain. However, acupressure, using finger rather than needles for acupoints has been used to treat various pain Disorders and may be useful for low back pain, according to the authors. The current Study is an open randomized controlled trial using Chinese versions of validated standard outcome measures to compare the efficacy of acupressure with that of physical therapy in alleviating the pain and disability associated with low back pain in the short term and for 6 months in patients presenting to an outpatient specialist orthopedic Clinic in Taiwan.

Study Highlights

• Inclusion criteria were aged 18 to 81 years, chronic low back pain for 4 months diagnosed by a senior orthopedic specialist and absence of organic disease, cancer, psychiatric disease, or acute severe pain.
  
• Exclusion criteria were pregnancy and contraindication to acupressure.
  
• 64 patients were randomized to acupressure and 65 to physical therapy.
  
• Each participant received 6 treatment sessions within a 1-month period.
  
• Acupressure was delivered by 1 experienced therapist. Technique and acupoints used were not described.
  
• Physical therapy was provided by therapists in the orthopedic Clinic and included pelvic manual traction, spinal manipulation, thermotherapy, infrared light therapy, electrical stimulation, and exercise therapy as recommended by the physical therapist.
  
• Primary outcome was the Roland and Morris disability score administered in Chinese to participants.
  
• Secondary outcomes were core outcome measures, including a visual analog pain Scale and Oswestry disability score also administered in Chinese.
  
• The Roland and Morris disability score defined minimal disability as a score of 0 to 12 and significant disability as a score of 13 to 24.
  
• The modified Oswestry Scale was used and defined degree of disability as "minimal" (0 - 11), "moderate" (12 - 22), "severe" (23 - 32), "crippled" (33 - 43), and "bed bound" (>/= 44).
  
• Questionnaires were administered at baseline, posttreatment at 1 month, and at 6 months' posttreatment.
  
• Therapists were blinded to participant baseline assessments.
  
• Mean age was 51 years, 30% were men, 84% were married, 12% to 27% were office workers, and 13% were heavy laborers.
  
• Median time since onset of low back pain was 3.3 years in the acupressure and 1.6 years in the physical therapy group.
  
• The mean total Roland and Morris score after treatment was significantly lower in the acupressure group regardless of the difference in absolute score (-3.8; 95% CI, -5.7 to -1.9) and mean change from baseline (-4.64; 95% CI, -6.39 to -2.89).
  
• Acupressure conferred an 89% reduction in significant disability with a number needed to treat of 5.98.
  
• After adjustment for pretreatment score, mean scores were lower for the acupressure group for "low back pain," "leg pain," "pain interferes with normal work," "days cut down on doing things," and "days off from work/school."
  
• Mean scores after treatment were higher in the acupressure group for "satisfaction of life with the symptoms" and "satisfaction with previous treatment."
  
• Mean scores for the pain visual scale and sleeping with back pain were lower in the acupressure group after treatment.
  
• The statistically significant improvements in all these areas remained for the 6-month follow-up questionnaire.
  
• The mean total Oswestry disability questionnaire score after treatment was significantly lower in the acupressure group than in the physical therapy group regardless of the difference in absolute score or mean change from baseline.
  
• The odds ratio of increasing 1 grade of disability was 0.22 (95% CI, 0.11 - 0.48, P = .0001) for the acupressure group, and the difference remained significant after adjustment for pretreatment score and other baseline characteristics.
  
• The estimated number needed to treat for acupressure to reduce the disability by 1 grade was 6.15.
  
• The improvement in Oswestry score in the acupressure group vs the physical therapy group remained at 6 months with a number needed to treat of 4.58.
  

Pearls for Practice

• Acupressure compared with physical therapy for 1 month is associated with an 89% reduction in significant disability in patients with low back pain.
  
• The beneficial effects of acupressure compared with physical therapy for low back pain on disability, function, and pain for 1 month persist at 6 months' posttreatment.
  

Saludos Cordiales

Dr. José Manuel Ferrer Guerra