Michele G. Sullivan

PHILADELPHIA — Most asthma patients are not well controlled on their current therapy, contrary to what they may believe or tell their physicians, Laura Sutton, Pharm.D., reported in a poster at the annual meeting of the American College of Allergy, Asthma, and Immunology.

In a recent survey of adult asthma patients, 61% reported moderately or poorly controlled symptoms, although almost half of that group rated their asthma as being well controlled, said Dr. Sutton, manager of clinical development, GlaxoSmithKline.

She and her colleagues administered a survey to 1,306 adult asthma patients who were taking prescription medication for their disease. The participants completed a medical history questionnaire and the 5-item Asthma Control Test and answered additional questions about the impact of asthma on their lives and their concerns about their illness.

On the Asthma Control Test, 39% of patients scored 20 or higher, indicating that their asthma was well or completely controlled clinically, and 61% scored 19 or lower, indicating that their asthma was moderately or poorly controlled. But 30% of those in the moderately/poorly controlled group believed that their asthma was controlled, despite their low scores on the test.

In patients in the moderately/poorly controlled group, the perception of having controlled asthma varied among treatments: 40% of those on montelukast (with or without a short-acting β-agonist) thought their condition was controlled, as did 39% of those on inhaled corticosteroids and 50% of those on a short-acting β-agonist alone. Those with moderately/poorly controlled asthma reported significantly more disruptions and worry in their daily lives. “[They] are constantly aware of their disease and try to avoid triggers. … They also feel less satisfied with life.”

Nevertheless, 56% of those with controlled asthma and 28% of those with moderately/poorly controlled asthma still said their symptoms were not severe enough to warrant medication on a daily basis.

The survey findings highlight the disconnect between clinical symptoms and patient perceptions, Dr. Sutton said in an interview. “Many patients learn to cope with frequent asthma symptoms or adapt their lifestyle to accommodate their asthma, not understanding what the goals are for well-controlled asthma. That's why it is so important to monitor asthma control [and to talk] with a health care provider if a patient continues to experience symptoms on his or her current medication.”

Five Questions to a Quick Assessment

The Asthma Control Test is a quick and easy way to obtain a reliable assessment of asthma control under a patient's current treatment plan, Dr. Sutton said.

The five questions in the test are based on measures of asthma control established by the National Institutes of Health. Scores range from 5 to 25, with higher scores indicating better control of the disease and lower scores indicating poor or moderate control (5–14 is deemed “poorly controlled”; 15–19, “moderately controlled”; and 20–25, “under control”). The test includes the following questions:

▸ In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school, or at home?

▸ During the past 4 weeks, how often have you had shortness of breath?

▸ During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness, or pain) wake you up at night or earlier than usual in the morning?

▸ During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication?

▸ How would you rate your asthma control during the past 4 weeks?

The Asthma Control Test takes less than 1 minute to complete and is available in English and Spanish, for adults and children. It can be accessed online at

www.asthmacontrol.com

PHILADELPHIA — Most asthma patients are not well controlled on their current therapy, contrary to what they may believe or tell their physicians, Laura Sutton, Pharm.D., reported in a poster at the annual meeting of the American College of Allergy, Asthma, and Immunology.

In a recent survey of adult asthma patients, 61% reported moderately or poorly controlled symptoms, although almost half of that group rated their asthma as being well controlled, said Dr. Sutton, manager of clinical development, GlaxoSmithKline.

She and her colleagues administered a survey to 1,306 adult asthma patients who were taking prescription medication for their disease. The participants completed a medical history questionnaire and the 5-item Asthma Control Test and answered additional questions about the impact of asthma on their lives and their concerns about their illness.

On the Asthma Control Test, 39% of patients scored 20 or higher, indicating that their asthma was well or completely controlled clinically, and 61% scored 19 or lower, indicating that their asthma was moderately or poorly controlled. But 30% of those in the moderately/poorly controlled group believed that their asthma was controlled, despite their low scores on the test.

In patients in the moderately/poorly controlled group, the perception of having controlled asthma varied among treatments: 40% of those on montelukast (with or without a short-acting β-agonist) thought their condition was controlled, as did 39% of those on inhaled corticosteroids and 50% of those on a short-acting β-agonist alone. Those with moderately/poorly controlled asthma reported significantly more disruptions and worry in their daily lives. “[They] are constantly aware of their disease and try to avoid triggers. … They also feel less satisfied with life.”

Nevertheless, 56% of those with controlled asthma and 28% of those with moderately/poorly controlled asthma still said their symptoms were not severe enough to warrant medication on a daily basis.

The survey findings highlight the disconnect between clinical symptoms and patient perceptions, Dr. Sutton said in an interview. “Many patients learn to cope with frequent asthma symptoms or adapt their lifestyle to accommodate their asthma, not understanding what the goals are for well-controlled asthma. That's why it is so important to monitor asthma control [and to talk] with a health care provider if a patient continues to experience symptoms on his or her current medication.”

Five Questions to a Quick Assessment

The Asthma Control Test is a quick and easy way to obtain a reliable assessment of asthma control under a patient's current treatment plan, Dr. Sutton said.

The five questions in the test are based on measures of asthma control established by the National Institutes of Health. Scores range from 5 to 25, with higher scores indicating better control of the disease and lower scores indicating poor or moderate control (5–14 is deemed “poorly controlled”; 15–19, “moderately controlled”; and 20–25, “under control”). The test includes the following questions:

▸ In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school, or at home?

▸ During the past 4 weeks, how often have you had shortness of breath?

▸ During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness, or pain) wake you up at night or earlier than usual in the morning?

▸ During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication?

▸ How would you rate your asthma control during the past 4 weeks?

The Asthma Control Test takes less than 1 minute to complete and is available in English and Spanish, for adults and children. It can be accessed online at

www.asthmacontrol.com

PHILADELPHIA — Most asthma patients are not well controlled on their current therapy, contrary to what they may believe or tell their physicians, Laura Sutton, Pharm.D., reported in a poster at the annual meeting of the American College of Allergy, Asthma, and Immunology.

In a recent survey of adult asthma patients, 61% reported moderately or poorly controlled symptoms, although almost half of that group rated their asthma as being well controlled, said Dr. Sutton, manager of clinical development, GlaxoSmithKline.

She and her colleagues administered a survey to 1,306 adult asthma patients who were taking prescription medication for their disease. The participants completed a medical history questionnaire and the 5-item Asthma Control Test and answered additional questions about the impact of asthma on their lives and their concerns about their illness.

On the Asthma Control Test, 39% of patients scored 20 or higher, indicating that their asthma was well or completely controlled clinically, and 61% scored 19 or lower, indicating that their asthma was moderately or poorly controlled. But 30% of those in the moderately/poorly controlled group believed that their asthma was controlled, despite their low scores on the test.

In patients in the moderately/poorly controlled group, the perception of having controlled asthma varied among treatments: 40% of those on montelukast (with or without a short-acting β-agonist) thought their condition was controlled, as did 39% of those on inhaled corticosteroids and 50% of those on a short-acting β-agonist alone. Those with moderately/poorly controlled asthma reported significantly more disruptions and worry in their daily lives. “[They] are constantly aware of their disease and try to avoid triggers. … They also feel less satisfied with life.”

Nevertheless, 56% of those with controlled asthma and 28% of those with moderately/poorly controlled asthma still said their symptoms were not severe enough to warrant medication on a daily basis.

The survey findings highlight the disconnect between clinical symptoms and patient perceptions, Dr. Sutton said in an interview. “Many patients learn to cope with frequent asthma symptoms or adapt their lifestyle to accommodate their asthma, not understanding what the goals are for well-controlled asthma. That's why it is so important to monitor asthma control [and to talk] with a health care provider if a patient continues to experience symptoms on his or her current medication.”

Five Questions to a Quick Assessment

The Asthma Control Test is a quick and easy way to obtain a reliable assessment of asthma control under a patient's current treatment plan, Dr. Sutton said.

The five questions in the test are based on measures of asthma control established by the National Institutes of Health. Scores range from 5 to 25, with higher scores indicating better control of the disease and lower scores indicating poor or moderate control (5–14 is deemed “poorly controlled”; 15–19, “moderately controlled”; and 20–25, “under control”). The test includes the following questions:

▸ In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school, or at home?

▸ During the past 4 weeks, how often have you had shortness of breath?

▸ During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness, or pain) wake you up at night or earlier than usual in the morning?

▸ During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication?

▸ How would you rate your asthma control during the past 4 weeks?

The Asthma Control Test takes less than 1 minute to complete and is available in English and Spanish, for adults and children. It can be accessed online at

www.asthmacontrol.com

PITTSBURGH — Treatment-limiting adverse events occurred in more than 30% of patients who received a vagus nerve stimulator for the treatment of seizure disorders, Dr. Phillip Pearl reported at the annual meeting of the Child Neurology Society.

The number of adverse events may increase even more as vagus nerve stimulator (VNS) devices become more common among new populations of patients with seizure disorders, Dr. Pearl said. “I think this is probably the tip of the iceberg and that we will be seeing more cases as more people receive this device and as the longevity of VNS therapy increases beyond what was studied for the initial approval.”

Dr. Pearl reported adverse events among 62 patients who had VNS devices implanted in 1998–2005 at the Children's National Medical Center, Washington, where he is a pediatric neurologist. The patients ranged in age from 3 to 29 years (median 12 years). The median duration of therapy was 40 months (range 1–96 months).

Of the 62 patients, 35% (22 patients) had at least one clinically significant adverse event. The most common were persistent drooling (six), coughing (five), throat discomfort or spasms (four), and dysphagia (three). Two patients had difficulty breathing, with one requiring device removal. Two experienced vomiting while the VNS current was delivered, and two more experienced vocal cord weakness. All of these adverse events required some limiting of the current output of the device. Two more patients experienced axillary wound infections that required oral antibiotic treatment.

Of the patients with adverse events, eight needed nonroutine surgical intervention. The device was removed from five patients (8%), including a 13-year-old girl who developed serious complications from wound infection requiring intravenous antibiotics. She also needed a percutaneous endoscopic gastroscopy tube because of vocal cord paralysis and persistent dysphagia. The other four explantations were necessary because of persistent problems with breathing, coughing, or throat discomfort.

There were also two lead failures, Dr. Pearl said. One was discovered during a routine device interrogation more than 7 years after the initial implant. The other one was discovered after seizure control worsened.

In addition to these adverse events, two patients experienced unique unanticipated problems. One was a 13-year-old boy who had received the implant for intractable generalized seizures and was seen at an emergency department for convulsive status. Peripheral vein access was limited; an emergency physician searching for an access site misidentified the VNS wire in the boy's neck as the jugular vein. “The wire was stabbed several times until it became apparent that it was not a vein,” Dr. Pearl said. Interrogation of the device a few days later showed no evidence of malfunction. One year later, the device did malfunction; the patient experienced increased seizures and needed a replacement.

PITTSBURGH — Treatment-limiting adverse events occurred in more than 30% of patients who received a vagus nerve stimulator for the treatment of seizure disorders, Dr. Phillip Pearl reported at the annual meeting of the Child Neurology Society.

The number of adverse events may increase even more as vagus nerve stimulator (VNS) devices become more common among new populations of patients with seizure disorders, Dr. Pearl said. “I think this is probably the tip of the iceberg and that we will be seeing more cases as more people receive this device and as the longevity of VNS therapy increases beyond what was studied for the initial approval.”

Dr. Pearl reported adverse events among 62 patients who had VNS devices implanted in 1998–2005 at the Children's National Medical Center, Washington, where he is a pediatric neurologist. The patients ranged in age from 3 to 29 years (median 12 years). The median duration of therapy was 40 months (range 1–96 months).

Of the 62 patients, 35% (22 patients) had at least one clinically significant adverse event. The most common were persistent drooling (six), coughing (five), throat discomfort or spasms (four), and dysphagia (three). Two patients had difficulty breathing, with one requiring device removal. Two experienced vomiting while the VNS current was delivered, and two more experienced vocal cord weakness. All of these adverse events required some limiting of the current output of the device. Two more patients experienced axillary wound infections that required oral antibiotic treatment.

Of the patients with adverse events, eight needed nonroutine surgical intervention. The device was removed from five patients (8%), including a 13-year-old girl who developed serious complications from wound infection requiring intravenous antibiotics. She also needed a percutaneous endoscopic gastroscopy tube because of vocal cord paralysis and persistent dysphagia. The other four explantations were necessary because of persistent problems with breathing, coughing, or throat discomfort.

There were also two lead failures, Dr. Pearl said. One was discovered during a routine device interrogation more than 7 years after the initial implant. The other one was discovered after seizure control worsened.

In addition to these adverse events, two patients experienced unique unanticipated problems. One was a 13-year-old boy who had received the implant for intractable generalized seizures and was seen at an emergency department for convulsive status. Peripheral vein access was limited; an emergency physician searching for an access site misidentified the VNS wire in the boy's neck as the jugular vein. “The wire was stabbed several times until it became apparent that it was not a vein,” Dr. Pearl said. Interrogation of the device a few days later showed no evidence of malfunction. One year later, the device did malfunction; the patient experienced increased seizures and needed a replacement.

PITTSBURGH — Treatment-limiting adverse events occurred in more than 30% of patients who received a vagus nerve stimulator for the treatment of seizure disorders, Dr. Phillip Pearl reported at the annual meeting of the Child Neurology Society.

The number of adverse events may increase even more as vagus nerve stimulator (VNS) devices become more common among new populations of patients with seizure disorders, Dr. Pearl said. “I think this is probably the tip of the iceberg and that we will be seeing more cases as more people receive this device and as the longevity of VNS therapy increases beyond what was studied for the initial approval.”

Dr. Pearl reported adverse events among 62 patients who had VNS devices implanted in 1998–2005 at the Children's National Medical Center, Washington, where he is a pediatric neurologist. The patients ranged in age from 3 to 29 years (median 12 years). The median duration of therapy was 40 months (range 1–96 months).

Of the 62 patients, 35% (22 patients) had at least one clinically significant adverse event. The most common were persistent drooling (six), coughing (five), throat discomfort or spasms (four), and dysphagia (three). Two patients had difficulty breathing, with one requiring device removal. Two experienced vomiting while the VNS current was delivered, and two more experienced vocal cord weakness. All of these adverse events required some limiting of the current output of the device. Two more patients experienced axillary wound infections that required oral antibiotic treatment.

Of the patients with adverse events, eight needed nonroutine surgical intervention. The device was removed from five patients (8%), including a 13-year-old girl who developed serious complications from wound infection requiring intravenous antibiotics. She also needed a percutaneous endoscopic gastroscopy tube because of vocal cord paralysis and persistent dysphagia. The other four explantations were necessary because of persistent problems with breathing, coughing, or throat discomfort.

There were also two lead failures, Dr. Pearl said. One was discovered during a routine device interrogation more than 7 years after the initial implant. The other one was discovered after seizure control worsened.

In addition to these adverse events, two patients experienced unique unanticipated problems. One was a 13-year-old boy who had received the implant for intractable generalized seizures and was seen at an emergency department for convulsive status. Peripheral vein access was limited; an emergency physician searching for an access site misidentified the VNS wire in the boy's neck as the jugular vein. “The wire was stabbed several times until it became apparent that it was not a vein,” Dr. Pearl said. Interrogation of the device a few days later showed no evidence of malfunction. One year later, the device did malfunction; the patient experienced increased seizures and needed a replacement.

PITTSBURGH — Two previously undescribed self-limiting leukodystrophies appear to affect infants and children, leaving them with residual neurologic deficits despite resolution of severe abnormalities of white matter with cavitations, Dr. SakkuBai Naidu, said at the annual meeting of the Child Neurology Society.

Dr. Naidu, director of the neurogenetics unit at the Kennedy Krieger Institute, Baltimore, described the disorders in eight children.

The first unnamed disorder she described occurred in six neonates, two of whom were monozygotic twins. All six infants developed neurologic symptoms within the first week of life. Apathy appeared initially, followed by lethargy and seizures requiring intubation. “The initial magnetic resonance imaging was not informative, except for abnormal diffusion-weighted imaging,” she said in an interview. “However, 2 weeks later, the white matter developed large cystic cavitations throughout the corona radiata.”

At that point, the infants had improved clinically, were weaned from ventilators, and placed on anticonvulsants. They later developed hypotonia progressing to mild spasticity, without recurrence of seizures.

Follow-up MRIs at 1 year showed complete resolution of the cavitations without significant brain atrophy. However, all the infants had cortical blindness and were developmentally delayed.

The second recently discovered leukodystrophy disorder was found in two older children who were healthy and developmentally normal until the second decade of life, Dr. Naidu reported. Initial symptoms were insidious, starting with progressive dementia, and then followed by dystonia, rigidity, and ataxia. Imaging showed a similar kind of bilateral cystic cavitation in the cerebellum with abnormal white matter.

By the end of the second decade of life, however, disease progression had stabilized. Imaging showed that the lesions had improved, although both children were left with residual rigidity, ataxia requiring aids for walking, and dementia.

“The most devastating MRI changes and clinical manifestations in the two conditions appear to have an age-associated onset, but self-limiting course, suggesting that timing identifies specific MRI changes, and time determines the clinical outcome in some disorders,” Dr. Naidu said.

PITTSBURGH — Two previously undescribed self-limiting leukodystrophies appear to affect infants and children, leaving them with residual neurologic deficits despite resolution of severe abnormalities of white matter with cavitations, Dr. SakkuBai Naidu, said at the annual meeting of the Child Neurology Society.

Dr. Naidu, director of the neurogenetics unit at the Kennedy Krieger Institute, Baltimore, described the disorders in eight children.

The first unnamed disorder she described occurred in six neonates, two of whom were monozygotic twins. All six infants developed neurologic symptoms within the first week of life. Apathy appeared initially, followed by lethargy and seizures requiring intubation. “The initial magnetic resonance imaging was not informative, except for abnormal diffusion-weighted imaging,” she said in an interview. “However, 2 weeks later, the white matter developed large cystic cavitations throughout the corona radiata.”

At that point, the infants had improved clinically, were weaned from ventilators, and placed on anticonvulsants. They later developed hypotonia progressing to mild spasticity, without recurrence of seizures.

Follow-up MRIs at 1 year showed complete resolution of the cavitations without significant brain atrophy. However, all the infants had cortical blindness and were developmentally delayed.

The second recently discovered leukodystrophy disorder was found in two older children who were healthy and developmentally normal until the second decade of life, Dr. Naidu reported. Initial symptoms were insidious, starting with progressive dementia, and then followed by dystonia, rigidity, and ataxia. Imaging showed a similar kind of bilateral cystic cavitation in the cerebellum with abnormal white matter.

By the end of the second decade of life, however, disease progression had stabilized. Imaging showed that the lesions had improved, although both children were left with residual rigidity, ataxia requiring aids for walking, and dementia.

“The most devastating MRI changes and clinical manifestations in the two conditions appear to have an age-associated onset, but self-limiting course, suggesting that timing identifies specific MRI changes, and time determines the clinical outcome in some disorders,” Dr. Naidu said.

PITTSBURGH — Two previously undescribed self-limiting leukodystrophies appear to affect infants and children, leaving them with residual neurologic deficits despite resolution of severe abnormalities of white matter with cavitations, Dr. SakkuBai Naidu, said at the annual meeting of the Child Neurology Society.

Dr. Naidu, director of the neurogenetics unit at the Kennedy Krieger Institute, Baltimore, described the disorders in eight children.

The first unnamed disorder she described occurred in six neonates, two of whom were monozygotic twins. All six infants developed neurologic symptoms within the first week of life. Apathy appeared initially, followed by lethargy and seizures requiring intubation. “The initial magnetic resonance imaging was not informative, except for abnormal diffusion-weighted imaging,” she said in an interview. “However, 2 weeks later, the white matter developed large cystic cavitations throughout the corona radiata.”

At that point, the infants had improved clinically, were weaned from ventilators, and placed on anticonvulsants. They later developed hypotonia progressing to mild spasticity, without recurrence of seizures.

Follow-up MRIs at 1 year showed complete resolution of the cavitations without significant brain atrophy. However, all the infants had cortical blindness and were developmentally delayed.

The second recently discovered leukodystrophy disorder was found in two older children who were healthy and developmentally normal until the second decade of life, Dr. Naidu reported. Initial symptoms were insidious, starting with progressive dementia, and then followed by dystonia, rigidity, and ataxia. Imaging showed a similar kind of bilateral cystic cavitation in the cerebellum with abnormal white matter.

By the end of the second decade of life, however, disease progression had stabilized. Imaging showed that the lesions had improved, although both children were left with residual rigidity, ataxia requiring aids for walking, and dementia.

“The most devastating MRI changes and clinical manifestations in the two conditions appear to have an age-associated onset, but self-limiting course, suggesting that timing identifies specific MRI changes, and time determines the clinical outcome in some disorders,” Dr. Naidu said.

PITTSBURGH — Children taking the anticonvulsant vigabatrin should have baseline and follow-up magnetic resonance imaging, because the drug has been associated with new-onset MRI hyperintensities in about 20% of those who take it, Dr. Phillip L. Pearl reported in a poster at the annual meeting of the Child Neurology Society.

Although the drug has never received Food and Drug Administration approval—because it can cause retinotoxicity with visual field constriction in about 30% of patients—some patients do receive it for compassionate use or in Institutional Review Board-approved protocols, Dr. Pearl said in an interview. U.S. patients usually obtain it from Canada. Vigabatrin is widely available outside the United States.

“Our results seem to support the original preclinical concerns about this drug,” said Dr. Pearl, a pediatric neurologist at the Children's National Medical Center, Washington.

The drug irreversibly inhibits gamma-aminobutyric acid transaminase. He described vigabatrin's effects on imaging in 15 patients (aged 11 months to 11 years) who underwent MRIs while taking it. Diagnoses included tuberous sclerosis complex (five patients), cortical dysplasia (five), cryptogenic infantile spasms (two), Down syndrome (one), metabolic encephalopathy (one), and mesial temporal sclerosis (one).

All of the patients had abnormal MRI scans during the course of vigabatrin therapy. However, three infants with normal baseline scans (two with cryptogenic infantile spasms and one with Down syndrome, all aged 12–13 months) experienced new-onset, vigabatrin-related T2 hyperintensities, Dr. Pearl said.

In one patient with infantile spasms, the abnormal signal occurred in the basal ganglia, thalami, anterior commissure, and brainstem. The second patient, who had Down syndrome, experienced the increased signal in the thalami, tectum, and corpus callosum. The signal occurred in the brainstem, palladi, and dentate nuclei of the third patient, who had infantile spasms. Diffusion-weighted imaging indicated intracellular cytotoxic edema in all three.

At the time of the abnormal scan, the mean dose of vigabatrin was 143 mg/kg per day, and the mean duration of therapy was just over 3 months. All of the abnormal signalling resolved when vigabatrin was discontinued. The abnormal scans in the other 12 patients were all related to their underlying diagnoses. The mean dose of vigabatrin at the time of their abnormal scan was 77 mg/kg per day, and the mean duration of therapy was 14 months.

Because the new-onset abnormalities appeared in very young patients, Dr. Pearl said, infants may represent a high-risk group and should be carefully followed by a neurologist. He said the abnormalities may be symptomatic, but he has not identified their clinical significance with certainty.

New-onset hyperintensities related to vigabatrin may be even more common, according to Dr. Pearl.

A scan of basal ganglia of a child on VGB shows signal abnormality.

The signal abnormality resolved once the child discontinued VGB therapy. Photos courtesy Dr. Phillip L. Pearl

PITTSBURGH — Children taking the anticonvulsant vigabatrin should have baseline and follow-up magnetic resonance imaging, because the drug has been associated with new-onset MRI hyperintensities in about 20% of those who take it, Dr. Phillip L. Pearl reported in a poster at the annual meeting of the Child Neurology Society.

Although the drug has never received Food and Drug Administration approval—because it can cause retinotoxicity with visual field constriction in about 30% of patients—some patients do receive it for compassionate use or in Institutional Review Board-approved protocols, Dr. Pearl said in an interview. U.S. patients usually obtain it from Canada. Vigabatrin is widely available outside the United States.

“Our results seem to support the original preclinical concerns about this drug,” said Dr. Pearl, a pediatric neurologist at the Children's National Medical Center, Washington.

The drug irreversibly inhibits gamma-aminobutyric acid transaminase. He described vigabatrin's effects on imaging in 15 patients (aged 11 months to 11 years) who underwent MRIs while taking it. Diagnoses included tuberous sclerosis complex (five patients), cortical dysplasia (five), cryptogenic infantile spasms (two), Down syndrome (one), metabolic encephalopathy (one), and mesial temporal sclerosis (one).

All of the patients had abnormal MRI scans during the course of vigabatrin therapy. However, three infants with normal baseline scans (two with cryptogenic infantile spasms and one with Down syndrome, all aged 12–13 months) experienced new-onset, vigabatrin-related T2 hyperintensities, Dr. Pearl said.

In one patient with infantile spasms, the abnormal signal occurred in the basal ganglia, thalami, anterior commissure, and brainstem. The second patient, who had Down syndrome, experienced the increased signal in the thalami, tectum, and corpus callosum. The signal occurred in the brainstem, palladi, and dentate nuclei of the third patient, who had infantile spasms. Diffusion-weighted imaging indicated intracellular cytotoxic edema in all three.

At the time of the abnormal scan, the mean dose of vigabatrin was 143 mg/kg per day, and the mean duration of therapy was just over 3 months. All of the abnormal signalling resolved when vigabatrin was discontinued. The abnormal scans in the other 12 patients were all related to their underlying diagnoses. The mean dose of vigabatrin at the time of their abnormal scan was 77 mg/kg per day, and the mean duration of therapy was 14 months.

Because the new-onset abnormalities appeared in very young patients, Dr. Pearl said, infants may represent a high-risk group and should be carefully followed by a neurologist. He said the abnormalities may be symptomatic, but he has not identified their clinical significance with certainty.

New-onset hyperintensities related to vigabatrin may be even more common, according to Dr. Pearl.

A scan of basal ganglia of a child on VGB shows signal abnormality.

The signal abnormality resolved once the child discontinued VGB therapy. Photos courtesy Dr. Phillip L. Pearl

PITTSBURGH — Children taking the anticonvulsant vigabatrin should have baseline and follow-up magnetic resonance imaging, because the drug has been associated with new-onset MRI hyperintensities in about 20% of those who take it, Dr. Phillip L. Pearl reported in a poster at the annual meeting of the Child Neurology Society.

Although the drug has never received Food and Drug Administration approval—because it can cause retinotoxicity with visual field constriction in about 30% of patients—some patients do receive it for compassionate use or in Institutional Review Board-approved protocols, Dr. Pearl said in an interview. U.S. patients usually obtain it from Canada. Vigabatrin is widely available outside the United States.

“Our results seem to support the original preclinical concerns about this drug,” said Dr. Pearl, a pediatric neurologist at the Children's National Medical Center, Washington.

The drug irreversibly inhibits gamma-aminobutyric acid transaminase. He described vigabatrin's effects on imaging in 15 patients (aged 11 months to 11 years) who underwent MRIs while taking it. Diagnoses included tuberous sclerosis complex (five patients), cortical dysplasia (five), cryptogenic infantile spasms (two), Down syndrome (one), metabolic encephalopathy (one), and mesial temporal sclerosis (one).

All of the patients had abnormal MRI scans during the course of vigabatrin therapy. However, three infants with normal baseline scans (two with cryptogenic infantile spasms and one with Down syndrome, all aged 12–13 months) experienced new-onset, vigabatrin-related T2 hyperintensities, Dr. Pearl said.

In one patient with infantile spasms, the abnormal signal occurred in the basal ganglia, thalami, anterior commissure, and brainstem. The second patient, who had Down syndrome, experienced the increased signal in the thalami, tectum, and corpus callosum. The signal occurred in the brainstem, palladi, and dentate nuclei of the third patient, who had infantile spasms. Diffusion-weighted imaging indicated intracellular cytotoxic edema in all three.

At the time of the abnormal scan, the mean dose of vigabatrin was 143 mg/kg per day, and the mean duration of therapy was just over 3 months. All of the abnormal signalling resolved when vigabatrin was discontinued. The abnormal scans in the other 12 patients were all related to their underlying diagnoses. The mean dose of vigabatrin at the time of their abnormal scan was 77 mg/kg per day, and the mean duration of therapy was 14 months.

Because the new-onset abnormalities appeared in very young patients, Dr. Pearl said, infants may represent a high-risk group and should be carefully followed by a neurologist. He said the abnormalities may be symptomatic, but he has not identified their clinical significance with certainty.

New-onset hyperintensities related to vigabatrin may be even more common, according to Dr. Pearl.

A scan of basal ganglia of a child on VGB shows signal abnormality.

The signal abnormality resolved once the child discontinued VGB therapy. Photos courtesy Dr. Phillip L. Pearl

The demise of torcetrapib may be a “bitter disappointment” to researchers, but it's too soon to give up on the entire class of HDL cholesterol-raising agents, several of which are still under development, experts say.

“While this is a huge setback for the field of lipid therapy, it would be a big mistake for patients and physicians to get the impression that this research is a lost cause,” said Dr. Frederick Samaha of the University of Pennsylvania, Philadelphia. “There are several different drugs being looked at. We can't presume from the failure of one that all of them will have similar problems.”

Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, was furthest along that pipeline, however, and was the only one in a phase III trial (ILLUMINATE). The study randomized 15,000 patients with existing coronary heart disease to atorvastatin alone or to a combination of atorvastatin and torcetrapib.

However, Pfizer Inc. abruptly halted it after an interim data analysis showed significantly more deaths in the combination arm than in the monotherapy arm (82 vs. 51). Although details haven't been released, the imbalance in mortality appears to have been driven by cardiovascular events, Dr. Samaha said in an interview.

“It's very disappointing. Of all the HDL-raising drugs, this class holds the most promise. [CETP inhibitors] increase HDL by 50%–100%, much more than even the second most effective drug, niacin. So we had a lot of really high hopes for torcetrapib.”

The question facing researchers, he said, is whether the mortality risk associated with torcetrapib will extend to any of the other CETP inhibitors under development by Hoffmann-La Roche Inc., Merck & Co., AstraZeneca Pharmaceuticals LP, and Bayer Pharmaceuticals Corp. “We can't tell right now whether this is a class effect, or whether it's specific to this one drug alone,” said Dr. Samaha, who is investigating the effect of niacin plus statins on cardiovascular events in the AIM-HIGH trial.

There are two possible culprits behind the increased mortality among torcetrapib patients, he said: the drug's hypertensive effects, which caused significant blood pressure hikes in a small number of patients in the phase II studies, and accelerated atherogenesis.

Blood pressure effects are likely to be drug specific, as other CETP inhibitors in development haven't thus far shown similar problems. But a finding that torcetrapib—a drug designed to prevent or decrease atherosclerotic plaque—actually increases it could have devastating implications for all CETP research. “That would most likely be a class effect that we would see with any of these drugs,” said James McKenney, Pharm.D., a primary investigator for torcetrapib's 2006 safety and efficacy studies.

CETP inhibitors increase HDL cholesterol by limiting the amount of cholesterol that leaves the HDL particle, Dr. Samaha said. “What you end up with is larger HDL particles with more cholesterol associated with them. Whether those particles are still as cardioprotective [as normally occurring HDL] is something we don't know.”

Boosting HDL levels this way has always been a controversial idea, according to Dr. Michael Davidson, director of preventive cardiology at Rush University Medical Center, Chicago. But “a lot of us were still optimistic, because the 50% increase in HDL that we saw in the earlier studies was so significant that it should have resulted in a significant mortality risk reduction.”

That reduction should also have been large enough to offset the potential problem of hypertension, said Dr. Davidson.

Although Pfizer has yet to release the causes of the deaths in its phase III study, Dr. Davidson thinks the drug's hypertensive effects may play into the picture. “Perhaps we didn't see a clear signal about this in the earlier trials because they included relatively healthy subjects, while the phase III trial involved sicker patients who had pre-existing cardiovascular disease.”

But because the other CETP inhibitors under development haven't shown any effect on blood pressure thus far, torcetrapib may be an outlier among them. “I believe this class of drugs still has a lot of potential.” However, he cautioned, until the deaths in both arms of the ILLUMINATE trial have been adjudicated, it will be impossible to understand the drug's full risk picture.

The demise of torcetrapib may be a “bitter disappointment” to researchers, but it's too soon to give up on the entire class of HDL cholesterol-raising agents, several of which are still under development, experts say.

“While this is a huge setback for the field of lipid therapy, it would be a big mistake for patients and physicians to get the impression that this research is a lost cause,” said Dr. Frederick Samaha of the University of Pennsylvania, Philadelphia. “There are several different drugs being looked at. We can't presume from the failure of one that all of them will have similar problems.”

Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, was furthest along that pipeline, however, and was the only one in a phase III trial (ILLUMINATE). The study randomized 15,000 patients with existing coronary heart disease to atorvastatin alone or to a combination of atorvastatin and torcetrapib.

However, Pfizer Inc. abruptly halted it after an interim data analysis showed significantly more deaths in the combination arm than in the monotherapy arm (82 vs. 51). Although details haven't been released, the imbalance in mortality appears to have been driven by cardiovascular events, Dr. Samaha said in an interview.

“It's very disappointing. Of all the HDL-raising drugs, this class holds the most promise. [CETP inhibitors] increase HDL by 50%–100%, much more than even the second most effective drug, niacin. So we had a lot of really high hopes for torcetrapib.”

The question facing researchers, he said, is whether the mortality risk associated with torcetrapib will extend to any of the other CETP inhibitors under development by Hoffmann-La Roche Inc., Merck & Co., AstraZeneca Pharmaceuticals LP, and Bayer Pharmaceuticals Corp. “We can't tell right now whether this is a class effect, or whether it's specific to this one drug alone,” said Dr. Samaha, who is investigating the effect of niacin plus statins on cardiovascular events in the AIM-HIGH trial.

There are two possible culprits behind the increased mortality among torcetrapib patients, he said: the drug's hypertensive effects, which caused significant blood pressure hikes in a small number of patients in the phase II studies, and accelerated atherogenesis.

Blood pressure effects are likely to be drug specific, as other CETP inhibitors in development haven't thus far shown similar problems. But a finding that torcetrapib—a drug designed to prevent or decrease atherosclerotic plaque—actually increases it could have devastating implications for all CETP research. “That would most likely be a class effect that we would see with any of these drugs,” said James McKenney, Pharm.D., a primary investigator for torcetrapib's 2006 safety and efficacy studies.

CETP inhibitors increase HDL cholesterol by limiting the amount of cholesterol that leaves the HDL particle, Dr. Samaha said. “What you end up with is larger HDL particles with more cholesterol associated with them. Whether those particles are still as cardioprotective [as normally occurring HDL] is something we don't know.”

Boosting HDL levels this way has always been a controversial idea, according to Dr. Michael Davidson, director of preventive cardiology at Rush University Medical Center, Chicago. But “a lot of us were still optimistic, because the 50% increase in HDL that we saw in the earlier studies was so significant that it should have resulted in a significant mortality risk reduction.”

That reduction should also have been large enough to offset the potential problem of hypertension, said Dr. Davidson.

Although Pfizer has yet to release the causes of the deaths in its phase III study, Dr. Davidson thinks the drug's hypertensive effects may play into the picture. “Perhaps we didn't see a clear signal about this in the earlier trials because they included relatively healthy subjects, while the phase III trial involved sicker patients who had pre-existing cardiovascular disease.”

But because the other CETP inhibitors under development haven't shown any effect on blood pressure thus far, torcetrapib may be an outlier among them. “I believe this class of drugs still has a lot of potential.” However, he cautioned, until the deaths in both arms of the ILLUMINATE trial have been adjudicated, it will be impossible to understand the drug's full risk picture.

The demise of torcetrapib may be a “bitter disappointment” to researchers, but it's too soon to give up on the entire class of HDL cholesterol-raising agents, several of which are still under development, experts say.

“While this is a huge setback for the field of lipid therapy, it would be a big mistake for patients and physicians to get the impression that this research is a lost cause,” said Dr. Frederick Samaha of the University of Pennsylvania, Philadelphia. “There are several different drugs being looked at. We can't presume from the failure of one that all of them will have similar problems.”

Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, was furthest along that pipeline, however, and was the only one in a phase III trial (ILLUMINATE). The study randomized 15,000 patients with existing coronary heart disease to atorvastatin alone or to a combination of atorvastatin and torcetrapib.

However, Pfizer Inc. abruptly halted it after an interim data analysis showed significantly more deaths in the combination arm than in the monotherapy arm (82 vs. 51). Although details haven't been released, the imbalance in mortality appears to have been driven by cardiovascular events, Dr. Samaha said in an interview.

“It's very disappointing. Of all the HDL-raising drugs, this class holds the most promise. [CETP inhibitors] increase HDL by 50%–100%, much more than even the second most effective drug, niacin. So we had a lot of really high hopes for torcetrapib.”

The question facing researchers, he said, is whether the mortality risk associated with torcetrapib will extend to any of the other CETP inhibitors under development by Hoffmann-La Roche Inc., Merck & Co., AstraZeneca Pharmaceuticals LP, and Bayer Pharmaceuticals Corp. “We can't tell right now whether this is a class effect, or whether it's specific to this one drug alone,” said Dr. Samaha, who is investigating the effect of niacin plus statins on cardiovascular events in the AIM-HIGH trial.

There are two possible culprits behind the increased mortality among torcetrapib patients, he said: the drug's hypertensive effects, which caused significant blood pressure hikes in a small number of patients in the phase II studies, and accelerated atherogenesis.

Blood pressure effects are likely to be drug specific, as other CETP inhibitors in development haven't thus far shown similar problems. But a finding that torcetrapib—a drug designed to prevent or decrease atherosclerotic plaque—actually increases it could have devastating implications for all CETP research. “That would most likely be a class effect that we would see with any of these drugs,” said James McKenney, Pharm.D., a primary investigator for torcetrapib's 2006 safety and efficacy studies.

CETP inhibitors increase HDL cholesterol by limiting the amount of cholesterol that leaves the HDL particle, Dr. Samaha said. “What you end up with is larger HDL particles with more cholesterol associated with them. Whether those particles are still as cardioprotective [as normally occurring HDL] is something we don't know.”

Boosting HDL levels this way has always been a controversial idea, according to Dr. Michael Davidson, director of preventive cardiology at Rush University Medical Center, Chicago. But “a lot of us were still optimistic, because the 50% increase in HDL that we saw in the earlier studies was so significant that it should have resulted in a significant mortality risk reduction.”

That reduction should also have been large enough to offset the potential problem of hypertension, said Dr. Davidson.

Although Pfizer has yet to release the causes of the deaths in its phase III study, Dr. Davidson thinks the drug's hypertensive effects may play into the picture. “Perhaps we didn't see a clear signal about this in the earlier trials because they included relatively healthy subjects, while the phase III trial involved sicker patients who had pre-existing cardiovascular disease.”

But because the other CETP inhibitors under development haven't shown any effect on blood pressure thus far, torcetrapib may be an outlier among them. “I believe this class of drugs still has a lot of potential.” However, he cautioned, until the deaths in both arms of the ILLUMINATE trial have been adjudicated, it will be impossible to understand the drug's full risk picture.

Officials in charge of disclosing financial interests in research agree that disclosure is important, but are confused about how to do so effectively and appropriately, Kevin P. Weinfurt, Ph.D., and his colleagues reported.

Their survey of 42 such officials revealed widely varying opinions on when disclosure should be made, the financial limits that should trigger it, and how much information to share with prospective research subjects, said Dr. Weinfurt of the department of psychiatry at Duke University, Durham, N.C., and his coinvestigators.

“Part of their struggle relates to a lack of clarity regarding the ultimate goals of disclosure,” the researchers wrote.”There is also a lack of systematic data regarding how potential research participants can and will use such information in their decision-making” (J. Law Med. Ethics 2006;34: 581–91).

The study was based on detailed personal interviews with eight investigators, 23 review board chairs, and 14 conflict of interest committee chairs. The survey was designed to elicit respondents' understandings of how disclosure is done at their institutions and their thoughts on the importance of disclosure, including its risks and benefits to the institution and research subjects.

More than half of those interviewed agreed that disclosure should occur under all circumstances; the rest said disclosure would depend on the degree of the financial relationship. The most commonly expressed reason for disclosing a financial relationship was to facilitate better-informed decision making for potential subjects. Other reasons included trust and transparency issues, reducing liability risk, and managing public perception of the institution.

About 80% of respondents said the disclosure should include the name of the funding source. But some said the name of the company or organization wasn't as important as a description–whether it was a nonprofit organization, pharmaceutical company, or government body, for instance.

They also differed on whether the amount of financial interest should be disclosed. Conflict of interest committee chairs were most likely to want to share this information (93%), while investigators were least likely (63%). Those who expressed concern about disclosing the amount felt that level of detail could become cumbersome or confusing in the informed consent statement, and that research subjects might overestimate the impact that particular amounts might actually have on research outcomes. There was no consensus on what amount should trigger disclosure–the lower limit ranged from $1 to $50,000.

There was general agreement that the nature of the relationship should be disclosed, but no agreement about whether the disclosure should explain the possible impact of those relationships. Again, concern about overcomplicating the consent statement semed to be at the root of these issues. Some respondents said the disclosure should include an explanation of how an unscrupulous investigator might alter the research results.

Most respondents dismissed the idea that disclosure could lower enrollment. There was little sympathy among the group for researchers who complained that full disclosure was an invasion of their financial privacy.

There was also concern about how to best highlight disclosure information without overemphasizing its importance or potential risk to a study's integrity. Some respondents said their consent form highlights the information in bold type, while others place it strategically in the document–at the very beginning, for example. Many also emphasized that the informed consent process should include a discussion of conflict of interest, not just a read-through of the document.

“Our data suggest that it will be difficult to achieve agreement on the issue of substantial understanding of financial interests,” the researchers concluded.

Officials in charge of disclosing financial interests in research agree that disclosure is important, but are confused about how to do so effectively and appropriately, Kevin P. Weinfurt, Ph.D., and his colleagues reported.

Their survey of 42 such officials revealed widely varying opinions on when disclosure should be made, the financial limits that should trigger it, and how much information to share with prospective research subjects, said Dr. Weinfurt of the department of psychiatry at Duke University, Durham, N.C., and his coinvestigators.

“Part of their struggle relates to a lack of clarity regarding the ultimate goals of disclosure,” the researchers wrote.”There is also a lack of systematic data regarding how potential research participants can and will use such information in their decision-making” (J. Law Med. Ethics 2006;34: 581–91).

The study was based on detailed personal interviews with eight investigators, 23 review board chairs, and 14 conflict of interest committee chairs. The survey was designed to elicit respondents' understandings of how disclosure is done at their institutions and their thoughts on the importance of disclosure, including its risks and benefits to the institution and research subjects.

More than half of those interviewed agreed that disclosure should occur under all circumstances; the rest said disclosure would depend on the degree of the financial relationship. The most commonly expressed reason for disclosing a financial relationship was to facilitate better-informed decision making for potential subjects. Other reasons included trust and transparency issues, reducing liability risk, and managing public perception of the institution.

About 80% of respondents said the disclosure should include the name of the funding source. But some said the name of the company or organization wasn't as important as a description–whether it was a nonprofit organization, pharmaceutical company, or government body, for instance.

They also differed on whether the amount of financial interest should be disclosed. Conflict of interest committee chairs were most likely to want to share this information (93%), while investigators were least likely (63%). Those who expressed concern about disclosing the amount felt that level of detail could become cumbersome or confusing in the informed consent statement, and that research subjects might overestimate the impact that particular amounts might actually have on research outcomes. There was no consensus on what amount should trigger disclosure–the lower limit ranged from $1 to $50,000.

There was general agreement that the nature of the relationship should be disclosed, but no agreement about whether the disclosure should explain the possible impact of those relationships. Again, concern about overcomplicating the consent statement semed to be at the root of these issues. Some respondents said the disclosure should include an explanation of how an unscrupulous investigator might alter the research results.

Most respondents dismissed the idea that disclosure could lower enrollment. There was little sympathy among the group for researchers who complained that full disclosure was an invasion of their financial privacy.

There was also concern about how to best highlight disclosure information without overemphasizing its importance or potential risk to a study's integrity. Some respondents said their consent form highlights the information in bold type, while others place it strategically in the document–at the very beginning, for example. Many also emphasized that the informed consent process should include a discussion of conflict of interest, not just a read-through of the document.

“Our data suggest that it will be difficult to achieve agreement on the issue of substantial understanding of financial interests,” the researchers concluded.

Officials in charge of disclosing financial interests in research agree that disclosure is important, but are confused about how to do so effectively and appropriately, Kevin P. Weinfurt, Ph.D., and his colleagues reported.

Their survey of 42 such officials revealed widely varying opinions on when disclosure should be made, the financial limits that should trigger it, and how much information to share with prospective research subjects, said Dr. Weinfurt of the department of psychiatry at Duke University, Durham, N.C., and his coinvestigators.

“Part of their struggle relates to a lack of clarity regarding the ultimate goals of disclosure,” the researchers wrote.”There is also a lack of systematic data regarding how potential research participants can and will use such information in their decision-making” (J. Law Med. Ethics 2006;34: 581–91).

The study was based on detailed personal interviews with eight investigators, 23 review board chairs, and 14 conflict of interest committee chairs. The survey was designed to elicit respondents' understandings of how disclosure is done at their institutions and their thoughts on the importance of disclosure, including its risks and benefits to the institution and research subjects.

More than half of those interviewed agreed that disclosure should occur under all circumstances; the rest said disclosure would depend on the degree of the financial relationship. The most commonly expressed reason for disclosing a financial relationship was to facilitate better-informed decision making for potential subjects. Other reasons included trust and transparency issues, reducing liability risk, and managing public perception of the institution.

About 80% of respondents said the disclosure should include the name of the funding source. But some said the name of the company or organization wasn't as important as a description–whether it was a nonprofit organization, pharmaceutical company, or government body, for instance.

They also differed on whether the amount of financial interest should be disclosed. Conflict of interest committee chairs were most likely to want to share this information (93%), while investigators were least likely (63%). Those who expressed concern about disclosing the amount felt that level of detail could become cumbersome or confusing in the informed consent statement, and that research subjects might overestimate the impact that particular amounts might actually have on research outcomes. There was no consensus on what amount should trigger disclosure–the lower limit ranged from $1 to $50,000.

There was general agreement that the nature of the relationship should be disclosed, but no agreement about whether the disclosure should explain the possible impact of those relationships. Again, concern about overcomplicating the consent statement semed to be at the root of these issues. Some respondents said the disclosure should include an explanation of how an unscrupulous investigator might alter the research results.

Most respondents dismissed the idea that disclosure could lower enrollment. There was little sympathy among the group for researchers who complained that full disclosure was an invasion of their financial privacy.

There was also concern about how to best highlight disclosure information without overemphasizing its importance or potential risk to a study's integrity. Some respondents said their consent form highlights the information in bold type, while others place it strategically in the document–at the very beginning, for example. Many also emphasized that the informed consent process should include a discussion of conflict of interest, not just a read-through of the document.

“Our data suggest that it will be difficult to achieve agreement on the issue of substantial understanding of financial interests,” the researchers concluded.

WASHINGTON – Sildenafil may be useful in treating the pain of diabetic neuropathy, Dr. Thomas Brannagan reported in a poster presented at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine.

Dr. Brannagan, a neurologist at Cornell University, New York, was inspired to conduct the study after diabetic patients taking sildenafil for erectile dysfunction experienced some relief from their neuropathic pain. The trial included eight patients: six men and two women. All reported pain of above 40 on a 0–100 visual analog pain scale, despite receiving one to seven medications each for neuropathic pain.

The patients received an upwardly titrated dose of sildenafil from 25 mg/day the first week to 50 mg/day after week 1 and up to 100 mg/day thereafter, if necessary and tolerated. They also maintained their existing pain medications. Every week they recorded pain on the following scales: 11-point Likert; a 10-point sleep interference; Rand-36 quality of life; and Toronto Clinical Neuropathy.

Two patients discontinued the drug because of rash, while four patients completed the 8-week trial. The four patients experienced a significant reduction in pain, with the average weekly Likert score decreasing from 5.6 at baseline to 1.5, Dr. Brannagan reported.

When all patients were considered, with the last observation carried forward, the average weekly Likert pain score decreased from 6.3 to 3.7. Four patients had a score reduction of more than two points, and three had at least a 50% reduction in pain. Scores in all other areas improved as well: visual analog pain score, 49 to 31; Rand score, 46 to 65; sleep score, 8 to 4; and Toronto score, 12/19 to 10/19, said Dr. Brannagan, who is a consultant for Eli Lilly & Co.

WASHINGTON – Sildenafil may be useful in treating the pain of diabetic neuropathy, Dr. Thomas Brannagan reported in a poster presented at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine.

Dr. Brannagan, a neurologist at Cornell University, New York, was inspired to conduct the study after diabetic patients taking sildenafil for erectile dysfunction experienced some relief from their neuropathic pain. The trial included eight patients: six men and two women. All reported pain of above 40 on a 0–100 visual analog pain scale, despite receiving one to seven medications each for neuropathic pain.

The patients received an upwardly titrated dose of sildenafil from 25 mg/day the first week to 50 mg/day after week 1 and up to 100 mg/day thereafter, if necessary and tolerated. They also maintained their existing pain medications. Every week they recorded pain on the following scales: 11-point Likert; a 10-point sleep interference; Rand-36 quality of life; and Toronto Clinical Neuropathy.

Two patients discontinued the drug because of rash, while four patients completed the 8-week trial. The four patients experienced a significant reduction in pain, with the average weekly Likert score decreasing from 5.6 at baseline to 1.5, Dr. Brannagan reported.

When all patients were considered, with the last observation carried forward, the average weekly Likert pain score decreased from 6.3 to 3.7. Four patients had a score reduction of more than two points, and three had at least a 50% reduction in pain. Scores in all other areas improved as well: visual analog pain score, 49 to 31; Rand score, 46 to 65; sleep score, 8 to 4; and Toronto score, 12/19 to 10/19, said Dr. Brannagan, who is a consultant for Eli Lilly & Co.

WASHINGTON – Sildenafil may be useful in treating the pain of diabetic neuropathy, Dr. Thomas Brannagan reported in a poster presented at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine.

Dr. Brannagan, a neurologist at Cornell University, New York, was inspired to conduct the study after diabetic patients taking sildenafil for erectile dysfunction experienced some relief from their neuropathic pain. The trial included eight patients: six men and two women. All reported pain of above 40 on a 0–100 visual analog pain scale, despite receiving one to seven medications each for neuropathic pain.

The patients received an upwardly titrated dose of sildenafil from 25 mg/day the first week to 50 mg/day after week 1 and up to 100 mg/day thereafter, if necessary and tolerated. They also maintained their existing pain medications. Every week they recorded pain on the following scales: 11-point Likert; a 10-point sleep interference; Rand-36 quality of life; and Toronto Clinical Neuropathy.

Two patients discontinued the drug because of rash, while four patients completed the 8-week trial. The four patients experienced a significant reduction in pain, with the average weekly Likert score decreasing from 5.6 at baseline to 1.5, Dr. Brannagan reported.

When all patients were considered, with the last observation carried forward, the average weekly Likert pain score decreased from 6.3 to 3.7. Four patients had a score reduction of more than two points, and three had at least a 50% reduction in pain. Scores in all other areas improved as well: visual analog pain score, 49 to 31; Rand score, 46 to 65; sleep score, 8 to 4; and Toronto score, 12/19 to 10/19, said Dr. Brannagan, who is a consultant for Eli Lilly & Co.

The demise of torcetrapib may be a “bitter disappointment” to researchers, but it's too soon to give up on the entire class of HDL cholesterol-raising agents, several of which are still under development, experts say.

“While this is a huge setback for the field of lipid therapy, it would be a big mistake for patients and physicians to get the impression that this research is a lost cause,” said Dr. Frederick Samaha of the University of Pennsylvania, Philadelphia. “There are several different drugs being looked at. We can't presume from the failure of one that all of them will have similar problems.”

Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, was furthest along that pipeline, however, and was the only one in a phase III trial (ILLUMINATE). The study randomized 15,000 patients with existing coronary heart disease to atorvastatin alone or to a combination of atorvastatin and torcetrapib.

But Pfizer Inc. abruptly halted it after an interim data analysis showed significantly more deaths in the combination arm than in the monotherapy arm (82 vs. 51). Although details haven't been released, the imbalance in mortality appears to have been driven by cardiovascular events, Dr. Samaha said in an interview.

“It's very disappointing. Of all the HDL-raising drugs, this class holds the most promise. [CETP inhibitors] increase HDL by 50%–100%, much more than even the second most effective drug, niacin. So we had a lot of really high hopes for torcetrapib.”

The question facing researchers, he said, is whether the mortality risk associated with torcetrapib will extend to any of the other CETP inhibitors under development by Hoffmann-La Roche Inc., Merck & Co., AstraZeneca Pharmaceuticals LP, and Bayer Pharmaceuticals Corp. “We can't tell right now whether this is a class effect, or whether it's specific to this one drug alone,” said Dr. Samaha, who is investigating the effect of niacin plus statins on cardiovascular events in the AIM-HIGH trial.

There are two possible culprits behind the increased mortality among torcetrapib patients, he said: the drug's hypertensive effects, which caused significant blood pressure hikes in a small number of patients in the phase II studies, and accelerated atherogenesis.

Blood pressure effects are likely to be drug specific, as other CETP inhibitors in development haven't thus far shown similar problems. But a finding that torcetrapib, a drug designed to prevent or decrease atherosclerotic plaque, actually increases it could have devastating implications for all CETP research. “That would most likely be a class effect that we would see with any of these drugs,” said James McKenney, Pharm.D., a primary investigator for torcetrapib's 2006 safety and efficacy studies.

CETP inhibitors increase HDL cholesterol by limiting the amount of cholesterol that leaves the HDL particle, Dr. Samaha said. “What you end up with is larger HDL particles with more cholesterol associated with them. Whether those particles are still as cardioprotective [as normally occurring HDL] is something we don't know.”

He's not alone in voicing this concern. Boosting HDL levels this way has always been a controversial idea, according to Dr. Michael Davidson, director of preventive cardiology at Rush University Medical Center, Chicago. But despite uncertainty about the cardioprotective effects of CETP-modulated HDL cholesterol, he said in an interview, “a lot of us were still optimistic, because the 50% increase in HDL that we saw in the earlier studies was so significant that it should have resulted in a significant mortality risk reduction.”

That reduction should also have been large enough to offset the potential problem of hypertension, said Dr. Davidson, who worked with Dr. McKenney on the phase II studies (J. Am. Coll. Cardiol. 2006;48:1774–81; 1782–90).

In those studies, blood pressure increases were widely variable in both groups; however, significant jumps—systolic increases greater than 10 mm Hg from baseline or diastolic increases greater than 15 mm Hg from baseline—occurred in only about 3% of patients. “It was a concern,” Dr. Davidson said, “but we thought raising the HDL that much would offset any potential risks. Obviously, this blood pressure issue may be much more serious than we first imagined.”

While Pfizer has yet to release the causes of the deaths in its phase III study, Dr. Davidson thinks the drug's hypertensive effects may play into the picture. “Perhaps we didn't see a clear signal about this in the earlier trials because they included relatively healthy subjects, while the phase III trial involved sicker patients who had preexisting cardiovascular disease.”

But because the other CETP inhibitors under development haven't shown any effect on blood pressure thus far, torcetrapib may be an outlier among them. “It may just be a specific issue to this drug. I believe this class of drugs still has a lot of potential.” However, he cautioned, until the deaths in both arms of the ILLUMINATE trial have been adjudicated, it will be impossible to understand the drug's full risk picture.

Two upcoming imaging trials will provide valuable additional clues to torcetrapib's risks. One of these, the ILLUSTRATE trial, uses intravascular ultrasound to evaluate atherosclerotic plaque burden, said Dr. Steven Nissen, a principal investigator in that study.

ILLUSTRATE included 1,190 patients randomized to the combination of torcetrapib and atorvastatin or to atorvastatin alone. Data collection is complete; Dr. Nissen, medical director of the Cleveland Clinic Cardiovascular Coordinating Center, said he will present the results at the American College of Cardiology meeting in March.

The demise of torcetrapib may be a “bitter disappointment” to researchers, but it's too soon to give up on the entire class of HDL cholesterol-raising agents, several of which are still under development, experts say.

“While this is a huge setback for the field of lipid therapy, it would be a big mistake for patients and physicians to get the impression that this research is a lost cause,” said Dr. Frederick Samaha of the University of Pennsylvania, Philadelphia. “There are several different drugs being looked at. We can't presume from the failure of one that all of them will have similar problems.”

Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, was furthest along that pipeline, however, and was the only one in a phase III trial (ILLUMINATE). The study randomized 15,000 patients with existing coronary heart disease to atorvastatin alone or to a combination of atorvastatin and torcetrapib.

But Pfizer Inc. abruptly halted it after an interim data analysis showed significantly more deaths in the combination arm than in the monotherapy arm (82 vs. 51). Although details haven't been released, the imbalance in mortality appears to have been driven by cardiovascular events, Dr. Samaha said in an interview.

“It's very disappointing. Of all the HDL-raising drugs, this class holds the most promise. [CETP inhibitors] increase HDL by 50%–100%, much more than even the second most effective drug, niacin. So we had a lot of really high hopes for torcetrapib.”

The question facing researchers, he said, is whether the mortality risk associated with torcetrapib will extend to any of the other CETP inhibitors under development by Hoffmann-La Roche Inc., Merck & Co., AstraZeneca Pharmaceuticals LP, and Bayer Pharmaceuticals Corp. “We can't tell right now whether this is a class effect, or whether it's specific to this one drug alone,” said Dr. Samaha, who is investigating the effect of niacin plus statins on cardiovascular events in the AIM-HIGH trial.

There are two possible culprits behind the increased mortality among torcetrapib patients, he said: the drug's hypertensive effects, which caused significant blood pressure hikes in a small number of patients in the phase II studies, and accelerated atherogenesis.

Blood pressure effects are likely to be drug specific, as other CETP inhibitors in development haven't thus far shown similar problems. But a finding that torcetrapib, a drug designed to prevent or decrease atherosclerotic plaque, actually increases it could have devastating implications for all CETP research. “That would most likely be a class effect that we would see with any of these drugs,” said James McKenney, Pharm.D., a primary investigator for torcetrapib's 2006 safety and efficacy studies.

CETP inhibitors increase HDL cholesterol by limiting the amount of cholesterol that leaves the HDL particle, Dr. Samaha said. “What you end up with is larger HDL particles with more cholesterol associated with them. Whether those particles are still as cardioprotective [as normally occurring HDL] is something we don't know.”

He's not alone in voicing this concern. Boosting HDL levels this way has always been a controversial idea, according to Dr. Michael Davidson, director of preventive cardiology at Rush University Medical Center, Chicago. But despite uncertainty about the cardioprotective effects of CETP-modulated HDL cholesterol, he said in an interview, “a lot of us were still optimistic, because the 50% increase in HDL that we saw in the earlier studies was so significant that it should have resulted in a significant mortality risk reduction.”

That reduction should also have been large enough to offset the potential problem of hypertension, said Dr. Davidson, who worked with Dr. McKenney on the phase II studies (J. Am. Coll. Cardiol. 2006;48:1774–81; 1782–90).

In those studies, blood pressure increases were widely variable in both groups; however, significant jumps—systolic increases greater than 10 mm Hg from baseline or diastolic increases greater than 15 mm Hg from baseline—occurred in only about 3% of patients. “It was a concern,” Dr. Davidson said, “but we thought raising the HDL that much would offset any potential risks. Obviously, this blood pressure issue may be much more serious than we first imagined.”

While Pfizer has yet to release the causes of the deaths in its phase III study, Dr. Davidson thinks the drug's hypertensive effects may play into the picture. “Perhaps we didn't see a clear signal about this in the earlier trials because they included relatively healthy subjects, while the phase III trial involved sicker patients who had preexisting cardiovascular disease.”

But because the other CETP inhibitors under development haven't shown any effect on blood pressure thus far, torcetrapib may be an outlier among them. “It may just be a specific issue to this drug. I believe this class of drugs still has a lot of potential.” However, he cautioned, until the deaths in both arms of the ILLUMINATE trial have been adjudicated, it will be impossible to understand the drug's full risk picture.

Two upcoming imaging trials will provide valuable additional clues to torcetrapib's risks. One of these, the ILLUSTRATE trial, uses intravascular ultrasound to evaluate atherosclerotic plaque burden, said Dr. Steven Nissen, a principal investigator in that study.

ILLUSTRATE included 1,190 patients randomized to the combination of torcetrapib and atorvastatin or to atorvastatin alone. Data collection is complete; Dr. Nissen, medical director of the Cleveland Clinic Cardiovascular Coordinating Center, said he will present the results at the American College of Cardiology meeting in March.

The demise of torcetrapib may be a “bitter disappointment” to researchers, but it's too soon to give up on the entire class of HDL cholesterol-raising agents, several of which are still under development, experts say.

“While this is a huge setback for the field of lipid therapy, it would be a big mistake for patients and physicians to get the impression that this research is a lost cause,” said Dr. Frederick Samaha of the University of Pennsylvania, Philadelphia. “There are several different drugs being looked at. We can't presume from the failure of one that all of them will have similar problems.”

Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, was furthest along that pipeline, however, and was the only one in a phase III trial (ILLUMINATE). The study randomized 15,000 patients with existing coronary heart disease to atorvastatin alone or to a combination of atorvastatin and torcetrapib.

But Pfizer Inc. abruptly halted it after an interim data analysis showed significantly more deaths in the combination arm than in the monotherapy arm (82 vs. 51). Although details haven't been released, the imbalance in mortality appears to have been driven by cardiovascular events, Dr. Samaha said in an interview.

“It's very disappointing. Of all the HDL-raising drugs, this class holds the most promise. [CETP inhibitors] increase HDL by 50%–100%, much more than even the second most effective drug, niacin. So we had a lot of really high hopes for torcetrapib.”

The question facing researchers, he said, is whether the mortality risk associated with torcetrapib will extend to any of the other CETP inhibitors under development by Hoffmann-La Roche Inc., Merck & Co., AstraZeneca Pharmaceuticals LP, and Bayer Pharmaceuticals Corp. “We can't tell right now whether this is a class effect, or whether it's specific to this one drug alone,” said Dr. Samaha, who is investigating the effect of niacin plus statins on cardiovascular events in the AIM-HIGH trial.

There are two possible culprits behind the increased mortality among torcetrapib patients, he said: the drug's hypertensive effects, which caused significant blood pressure hikes in a small number of patients in the phase II studies, and accelerated atherogenesis.

Blood pressure effects are likely to be drug specific, as other CETP inhibitors in development haven't thus far shown similar problems. But a finding that torcetrapib, a drug designed to prevent or decrease atherosclerotic plaque, actually increases it could have devastating implications for all CETP research. “That would most likely be a class effect that we would see with any of these drugs,” said James McKenney, Pharm.D., a primary investigator for torcetrapib's 2006 safety and efficacy studies.

CETP inhibitors increase HDL cholesterol by limiting the amount of cholesterol that leaves the HDL particle, Dr. Samaha said. “What you end up with is larger HDL particles with more cholesterol associated with them. Whether those particles are still as cardioprotective [as normally occurring HDL] is something we don't know.”

He's not alone in voicing this concern. Boosting HDL levels this way has always been a controversial idea, according to Dr. Michael Davidson, director of preventive cardiology at Rush University Medical Center, Chicago. But despite uncertainty about the cardioprotective effects of CETP-modulated HDL cholesterol, he said in an interview, “a lot of us were still optimistic, because the 50% increase in HDL that we saw in the earlier studies was so significant that it should have resulted in a significant mortality risk reduction.”

That reduction should also have been large enough to offset the potential problem of hypertension, said Dr. Davidson, who worked with Dr. McKenney on the phase II studies (J. Am. Coll. Cardiol. 2006;48:1774–81; 1782–90).

In those studies, blood pressure increases were widely variable in both groups; however, significant jumps—systolic increases greater than 10 mm Hg from baseline or diastolic increases greater than 15 mm Hg from baseline—occurred in only about 3% of patients. “It was a concern,” Dr. Davidson said, “but we thought raising the HDL that much would offset any potential risks. Obviously, this blood pressure issue may be much more serious than we first imagined.”

While Pfizer has yet to release the causes of the deaths in its phase III study, Dr. Davidson thinks the drug's hypertensive effects may play into the picture. “Perhaps we didn't see a clear signal about this in the earlier trials because they included relatively healthy subjects, while the phase III trial involved sicker patients who had preexisting cardiovascular disease.”

But because the other CETP inhibitors under development haven't shown any effect on blood pressure thus far, torcetrapib may be an outlier among them. “It may just be a specific issue to this drug. I believe this class of drugs still has a lot of potential.” However, he cautioned, until the deaths in both arms of the ILLUMINATE trial have been adjudicated, it will be impossible to understand the drug's full risk picture.

Two upcoming imaging trials will provide valuable additional clues to torcetrapib's risks. One of these, the ILLUSTRATE trial, uses intravascular ultrasound to evaluate atherosclerotic plaque burden, said Dr. Steven Nissen, a principal investigator in that study.

ILLUSTRATE included 1,190 patients randomized to the combination of torcetrapib and atorvastatin or to atorvastatin alone. Data collection is complete; Dr. Nissen, medical director of the Cleveland Clinic Cardiovascular Coordinating Center, said he will present the results at the American College of Cardiology meeting in March.

PHILADELPHIA — Patients can be safely switched from chlorofluorocarbon-propelled albuterol to hydrofluoroalkane-propelled albuterol, with no decrease in efficacy or increase in side effects.

However, the hydrofluoroalkane (HFA)-propelled drug penetrates deeper into the lower lung, which causes a greater peak in plasma concentrations. This increases the likelihood of heart rate increases in patients using lower doses of albuterol, Dr. Adam Wanner said at the annual meeting of the American College of Allergy, Asthma, and Immunology.

“With the HFA propellant, you get a slightly higher tachycardic response that takes off sooner than what you see with CFC [chlorofluorocarbon] propellants,” said Dr. Wanner, Joseph Weintraub Professor of Medicine, Pediatrics, and Biomedical Engineering at the University of Miami. At higher doses, however, the albuterol-induced tachycardia is equivalent between the formulations, he added.

The difference in lung penetration is due to the particle size each propellant delivers. HFA delivers a significantly smaller particle, with more of it deposited in the lower lung. “The device delivers the same amount of drug, but because it has greater penetration, you will see higher plasma concentrations for a short period of time,” he explained.

According to an international policy set by the Montreal Protocol on Substances that Deplete the Ozone Layer, a United Nations environment program, all developed countries must phase out CFCs by 2010. Medical aerosol propellants are a secondary target of the phase-out, which initially concentrated on CFCs in refrigeration. In the United States, the phase-out goal is Jan. 1, 2008. “After that, no CFC-propelled aerosol will be allowed in the U.S.,” said Dr. Wanner, who also serves on the United Nations' Medical Aerosol Technical Options Committee.

The data supporting the safety of switching propellants in albuterol are robust, collected from more than 20 studies, Dr. Wanner said. One of the most important investigations examined the switch to HFA-propelled albuterol among nearly 10,500 asthma patients in Great Britain. The prospective trial, which documented safety and short- and long-term efficacy over 1 year, found no increase in major or minor adverse events following the introduction of the HFA-powered inhaler (Int. J. Clin. Pharmacol. Ther. 2003;41:67–76).

A Texas study examined efficacy in more than 300 asthma patients who switched to HFA-propelled albuterol. Patients maintained pulmonary function and other measures of asthma control at levels comparable with baseline. Treatment was well tolerated, and the adverse event profile was similar to that of CFC-propelled medication. There were no clinically relevant effects on electrocardiography, vital signs, or lab values (Ann. Allergy Asthma Immunol. 2001;86:297–303).

Studies have also shown equivalency and safety in children and in patients with exercise-induced bronchoconstriction, Dr. Wanner said.

European countries are far ahead of the United States in phasing out HFA propellants in medical aerosols, he added. Many have opted for dry-powder inhalers rather than HFA propellants. All studies comparing the three formulations have concluded that there are no differences among them in safety or efficacy.

But only 20% of U.S. inhalers are dry-powder formulations, below the global average of 27% and far below the average in many other countries, including Japan, where dry-powder formulations account for 60% of inhalers, and Scandinavia, where 90% of inhalers are dry powder.

Leading up to 2008, the United States has had a linearly decreasing metric tonnage exemption for medical aerosols. In 1995, the exemption was 40,000 metric tons, he said. In 2007, the exemption will be less than 2,000 metric tons. After 2008, the annual exemption will be about 350 metric tons.

HFA inhalershave greater penetration, leading to higher plasma levelsfor a short period of time. DR. WANNER

PHILADELPHIA — Patients can be safely switched from chlorofluorocarbon-propelled albuterol to hydrofluoroalkane-propelled albuterol, with no decrease in efficacy or increase in side effects.

However, the hydrofluoroalkane (HFA)-propelled drug penetrates deeper into the lower lung, which causes a greater peak in plasma concentrations. This increases the likelihood of heart rate increases in patients using lower doses of albuterol, Dr. Adam Wanner said at the annual meeting of the American College of Allergy, Asthma, and Immunology.

“With the HFA propellant, you get a slightly higher tachycardic response that takes off sooner than what you see with CFC [chlorofluorocarbon] propellants,” said Dr. Wanner, Joseph Weintraub Professor of Medicine, Pediatrics, and Biomedical Engineering at the University of Miami. At higher doses, however, the albuterol-induced tachycardia is equivalent between the formulations, he added.

The difference in lung penetration is due to the particle size each propellant delivers. HFA delivers a significantly smaller particle, with more of it deposited in the lower lung. “The device delivers the same amount of drug, but because it has greater penetration, you will see higher plasma concentrations for a short period of time,” he explained.

According to an international policy set by the Montreal Protocol on Substances that Deplete the Ozone Layer, a United Nations environment program, all developed countries must phase out CFCs by 2010. Medical aerosol propellants are a secondary target of the phase-out, which initially concentrated on CFCs in refrigeration. In the United States, the phase-out goal is Jan. 1, 2008. “After that, no CFC-propelled aerosol will be allowed in the U.S.,” said Dr. Wanner, who also serves on the United Nations' Medical Aerosol Technical Options Committee.

The data supporting the safety of switching propellants in albuterol are robust, collected from more than 20 studies, Dr. Wanner said. One of the most important investigations examined the switch to HFA-propelled albuterol among nearly 10,500 asthma patients in Great Britain. The prospective trial, which documented safety and short- and long-term efficacy over 1 year, found no increase in major or minor adverse events following the introduction of the HFA-powered inhaler (Int. J. Clin. Pharmacol. Ther. 2003;41:67–76).

A Texas study examined efficacy in more than 300 asthma patients who switched to HFA-propelled albuterol. Patients maintained pulmonary function and other measures of asthma control at levels comparable with baseline. Treatment was well tolerated, and the adverse event profile was similar to that of CFC-propelled medication. There were no clinically relevant effects on electrocardiography, vital signs, or lab values (Ann. Allergy Asthma Immunol. 2001;86:297–303).

Studies have also shown equivalency and safety in children and in patients with exercise-induced bronchoconstriction, Dr. Wanner said.

European countries are far ahead of the United States in phasing out HFA propellants in medical aerosols, he added. Many have opted for dry-powder inhalers rather than HFA propellants. All studies comparing the three formulations have concluded that there are no differences among them in safety or efficacy.

But only 20% of U.S. inhalers are dry-powder formulations, below the global average of 27% and far below the average in many other countries, including Japan, where dry-powder formulations account for 60% of inhalers, and Scandinavia, where 90% of inhalers are dry powder.

Leading up to 2008, the United States has had a linearly decreasing metric tonnage exemption for medical aerosols. In 1995, the exemption was 40,000 metric tons, he said. In 2007, the exemption will be less than 2,000 metric tons. After 2008, the annual exemption will be about 350 metric tons.

HFA inhalershave greater penetration, leading to higher plasma levelsfor a short period of time. DR. WANNER

PHILADELPHIA — Patients can be safely switched from chlorofluorocarbon-propelled albuterol to hydrofluoroalkane-propelled albuterol, with no decrease in efficacy or increase in side effects.

However, the hydrofluoroalkane (HFA)-propelled drug penetrates deeper into the lower lung, which causes a greater peak in plasma concentrations. This increases the likelihood of heart rate increases in patients using lower doses of albuterol, Dr. Adam Wanner said at the annual meeting of the American College of Allergy, Asthma, and Immunology.

“With the HFA propellant, you get a slightly higher tachycardic response that takes off sooner than what you see with CFC [chlorofluorocarbon] propellants,” said Dr. Wanner, Joseph Weintraub Professor of Medicine, Pediatrics, and Biomedical Engineering at the University of Miami. At higher doses, however, the albuterol-induced tachycardia is equivalent between the formulations, he added.

The difference in lung penetration is due to the particle size each propellant delivers. HFA delivers a significantly smaller particle, with more of it deposited in the lower lung. “The device delivers the same amount of drug, but because it has greater penetration, you will see higher plasma concentrations for a short period of time,” he explained.

According to an international policy set by the Montreal Protocol on Substances that Deplete the Ozone Layer, a United Nations environment program, all developed countries must phase out CFCs by 2010. Medical aerosol propellants are a secondary target of the phase-out, which initially concentrated on CFCs in refrigeration. In the United States, the phase-out goal is Jan. 1, 2008. “After that, no CFC-propelled aerosol will be allowed in the U.S.,” said Dr. Wanner, who also serves on the United Nations' Medical Aerosol Technical Options Committee.

The data supporting the safety of switching propellants in albuterol are robust, collected from more than 20 studies, Dr. Wanner said. One of the most important investigations examined the switch to HFA-propelled albuterol among nearly 10,500 asthma patients in Great Britain. The prospective trial, which documented safety and short- and long-term efficacy over 1 year, found no increase in major or minor adverse events following the introduction of the HFA-powered inhaler (Int. J. Clin. Pharmacol. Ther. 2003;41:67–76).

A Texas study examined efficacy in more than 300 asthma patients who switched to HFA-propelled albuterol. Patients maintained pulmonary function and other measures of asthma control at levels comparable with baseline. Treatment was well tolerated, and the adverse event profile was similar to that of CFC-propelled medication. There were no clinically relevant effects on electrocardiography, vital signs, or lab values (Ann. Allergy Asthma Immunol. 2001;86:297–303).

Studies have also shown equivalency and safety in children and in patients with exercise-induced bronchoconstriction, Dr. Wanner said.

European countries are far ahead of the United States in phasing out HFA propellants in medical aerosols, he added. Many have opted for dry-powder inhalers rather than HFA propellants. All studies comparing the three formulations have concluded that there are no differences among them in safety or efficacy.

But only 20% of U.S. inhalers are dry-powder formulations, below the global average of 27% and far below the average in many other countries, including Japan, where dry-powder formulations account for 60% of inhalers, and Scandinavia, where 90% of inhalers are dry powder.

Leading up to 2008, the United States has had a linearly decreasing metric tonnage exemption for medical aerosols. In 1995, the exemption was 40,000 metric tons, he said. In 2007, the exemption will be less than 2,000 metric tons. After 2008, the annual exemption will be about 350 metric tons.

HFA inhalershave greater penetration, leading to higher plasma levelsfor a short period of time. DR. WANNER

BOSTON — Brothers of women with polycystic ovary syndrome share with their sisters similar metabolic features that indicate they may be at increased risk for decreased insulin sensitivity and glucose tolerance, high triglycerides, and dyscoagulability, Dr. Jean-Patrice Baillargeon said at the annual meeting of the Androgen Excess Society.

These characteristics, which are independent of both fat percentage and body mass index, suggest that polycystic ovary syndrome (PCOS) may represent an inherited constellation of symptoms that are expressed differently in men and women, said Dr. Baillargeon of the University of Sherbrooke (Que.).

He compared insulin sensitivity and other metabolic measures in 17 brothers of women with PCOS and 28 men who had no first-degree relatives with PCOS. Their average age was 28 years. There were no significant differences in body mass index (average 26.5 kg/m

At baseline, brothers had significantly higher levels of triglycerides (1.66 vs. 0.99 mmol/L), plasminogen activator inhibitor-1 (27 vs. 16 nmol/L), and factor VIII (27 vs. 16 nmol/L). “The increased PAI-1 and factor VIII show a dyscoagulability in the brothers,” Dr. Baillargeon said.

Three of the brothers (18%) had decreased insulin sensitivity after an oral glucose tolerance test; insulin sensitivity values were normal in all controls. The 2-hour glucose levels, insulin area under the curve, and glucose area under the curve were also significantly higher in brothers of women with PCOS. “The insulin sensitivity of the brothers was 38% less than that of the controls,” Dr. Baillargeon noted.

BOSTON — Brothers of women with polycystic ovary syndrome share with their sisters similar metabolic features that indicate they may be at increased risk for decreased insulin sensitivity and glucose tolerance, high triglycerides, and dyscoagulability, Dr. Jean-Patrice Baillargeon said at the annual meeting of the Androgen Excess Society.

These characteristics, which are independent of both fat percentage and body mass index, suggest that polycystic ovary syndrome (PCOS) may represent an inherited constellation of symptoms that are expressed differently in men and women, said Dr. Baillargeon of the University of Sherbrooke (Que.).

He compared insulin sensitivity and other metabolic measures in 17 brothers of women with PCOS and 28 men who had no first-degree relatives with PCOS. Their average age was 28 years. There were no significant differences in body mass index (average 26.5 kg/m

At baseline, brothers had significantly higher levels of triglycerides (1.66 vs. 0.99 mmol/L), plasminogen activator inhibitor-1 (27 vs. 16 nmol/L), and factor VIII (27 vs. 16 nmol/L). “The increased PAI-1 and factor VIII show a dyscoagulability in the brothers,” Dr. Baillargeon said.

Three of the brothers (18%) had decreased insulin sensitivity after an oral glucose tolerance test; insulin sensitivity values were normal in all controls. The 2-hour glucose levels, insulin area under the curve, and glucose area under the curve were also significantly higher in brothers of women with PCOS. “The insulin sensitivity of the brothers was 38% less than that of the controls,” Dr. Baillargeon noted.

BOSTON — Brothers of women with polycystic ovary syndrome share with their sisters similar metabolic features that indicate they may be at increased risk for decreased insulin sensitivity and glucose tolerance, high triglycerides, and dyscoagulability, Dr. Jean-Patrice Baillargeon said at the annual meeting of the Androgen Excess Society.

These characteristics, which are independent of both fat percentage and body mass index, suggest that polycystic ovary syndrome (PCOS) may represent an inherited constellation of symptoms that are expressed differently in men and women, said Dr. Baillargeon of the University of Sherbrooke (Que.).

He compared insulin sensitivity and other metabolic measures in 17 brothers of women with PCOS and 28 men who had no first-degree relatives with PCOS. Their average age was 28 years. There were no significant differences in body mass index (average 26.5 kg/m

At baseline, brothers had significantly higher levels of triglycerides (1.66 vs. 0.99 mmol/L), plasminogen activator inhibitor-1 (27 vs. 16 nmol/L), and factor VIII (27 vs. 16 nmol/L). “The increased PAI-1 and factor VIII show a dyscoagulability in the brothers,” Dr. Baillargeon said.

Three of the brothers (18%) had decreased insulin sensitivity after an oral glucose tolerance test; insulin sensitivity values were normal in all controls. The 2-hour glucose levels, insulin area under the curve, and glucose area under the curve were also significantly higher in brothers of women with PCOS. “The insulin sensitivity of the brothers was 38% less than that of the controls,” Dr. Baillargeon noted.