John R. Bell

In a population of mothers with type 1 diabetes and their singleton infants, third-trimester glycemic measures were more predictive of bearing a large-for-gestational-age infant than were earlier parameters, and third-trimester episodic hyperglycemia was most predictive of all.

Dr. Lucrecia Herranz and colleagues at the University Hospital of La Paz in Madrid recruited from the hospital 73 mothers, who had given birth to 37 large-for-gestational-age (LGA) infants and 36 appropriate-for-gestational-age (AGA) infants. The investigators reported their findings in Diabetes Research and Clinical Practice (2007;75:42–6).

After researchers controlled for tobacco smoking and history of microsomia, mothers of LGA infants had significantly higher mean overall glucose levels in all trimesters than did mothers of AGA infants. But the difference was most pronounced in the third trimester, when LGA infants' mothers registered a mean glucose level of 7.4 mmol/L, vs. 6.9 mmol/L for mothers of AGA infants. Mean postprandial glucose in the third trimester was 8.4 mmol/L for mothers of LGA babies and 7.9 mmol/L for AGA neonates' mothers. Moreover, the portion of glucose values higher than the goal was 42% for LGA mothers and 35% for AGA mothers. HbA_1c levels were significantly higher in the LGA group than in the AGA group only in the third trimester (6.2 vs. 5.9).

Logistic regression of all third-trimester glycemic measures showed that the percentage of third-trimester glucose values above the target value posed an increased likelihood of bearing an LGA infant (OR 1.09; 95% CI 1.02–1.15). AGA infants had a mean birth weight of 3,139 g, vs. 3,830 g for the LGA infants.

Notably, the two groups of mothers, all of whom had been managed at the hospital before conception, had no preconception differences in glycemic parameters.

Dr. Herranz and colleagues noted that their study supports the findings of prior studies that have posited an effect of intermittent maternal hyperglycemia on fetal growth. “Interestingly, our data show that of all third-trimester glycemic parameters, the percentage of glucose values above glycemic target is the most powerful predictor of LGA infants,” they wrote.

In a population of mothers with type 1 diabetes and their singleton infants, third-trimester glycemic measures were more predictive of bearing a large-for-gestational-age infant than were earlier parameters, and third-trimester episodic hyperglycemia was most predictive of all.

Dr. Lucrecia Herranz and colleagues at the University Hospital of La Paz in Madrid recruited from the hospital 73 mothers, who had given birth to 37 large-for-gestational-age (LGA) infants and 36 appropriate-for-gestational-age (AGA) infants. The investigators reported their findings in Diabetes Research and Clinical Practice (2007;75:42–6).

After researchers controlled for tobacco smoking and history of microsomia, mothers of LGA infants had significantly higher mean overall glucose levels in all trimesters than did mothers of AGA infants. But the difference was most pronounced in the third trimester, when LGA infants' mothers registered a mean glucose level of 7.4 mmol/L, vs. 6.9 mmol/L for mothers of AGA infants. Mean postprandial glucose in the third trimester was 8.4 mmol/L for mothers of LGA babies and 7.9 mmol/L for AGA neonates' mothers. Moreover, the portion of glucose values higher than the goal was 42% for LGA mothers and 35% for AGA mothers. HbA_1c levels were significantly higher in the LGA group than in the AGA group only in the third trimester (6.2 vs. 5.9).

Logistic regression of all third-trimester glycemic measures showed that the percentage of third-trimester glucose values above the target value posed an increased likelihood of bearing an LGA infant (OR 1.09; 95% CI 1.02–1.15). AGA infants had a mean birth weight of 3,139 g, vs. 3,830 g for the LGA infants.

Notably, the two groups of mothers, all of whom had been managed at the hospital before conception, had no preconception differences in glycemic parameters.

Dr. Herranz and colleagues noted that their study supports the findings of prior studies that have posited an effect of intermittent maternal hyperglycemia on fetal growth. “Interestingly, our data show that of all third-trimester glycemic parameters, the percentage of glucose values above glycemic target is the most powerful predictor of LGA infants,” they wrote.

In a population of mothers with type 1 diabetes and their singleton infants, third-trimester glycemic measures were more predictive of bearing a large-for-gestational-age infant than were earlier parameters, and third-trimester episodic hyperglycemia was most predictive of all.

Dr. Lucrecia Herranz and colleagues at the University Hospital of La Paz in Madrid recruited from the hospital 73 mothers, who had given birth to 37 large-for-gestational-age (LGA) infants and 36 appropriate-for-gestational-age (AGA) infants. The investigators reported their findings in Diabetes Research and Clinical Practice (2007;75:42–6).

After researchers controlled for tobacco smoking and history of microsomia, mothers of LGA infants had significantly higher mean overall glucose levels in all trimesters than did mothers of AGA infants. But the difference was most pronounced in the third trimester, when LGA infants' mothers registered a mean glucose level of 7.4 mmol/L, vs. 6.9 mmol/L for mothers of AGA infants. Mean postprandial glucose in the third trimester was 8.4 mmol/L for mothers of LGA babies and 7.9 mmol/L for AGA neonates' mothers. Moreover, the portion of glucose values higher than the goal was 42% for LGA mothers and 35% for AGA mothers. HbA_1c levels were significantly higher in the LGA group than in the AGA group only in the third trimester (6.2 vs. 5.9).

Logistic regression of all third-trimester glycemic measures showed that the percentage of third-trimester glucose values above the target value posed an increased likelihood of bearing an LGA infant (OR 1.09; 95% CI 1.02–1.15). AGA infants had a mean birth weight of 3,139 g, vs. 3,830 g for the LGA infants.

Notably, the two groups of mothers, all of whom had been managed at the hospital before conception, had no preconception differences in glycemic parameters.

Dr. Herranz and colleagues noted that their study supports the findings of prior studies that have posited an effect of intermittent maternal hyperglycemia on fetal growth. “Interestingly, our data show that of all third-trimester glycemic parameters, the percentage of glucose values above glycemic target is the most powerful predictor of LGA infants,” they wrote.

A pediatric dosing chart for the influenza drug oseltamivir (Tamiflu) sent by Roche Laboratories Inc. to health care providers last November contained an error and should have indicated a standard dosage of once daily—rather than twice daily—for 10 days, according to a letter from the company.

The erroneous chart, titled “Standard Dosage of the Tamiflu Oral Suspension for Prophylaxis of Influenza in Pediatric Patients,” had accompanied a November letter announcing reports of self-injury and delirium in patients taking Tamiflu.

The letter from Roche said that none of the Tamiflu on the market contains package inserts with the incorrect dosage chart.

Prescribing information is online at www.rocheusa.com/products/tamiflu/pi.pdf

A pediatric dosing chart for the influenza drug oseltamivir (Tamiflu) sent by Roche Laboratories Inc. to health care providers last November contained an error and should have indicated a standard dosage of once daily—rather than twice daily—for 10 days, according to a letter from the company.

The erroneous chart, titled “Standard Dosage of the Tamiflu Oral Suspension for Prophylaxis of Influenza in Pediatric Patients,” had accompanied a November letter announcing reports of self-injury and delirium in patients taking Tamiflu.

The letter from Roche said that none of the Tamiflu on the market contains package inserts with the incorrect dosage chart.

Prescribing information is online at www.rocheusa.com/products/tamiflu/pi.pdf

A pediatric dosing chart for the influenza drug oseltamivir (Tamiflu) sent by Roche Laboratories Inc. to health care providers last November contained an error and should have indicated a standard dosage of once daily—rather than twice daily—for 10 days, according to a letter from the company.

The erroneous chart, titled “Standard Dosage of the Tamiflu Oral Suspension for Prophylaxis of Influenza in Pediatric Patients,” had accompanied a November letter announcing reports of self-injury and delirium in patients taking Tamiflu.

The letter from Roche said that none of the Tamiflu on the market contains package inserts with the incorrect dosage chart.

Prescribing information is online at www.rocheusa.com/products/tamiflu/pi.pdf

Patients with impaired fasting glucose or impaired glucose tolerance who were screened for diabetes risk as part of an international diabetes study went on to develop type 2 diabetes at rates higher than those cited in textbooks and guidelines, according to a report published online in the journal Diabetologia.

The findings suggest that screening strategies based on incidence rates for the general population may not be useful for identifying type 2 diabetes in patients at high risk for the disease.

Of 1,160 patients (aged 40–69 years) who were screened at baseline, 70% (811) were reexamined at 1 year. Among those who were rescreened, there were 155 incident cases of diabetes, reported Dr. Signe Sætre Rasmussen of the Steno Diabetes Center, Gentofte, Denmark, and her colleagues at Aarhus (Denmark) University. The incidence of diabetes was 17.6/100 person-years in those with impaired fasting glucose and 18.8/100 person-years in those with impaired glucose tolerance.

These findings were based on data collected during the screening phase of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION), a screening and intervention study for type 2 diabetes in general practice. A treatment phase will follow (Diabetologia 2006 [Epub ahead of print]; DOI 10.1007/z00125–006–0530-y). Study participants were recruited based on their risk scores from a previous Danish diabetes screening study.

Dr. Rasmussen and colleagues concluded that the progression rates used by most screening programs are based on low rates listed in textbooks and guidelines. “Our study confirms that these are too low for high-risk settings, which would be the preferable strategy as general population-based screening programs are expensive, logistically difficult and of questionable benefit,” they wrote.

The study was funded by Novo Nordisk Inc., Astra-Zeneca Pharmaceuticals, Pfizer Inc., Servier Laboratories, GlaxoSmithKline, and HemoCue Inc. The authors reported no conflicts of interest.

Patients with impaired fasting glucose or impaired glucose tolerance who were screened for diabetes risk as part of an international diabetes study went on to develop type 2 diabetes at rates higher than those cited in textbooks and guidelines, according to a report published online in the journal Diabetologia.

The findings suggest that screening strategies based on incidence rates for the general population may not be useful for identifying type 2 diabetes in patients at high risk for the disease.

Of 1,160 patients (aged 40–69 years) who were screened at baseline, 70% (811) were reexamined at 1 year. Among those who were rescreened, there were 155 incident cases of diabetes, reported Dr. Signe Sætre Rasmussen of the Steno Diabetes Center, Gentofte, Denmark, and her colleagues at Aarhus (Denmark) University. The incidence of diabetes was 17.6/100 person-years in those with impaired fasting glucose and 18.8/100 person-years in those with impaired glucose tolerance.

These findings were based on data collected during the screening phase of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION), a screening and intervention study for type 2 diabetes in general practice. A treatment phase will follow (Diabetologia 2006 [Epub ahead of print]; DOI 10.1007/z00125–006–0530-y). Study participants were recruited based on their risk scores from a previous Danish diabetes screening study.

Dr. Rasmussen and colleagues concluded that the progression rates used by most screening programs are based on low rates listed in textbooks and guidelines. “Our study confirms that these are too low for high-risk settings, which would be the preferable strategy as general population-based screening programs are expensive, logistically difficult and of questionable benefit,” they wrote.

The study was funded by Novo Nordisk Inc., Astra-Zeneca Pharmaceuticals, Pfizer Inc., Servier Laboratories, GlaxoSmithKline, and HemoCue Inc. The authors reported no conflicts of interest.

Patients with impaired fasting glucose or impaired glucose tolerance who were screened for diabetes risk as part of an international diabetes study went on to develop type 2 diabetes at rates higher than those cited in textbooks and guidelines, according to a report published online in the journal Diabetologia.

The findings suggest that screening strategies based on incidence rates for the general population may not be useful for identifying type 2 diabetes in patients at high risk for the disease.

Of 1,160 patients (aged 40–69 years) who were screened at baseline, 70% (811) were reexamined at 1 year. Among those who were rescreened, there were 155 incident cases of diabetes, reported Dr. Signe Sætre Rasmussen of the Steno Diabetes Center, Gentofte, Denmark, and her colleagues at Aarhus (Denmark) University. The incidence of diabetes was 17.6/100 person-years in those with impaired fasting glucose and 18.8/100 person-years in those with impaired glucose tolerance.

These findings were based on data collected during the screening phase of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION), a screening and intervention study for type 2 diabetes in general practice. A treatment phase will follow (Diabetologia 2006 [Epub ahead of print]; DOI 10.1007/z00125–006–0530-y). Study participants were recruited based on their risk scores from a previous Danish diabetes screening study.

Dr. Rasmussen and colleagues concluded that the progression rates used by most screening programs are based on low rates listed in textbooks and guidelines. “Our study confirms that these are too low for high-risk settings, which would be the preferable strategy as general population-based screening programs are expensive, logistically difficult and of questionable benefit,” they wrote.

The study was funded by Novo Nordisk Inc., Astra-Zeneca Pharmaceuticals, Pfizer Inc., Servier Laboratories, GlaxoSmithKline, and HemoCue Inc. The authors reported no conflicts of interest.

A Congressional push for fast-track approval of generic biologics likely won't have any effect on insulin costs for most patients with diabetes, mainly because the types of insulins most patients use now are still on patent, according to an expert.

Patents for several insulin formulations—both regular and NPH—have expired in this decade: for example, Humulin (Eli Lilly & Co.) in 2001 and Novo-Nordisk's Novolin in 2005. However, the Food and Drug Administration has not issued its in-progress guidelines for approval of several new follow-on biologics, each of which is claimed by its manufacturer to contain the identical active ingredient as the approved product and therefore, they argue, should not need additional testing.

Debate remains as to whether existing regulations should allow for approval of such products. Applications for new biologics are regulated by the 1944 Public Health Service Act. However, small-molecule drug products are instead regulated by the Food, Drug, and Cosmetic Act of 1938, which allows the accelerated approval of new drugs based on prior evidence. In 2006, the FDA approved a follow-on of the recombinant human growth hormone Omnitrope, manufactured by Sandoz, but the agency said it considered that product to be not a generic but instead a “follow-on protein product,” because it had made no determination of therapeutic equivalence.

According to the FDA, other proteins that have received fast-track approval in this manner include GlucaGen (glucagon recombinant for injection), Hylenex (hyaluronidase recombinant human), Hydase and Amphadase (hyaluronidase), and Fortical (calcitonin salmon recombinant) nasal spray.

While the argument over existing regulations continues, some members of Congress are pushing forward with new proposals. A member of his staff confirmed that Rep. Henry Waxman (D-Calif.) will reintroduce a bill submitted last session, H.R. 6257, that would effectively force the FDA to fast-track approvals of follow-on generic biologics—a bill that some believe will lead to the production of generic insulins and thus lower costs for state governments and insurers. The date of reintroduction has not been determined, the staff member said.

A Senate version of the same bill, S. 4016, was sponsored by Sen. Hillary Clinton (D-N.Y.), with Sen. Charles Schumer (D-N.Y.), Sen. Patrick Leahy (D-Vt.), and Sen. Debbie Stabenow (D-Mich.) as cosponsors. In each house of Congress, the bill was referred to committee but expired in December, when the 109th Congress ended, as do all pending bills not passed before the end of a session.

On another front, two Democratic Congressmen from Michigan, John Dingell and Bart Stupak, wrote to FDA Commissioner Dr. Andrew von Eschenbach at the end of January, lamenting the “failure of FDA to use its existing authority to approve generic biopharmaceutical drugs.” The Congressmen also requested a list of the follow-on biologics for which the FDA has received abbreviated approval applications. The letter noted that the House Energy and Commerce Committee, which Rep. Dingell chairs, would use the requested information in its ongoing investigation into the overall generic drug approval process.

Dr. Bill Law Jr., immediate past president of the American Association of Clinical Endocrinologists, said in an interview that confusion in the lay media about the difference between nonanalogue human insulins and analogue human insulins has ended up helping these legislative efforts.

“It's only after the 20-year patent law has expired [on a human analogue insulin] that it would be eligible for a generic company to come in and make one,” said Dr. Law, an endocrinologist in private practice in Knoxville, Tenn. As to the nonanalogue varieties, “unless the companies can sell one for less than $16 a vial, it's not going to change the cost” to the patient, he said. This confusion has given rise to false hopes for a drastic reduction in insulin costs for most patients, according to Dr. Law.

Regarding approval of follow-on biologics, “it's totally different from making a pill, where you have complete control over what goes in that pill,” he said. “Everything else that's in that pill was specifically added by the manufacturer of that pill, whereas the analog insulin we're talking about making is created in a biologic system, like a yeast cell or bacterium, and then has to be highly purified to eliminate the cellular contaminants.”

Thus, the safety of a generic biologic cannot be established as easily as that of a drug, Dr. Law said. “Good science requires proof of safety. From my standpoint as a doctor treating patients, it's not enough just to show that in that bottle there's a certain amount of insulin. I want to know what else is in that bottle that came from a bunch of yeast and bacteria.”

In addition to the Congressional bill, a group of governors petitioned the FDA last summer, urging it to release its guidelines for the approval of follow-on biologics, which the agency began in 2002. The petition was supported by various consumer groups and the Generic Pharmaceutical Association, but the agency has not yet responded.

A Congressional push for fast-track approval of generic biologics likely won't have any effect on insulin costs for most patients with diabetes, mainly because the types of insulins most patients use now are still on patent, according to an expert.

Patents for several insulin formulations—both regular and NPH—have expired in this decade: for example, Humulin (Eli Lilly & Co.) in 2001 and Novo-Nordisk's Novolin in 2005. However, the Food and Drug Administration has not issued its in-progress guidelines for approval of several new follow-on biologics, each of which is claimed by its manufacturer to contain the identical active ingredient as the approved product and therefore, they argue, should not need additional testing.

Debate remains as to whether existing regulations should allow for approval of such products. Applications for new biologics are regulated by the 1944 Public Health Service Act. However, small-molecule drug products are instead regulated by the Food, Drug, and Cosmetic Act of 1938, which allows the accelerated approval of new drugs based on prior evidence. In 2006, the FDA approved a follow-on of the recombinant human growth hormone Omnitrope, manufactured by Sandoz, but the agency said it considered that product to be not a generic but instead a “follow-on protein product,” because it had made no determination of therapeutic equivalence.

According to the FDA, other proteins that have received fast-track approval in this manner include GlucaGen (glucagon recombinant for injection), Hylenex (hyaluronidase recombinant human), Hydase and Amphadase (hyaluronidase), and Fortical (calcitonin salmon recombinant) nasal spray.

While the argument over existing regulations continues, some members of Congress are pushing forward with new proposals. A member of his staff confirmed that Rep. Henry Waxman (D-Calif.) will reintroduce a bill submitted last session, H.R. 6257, that would effectively force the FDA to fast-track approvals of follow-on generic biologics—a bill that some believe will lead to the production of generic insulins and thus lower costs for state governments and insurers. The date of reintroduction has not been determined, the staff member said.

A Senate version of the same bill, S. 4016, was sponsored by Sen. Hillary Clinton (D-N.Y.), with Sen. Charles Schumer (D-N.Y.), Sen. Patrick Leahy (D-Vt.), and Sen. Debbie Stabenow (D-Mich.) as cosponsors. In each house of Congress, the bill was referred to committee but expired in December, when the 109th Congress ended, as do all pending bills not passed before the end of a session.

On another front, two Democratic Congressmen from Michigan, John Dingell and Bart Stupak, wrote to FDA Commissioner Dr. Andrew von Eschenbach at the end of January, lamenting the “failure of FDA to use its existing authority to approve generic biopharmaceutical drugs.” The Congressmen also requested a list of the follow-on biologics for which the FDA has received abbreviated approval applications. The letter noted that the House Energy and Commerce Committee, which Rep. Dingell chairs, would use the requested information in its ongoing investigation into the overall generic drug approval process.

Dr. Bill Law Jr., immediate past president of the American Association of Clinical Endocrinologists, said in an interview that confusion in the lay media about the difference between nonanalogue human insulins and analogue human insulins has ended up helping these legislative efforts.

“It's only after the 20-year patent law has expired [on a human analogue insulin] that it would be eligible for a generic company to come in and make one,” said Dr. Law, an endocrinologist in private practice in Knoxville, Tenn. As to the nonanalogue varieties, “unless the companies can sell one for less than $16 a vial, it's not going to change the cost” to the patient, he said. This confusion has given rise to false hopes for a drastic reduction in insulin costs for most patients, according to Dr. Law.

Regarding approval of follow-on biologics, “it's totally different from making a pill, where you have complete control over what goes in that pill,” he said. “Everything else that's in that pill was specifically added by the manufacturer of that pill, whereas the analog insulin we're talking about making is created in a biologic system, like a yeast cell or bacterium, and then has to be highly purified to eliminate the cellular contaminants.”

Thus, the safety of a generic biologic cannot be established as easily as that of a drug, Dr. Law said. “Good science requires proof of safety. From my standpoint as a doctor treating patients, it's not enough just to show that in that bottle there's a certain amount of insulin. I want to know what else is in that bottle that came from a bunch of yeast and bacteria.”

In addition to the Congressional bill, a group of governors petitioned the FDA last summer, urging it to release its guidelines for the approval of follow-on biologics, which the agency began in 2002. The petition was supported by various consumer groups and the Generic Pharmaceutical Association, but the agency has not yet responded.

A Congressional push for fast-track approval of generic biologics likely won't have any effect on insulin costs for most patients with diabetes, mainly because the types of insulins most patients use now are still on patent, according to an expert.

Patents for several insulin formulations—both regular and NPH—have expired in this decade: for example, Humulin (Eli Lilly & Co.) in 2001 and Novo-Nordisk's Novolin in 2005. However, the Food and Drug Administration has not issued its in-progress guidelines for approval of several new follow-on biologics, each of which is claimed by its manufacturer to contain the identical active ingredient as the approved product and therefore, they argue, should not need additional testing.

Debate remains as to whether existing regulations should allow for approval of such products. Applications for new biologics are regulated by the 1944 Public Health Service Act. However, small-molecule drug products are instead regulated by the Food, Drug, and Cosmetic Act of 1938, which allows the accelerated approval of new drugs based on prior evidence. In 2006, the FDA approved a follow-on of the recombinant human growth hormone Omnitrope, manufactured by Sandoz, but the agency said it considered that product to be not a generic but instead a “follow-on protein product,” because it had made no determination of therapeutic equivalence.

According to the FDA, other proteins that have received fast-track approval in this manner include GlucaGen (glucagon recombinant for injection), Hylenex (hyaluronidase recombinant human), Hydase and Amphadase (hyaluronidase), and Fortical (calcitonin salmon recombinant) nasal spray.

While the argument over existing regulations continues, some members of Congress are pushing forward with new proposals. A member of his staff confirmed that Rep. Henry Waxman (D-Calif.) will reintroduce a bill submitted last session, H.R. 6257, that would effectively force the FDA to fast-track approvals of follow-on generic biologics—a bill that some believe will lead to the production of generic insulins and thus lower costs for state governments and insurers. The date of reintroduction has not been determined, the staff member said.

A Senate version of the same bill, S. 4016, was sponsored by Sen. Hillary Clinton (D-N.Y.), with Sen. Charles Schumer (D-N.Y.), Sen. Patrick Leahy (D-Vt.), and Sen. Debbie Stabenow (D-Mich.) as cosponsors. In each house of Congress, the bill was referred to committee but expired in December, when the 109th Congress ended, as do all pending bills not passed before the end of a session.

On another front, two Democratic Congressmen from Michigan, John Dingell and Bart Stupak, wrote to FDA Commissioner Dr. Andrew von Eschenbach at the end of January, lamenting the “failure of FDA to use its existing authority to approve generic biopharmaceutical drugs.” The Congressmen also requested a list of the follow-on biologics for which the FDA has received abbreviated approval applications. The letter noted that the House Energy and Commerce Committee, which Rep. Dingell chairs, would use the requested information in its ongoing investigation into the overall generic drug approval process.

Dr. Bill Law Jr., immediate past president of the American Association of Clinical Endocrinologists, said in an interview that confusion in the lay media about the difference between nonanalogue human insulins and analogue human insulins has ended up helping these legislative efforts.

“It's only after the 20-year patent law has expired [on a human analogue insulin] that it would be eligible for a generic company to come in and make one,” said Dr. Law, an endocrinologist in private practice in Knoxville, Tenn. As to the nonanalogue varieties, “unless the companies can sell one for less than $16 a vial, it's not going to change the cost” to the patient, he said. This confusion has given rise to false hopes for a drastic reduction in insulin costs for most patients, according to Dr. Law.

Regarding approval of follow-on biologics, “it's totally different from making a pill, where you have complete control over what goes in that pill,” he said. “Everything else that's in that pill was specifically added by the manufacturer of that pill, whereas the analog insulin we're talking about making is created in a biologic system, like a yeast cell or bacterium, and then has to be highly purified to eliminate the cellular contaminants.”

Thus, the safety of a generic biologic cannot be established as easily as that of a drug, Dr. Law said. “Good science requires proof of safety. From my standpoint as a doctor treating patients, it's not enough just to show that in that bottle there's a certain amount of insulin. I want to know what else is in that bottle that came from a bunch of yeast and bacteria.”

In addition to the Congressional bill, a group of governors petitioned the FDA last summer, urging it to release its guidelines for the approval of follow-on biologics, which the agency began in 2002. The petition was supported by various consumer groups and the Generic Pharmaceutical Association, but the agency has not yet responded.

NASHVILLE, TENN. — Perimenopause does induce depression in a subgroup of women, as illustrated by results of several recent studies and by early findings from his own investigation, Dr. Peter J. Schmidt said at the annual meeting of the North American Menopause Society.

He and his colleagues conducted an observational study of 29 asymptomatic premenopausal women with regular menses and followed them with reproductive and behavioral measures for a mean of 5 years until they had gone through menopause.

Episodes of depression occurred sporadically, he reported, until the year before the last menstrual period, when the investigators observed four episodes of depression, followed by five episodes in the year after the last menstrual period. Overall, there were nine depressive episodes in eight women. Only two of the women had a prior history of depression, he noted.

“Overall, then, within the 24 months surrounding the last menstrual period, we identified approximately a 14-fold increased risk for an episode of depression to occur,” said Dr. Schmidt, chief of behavioral endocrinology at the National Institutes of Health, Bethesda, Md.

He noted that these happened late in the menopausal transition—a period marked by estrogen withdrawal and hypogonadism.

Despite assertions by some studies in the literature that the onset of menopause is not directly associated with mood disorders in women, considerable laboratory evidence bears out the relationship between estrogen and depression, Dr. Schmidt said.

Anxious phenotype has been implicated in studies of estrogen-receptor-knockout mice, and compounds that selectively modulate the estrogen receptor β have been identified as anxiolytic and reduce stress response to a novel environment.

Dr. Schmidt emphasized that depression has measurable physiologic consequences for women and noted as an example that one observational study from the Women's Health Initiative found that in women who had no history of cardiovascular problems, depressive symptoms were linked to an increased risk of cardiac death over 5 years' follow-up (Arch. Intern. Med. 2004;164:289–98).

Other negative outcomes linked to depression are stroke, metabolic syndrome, and dementia. He cited recent community-based epidemiologic studies that followed women with no prior history of depression and found that onset of menopause was associated with a 2–2.5-fold risk of depression.

He noted that several studies have found that depression frequently precedes a comorbid condition by several years, “suggesting in fact that depression is causing the medical condition or that the two conditions share a similar pathophysiology.”

NASHVILLE, TENN. — Perimenopause does induce depression in a subgroup of women, as illustrated by results of several recent studies and by early findings from his own investigation, Dr. Peter J. Schmidt said at the annual meeting of the North American Menopause Society.

He and his colleagues conducted an observational study of 29 asymptomatic premenopausal women with regular menses and followed them with reproductive and behavioral measures for a mean of 5 years until they had gone through menopause.

Episodes of depression occurred sporadically, he reported, until the year before the last menstrual period, when the investigators observed four episodes of depression, followed by five episodes in the year after the last menstrual period. Overall, there were nine depressive episodes in eight women. Only two of the women had a prior history of depression, he noted.

“Overall, then, within the 24 months surrounding the last menstrual period, we identified approximately a 14-fold increased risk for an episode of depression to occur,” said Dr. Schmidt, chief of behavioral endocrinology at the National Institutes of Health, Bethesda, Md.

He noted that these happened late in the menopausal transition—a period marked by estrogen withdrawal and hypogonadism.

Despite assertions by some studies in the literature that the onset of menopause is not directly associated with mood disorders in women, considerable laboratory evidence bears out the relationship between estrogen and depression, Dr. Schmidt said.

Anxious phenotype has been implicated in studies of estrogen-receptor-knockout mice, and compounds that selectively modulate the estrogen receptor β have been identified as anxiolytic and reduce stress response to a novel environment.

Dr. Schmidt emphasized that depression has measurable physiologic consequences for women and noted as an example that one observational study from the Women's Health Initiative found that in women who had no history of cardiovascular problems, depressive symptoms were linked to an increased risk of cardiac death over 5 years' follow-up (Arch. Intern. Med. 2004;164:289–98).

Other negative outcomes linked to depression are stroke, metabolic syndrome, and dementia. He cited recent community-based epidemiologic studies that followed women with no prior history of depression and found that onset of menopause was associated with a 2–2.5-fold risk of depression.

He noted that several studies have found that depression frequently precedes a comorbid condition by several years, “suggesting in fact that depression is causing the medical condition or that the two conditions share a similar pathophysiology.”

NASHVILLE, TENN. — Perimenopause does induce depression in a subgroup of women, as illustrated by results of several recent studies and by early findings from his own investigation, Dr. Peter J. Schmidt said at the annual meeting of the North American Menopause Society.

He and his colleagues conducted an observational study of 29 asymptomatic premenopausal women with regular menses and followed them with reproductive and behavioral measures for a mean of 5 years until they had gone through menopause.

Episodes of depression occurred sporadically, he reported, until the year before the last menstrual period, when the investigators observed four episodes of depression, followed by five episodes in the year after the last menstrual period. Overall, there were nine depressive episodes in eight women. Only two of the women had a prior history of depression, he noted.

“Overall, then, within the 24 months surrounding the last menstrual period, we identified approximately a 14-fold increased risk for an episode of depression to occur,” said Dr. Schmidt, chief of behavioral endocrinology at the National Institutes of Health, Bethesda, Md.

He noted that these happened late in the menopausal transition—a period marked by estrogen withdrawal and hypogonadism.

Despite assertions by some studies in the literature that the onset of menopause is not directly associated with mood disorders in women, considerable laboratory evidence bears out the relationship between estrogen and depression, Dr. Schmidt said.

Anxious phenotype has been implicated in studies of estrogen-receptor-knockout mice, and compounds that selectively modulate the estrogen receptor β have been identified as anxiolytic and reduce stress response to a novel environment.

Dr. Schmidt emphasized that depression has measurable physiologic consequences for women and noted as an example that one observational study from the Women's Health Initiative found that in women who had no history of cardiovascular problems, depressive symptoms were linked to an increased risk of cardiac death over 5 years' follow-up (Arch. Intern. Med. 2004;164:289–98).

Other negative outcomes linked to depression are stroke, metabolic syndrome, and dementia. He cited recent community-based epidemiologic studies that followed women with no prior history of depression and found that onset of menopause was associated with a 2–2.5-fold risk of depression.

He noted that several studies have found that depression frequently precedes a comorbid condition by several years, “suggesting in fact that depression is causing the medical condition or that the two conditions share a similar pathophysiology.”

The information offered by multislice CT and myocardial perfusion imaging is sufficiently different that both tools are meaningful to the diagnosis of coronary artery disease—but evidence may predispose MSCT to becoming the first-line test, Joanne D. Schuijf of Leiden (the Netherlands) University Medical Center and colleagues reported.

They reported results from 114 patients (mean age 60 years) who underwent single-photon emission CT (SPECT) myocardial perfusion imaging (MPI) along with noninvasive coronary angiography with MSCT after presenting to either of two outpatient clinics with chest pain (J. Am. Coll. Cardiol. 2006;48:2508–14). Each patient underwent both tests within 30 days of the other.

MSCT showed that 29% of the patients had nonobstructive coronary artery disease (CAD), with 35% diagnosed with at least one significant lesion. The remaining 36% of patients were determined by MSCT not to have CAD. Notably, of the patients with abnormal MSCT findings, 55% (40 patients) had normal results on MPI—a dichotomy illustrating that “only half of the observed lesions on MSCT may be of hemodynamic significance. Even among patients with obstructive CAD on MSCT, 50% had normal MPI,” the investigators wrote.

Their study “is a first attempt to apply MSCT in patients with an intermediate likelihood of CAD,” they noted. The consistency of MSCT findings with those of invasive coronary angiography indicated that “the high accuracy of MSCT demonstrated previously in patients with a high likelihood of CAD also applies to patients with an intermediate likelihood of CAD.”

With the advent of MSCT and its greater diagnostic sensitivity over MPI, “a paradigm shift occurs in the definition of CAD, displacing the emphasis from inducible ischemia to atherosclerosis,” Ms. Schuijf and colleagues wrote. “Based on the discrepancy between MSCT and MPI, one can argue that MSCT could be used as the first-line test. A normal MSCT excludes CAD, and the patient can be reassured.”

In an accompanying editorial, Dr. Sharmila Dorbala of Brigham and Women's Hospital, Boston, and colleagues noted that although the consistency between the findings via MSCT and those via invasive coronary angiography was “excellent,” the study—like its predecessors in the literature—showed a diagnostic inconsistency between MSCT and MPI.

However, their ultimate assessment of the study's findings seemed to indicate a diagnostic advantage to MSCT. “Except in patients with high-risk scan features, combined testing with [MSCT and MPI] may be an effective strategy to both diagnose extent of CAD and guide management to the appropriate vessel,” they wrote.

The information offered by multislice CT and myocardial perfusion imaging is sufficiently different that both tools are meaningful to the diagnosis of coronary artery disease—but evidence may predispose MSCT to becoming the first-line test, Joanne D. Schuijf of Leiden (the Netherlands) University Medical Center and colleagues reported.

They reported results from 114 patients (mean age 60 years) who underwent single-photon emission CT (SPECT) myocardial perfusion imaging (MPI) along with noninvasive coronary angiography with MSCT after presenting to either of two outpatient clinics with chest pain (J. Am. Coll. Cardiol. 2006;48:2508–14). Each patient underwent both tests within 30 days of the other.

MSCT showed that 29% of the patients had nonobstructive coronary artery disease (CAD), with 35% diagnosed with at least one significant lesion. The remaining 36% of patients were determined by MSCT not to have CAD. Notably, of the patients with abnormal MSCT findings, 55% (40 patients) had normal results on MPI—a dichotomy illustrating that “only half of the observed lesions on MSCT may be of hemodynamic significance. Even among patients with obstructive CAD on MSCT, 50% had normal MPI,” the investigators wrote.

Their study “is a first attempt to apply MSCT in patients with an intermediate likelihood of CAD,” they noted. The consistency of MSCT findings with those of invasive coronary angiography indicated that “the high accuracy of MSCT demonstrated previously in patients with a high likelihood of CAD also applies to patients with an intermediate likelihood of CAD.”

With the advent of MSCT and its greater diagnostic sensitivity over MPI, “a paradigm shift occurs in the definition of CAD, displacing the emphasis from inducible ischemia to atherosclerosis,” Ms. Schuijf and colleagues wrote. “Based on the discrepancy between MSCT and MPI, one can argue that MSCT could be used as the first-line test. A normal MSCT excludes CAD, and the patient can be reassured.”

In an accompanying editorial, Dr. Sharmila Dorbala of Brigham and Women's Hospital, Boston, and colleagues noted that although the consistency between the findings via MSCT and those via invasive coronary angiography was “excellent,” the study—like its predecessors in the literature—showed a diagnostic inconsistency between MSCT and MPI.

However, their ultimate assessment of the study's findings seemed to indicate a diagnostic advantage to MSCT. “Except in patients with high-risk scan features, combined testing with [MSCT and MPI] may be an effective strategy to both diagnose extent of CAD and guide management to the appropriate vessel,” they wrote.

The information offered by multislice CT and myocardial perfusion imaging is sufficiently different that both tools are meaningful to the diagnosis of coronary artery disease—but evidence may predispose MSCT to becoming the first-line test, Joanne D. Schuijf of Leiden (the Netherlands) University Medical Center and colleagues reported.

They reported results from 114 patients (mean age 60 years) who underwent single-photon emission CT (SPECT) myocardial perfusion imaging (MPI) along with noninvasive coronary angiography with MSCT after presenting to either of two outpatient clinics with chest pain (J. Am. Coll. Cardiol. 2006;48:2508–14). Each patient underwent both tests within 30 days of the other.

MSCT showed that 29% of the patients had nonobstructive coronary artery disease (CAD), with 35% diagnosed with at least one significant lesion. The remaining 36% of patients were determined by MSCT not to have CAD. Notably, of the patients with abnormal MSCT findings, 55% (40 patients) had normal results on MPI—a dichotomy illustrating that “only half of the observed lesions on MSCT may be of hemodynamic significance. Even among patients with obstructive CAD on MSCT, 50% had normal MPI,” the investigators wrote.

Their study “is a first attempt to apply MSCT in patients with an intermediate likelihood of CAD,” they noted. The consistency of MSCT findings with those of invasive coronary angiography indicated that “the high accuracy of MSCT demonstrated previously in patients with a high likelihood of CAD also applies to patients with an intermediate likelihood of CAD.”

With the advent of MSCT and its greater diagnostic sensitivity over MPI, “a paradigm shift occurs in the definition of CAD, displacing the emphasis from inducible ischemia to atherosclerosis,” Ms. Schuijf and colleagues wrote. “Based on the discrepancy between MSCT and MPI, one can argue that MSCT could be used as the first-line test. A normal MSCT excludes CAD, and the patient can be reassured.”

In an accompanying editorial, Dr. Sharmila Dorbala of Brigham and Women's Hospital, Boston, and colleagues noted that although the consistency between the findings via MSCT and those via invasive coronary angiography was “excellent,” the study—like its predecessors in the literature—showed a diagnostic inconsistency between MSCT and MPI.

However, their ultimate assessment of the study's findings seemed to indicate a diagnostic advantage to MSCT. “Except in patients with high-risk scan features, combined testing with [MSCT and MPI] may be an effective strategy to both diagnose extent of CAD and guide management to the appropriate vessel,” they wrote.

A pediatric dosing chart for the influenza drug oseltamivir (Tamiflu) sent by Roche Laboratories Inc. to health care providers last November contained an error and should have indicated a standard dosage of once daily—rather than twice daily—for 10 days, according to a Dec. 26 letter from the company.

The erroneous chart, titled “Standard Dosage of the Tamiflu Oral Suspension for Prophylaxis of Influenza in Pediatric Patients,” had accompanied a Nov. 13 letter announcing that reports of self-injury and delirium in patients taking Tamiflu had been added to the precautions section of the product's package insert.

The company urges medical professionals to discard the incorrect chart.

The letter from Roche noted that none of the Tamiflu on the market contains package inserts with the incorrect dosage chart.

Complete prescribing information is available online at www.rocheusa.com/products/tamiflu/pi.pdf

Questions can be directed to Roche at 800–526–6367.

A pediatric dosing chart for the influenza drug oseltamivir (Tamiflu) sent by Roche Laboratories Inc. to health care providers last November contained an error and should have indicated a standard dosage of once daily—rather than twice daily—for 10 days, according to a Dec. 26 letter from the company.

The erroneous chart, titled “Standard Dosage of the Tamiflu Oral Suspension for Prophylaxis of Influenza in Pediatric Patients,” had accompanied a Nov. 13 letter announcing that reports of self-injury and delirium in patients taking Tamiflu had been added to the precautions section of the product's package insert.

The company urges medical professionals to discard the incorrect chart.

The letter from Roche noted that none of the Tamiflu on the market contains package inserts with the incorrect dosage chart.

Complete prescribing information is available online at www.rocheusa.com/products/tamiflu/pi.pdf

Questions can be directed to Roche at 800–526–6367.

A pediatric dosing chart for the influenza drug oseltamivir (Tamiflu) sent by Roche Laboratories Inc. to health care providers last November contained an error and should have indicated a standard dosage of once daily—rather than twice daily—for 10 days, according to a Dec. 26 letter from the company.

The erroneous chart, titled “Standard Dosage of the Tamiflu Oral Suspension for Prophylaxis of Influenza in Pediatric Patients,” had accompanied a Nov. 13 letter announcing that reports of self-injury and delirium in patients taking Tamiflu had been added to the precautions section of the product's package insert.

The company urges medical professionals to discard the incorrect chart.

The letter from Roche noted that none of the Tamiflu on the market contains package inserts with the incorrect dosage chart.

Complete prescribing information is available online at www.rocheusa.com/products/tamiflu/pi.pdf

Questions can be directed to Roche at 800–526–6367.

BALTIMORE — In the decision of which drug to prescribe a patient with restless legs syndrome, the frequency and painfulness of symptoms are crucial to making the correct choice, Dr. Christopher J. Earley said at a neurology meeting sponsored by Johns Hopkins University.

“For [75%]-80%, depending on the population that you deal with, pain is not what they experience,” said Dr. Earley, a neurologist at Johns Hopkins. A far greater portion instead describe their RLS as uncomfortable, he said. But for those with painful RLS, that pain must be treated. “So I tend to use the antiseizure medications [e.g., gabapentin, lamotrigine, pregabalin] or the opiates as my first line of treatment, as opposed to the dopamine [DA] agents, when I'm dealing with painful symptoms,” he said. If it's partially responsive… then I will consider the dopamine agonists. If I really get desperate… I might consider sedation.”

For painless nightly RLS, he advises a DA agonist as first-line therapy, opiates as a second-line choice, and sedatives as third-line treatment. Frequent painless RLS (2–3 nights per week) warrants a sedative first, followed by opiates and, if those fail, levodopa. For occasional RLS (less than twice per week), he advises either a half or whole tablet of carbidopa 25 mg/levodopa 100 mg (available as Sinemet and Parcopa brands) as needed for first-line therapy. “This is going to be effective in 99.9% of patients, barring side effects like nausea,” he said. He recommends a DA agonist and a sedative as second- and third-line treatment, respectively. Drugs that can aggravate RLS include neuroleptics and antiemetics, as well as SSRIs and tricyclic antidepressants (except for bupropion and trazodone) and antihistamines.

A disadvantage of the DA agonists is that they take 2 hours to reach peak dose effect (3 hours if taken with a meal or after symptom onset), compared with 30–60 minutes for opiates. Thus dopamine agonists are most useful for situations such as airplane flights, he said, but less practical for nighttime RLS. Dr. Earley favors levodopa for occasional nonpainful RLS. “If you have any doubts about whether this is RLS or not RLS, you can use the levodopa”-carbidopa combination (carbidopa 25 mg/levodopa 100 mg) of half to 11/2 tablets for 3 days. “If they get no real benefits from that, this is not RLS—at least not the RLS that I know.”

The DA agonists do have other disadvantages besides their delayed effect, Dr. Earley noted. They can cause compulsive behaviors—though this has been observed more in patients with Parkinson's disease than with RLS. They also can cause hypersomnia. “It's almost like narcolepsy,” he said. Moreover, DA agonists risk the phenomenon of augmentation, whereby an increase in dosage leads to an increase in symptoms, so that a patient is treated effectively for a time period in which RLS occurs (e.g., bedtime), but then the RLS begins to occur either before or after the treated period. “Augmentation is the single biggest reason why you have to stop this drug,” Dr. Earley warned. He consulted on the case of a woman whose RLS progressed over the course of 2 years from initially requiring one dose of Sinemet nightly “to taking Sinemet every hour on the hour, and she was only getting 2 or 3 hours of sleep.”

He advised that when patients taking a DA agonist for sleep complain of RLS symptoms before or after bedtime, the physician should not prescribe additional drug. As long as the patient can sleep without RLS awakening them or interfering with their falling asleep, RLS symptoms at other times of the day are not worth medicating. They are free to walk around in the evenings and the primary lifestyle problem of RLS interference with sleep is still under control, he said.

Notably, opiates do not pose augmentation risk, he said. With opiates, “you're going to get about 85% of them up walking away relatively happy.” Options in this drug category are codeine, propoxyphene, controlled-release oxycodone, methadone, and the fentanyl patch. Dr. Earley observed that methadone is by far the least expensive, at approximately $.05 per dose.

Iron deficiency has been implicated as a possible cause of RLS, he noted. “I check ferritins in everybody,” he said. Deficiency is defined as less than 18 ng/mL or iron saturation less than 16%. He recommends ferrous sulfate 325 mg plus 200 mg vitamin C or orange juice, to be given on an empty stomach in the absence of calcium or milk.

BALTIMORE — In the decision of which drug to prescribe a patient with restless legs syndrome, the frequency and painfulness of symptoms are crucial to making the correct choice, Dr. Christopher J. Earley said at a neurology meeting sponsored by Johns Hopkins University.

“For [75%]-80%, depending on the population that you deal with, pain is not what they experience,” said Dr. Earley, a neurologist at Johns Hopkins. A far greater portion instead describe their RLS as uncomfortable, he said. But for those with painful RLS, that pain must be treated. “So I tend to use the antiseizure medications [e.g., gabapentin, lamotrigine, pregabalin] or the opiates as my first line of treatment, as opposed to the dopamine [DA] agents, when I'm dealing with painful symptoms,” he said. If it's partially responsive… then I will consider the dopamine agonists. If I really get desperate… I might consider sedation.”

For painless nightly RLS, he advises a DA agonist as first-line therapy, opiates as a second-line choice, and sedatives as third-line treatment. Frequent painless RLS (2–3 nights per week) warrants a sedative first, followed by opiates and, if those fail, levodopa. For occasional RLS (less than twice per week), he advises either a half or whole tablet of carbidopa 25 mg/levodopa 100 mg (available as Sinemet and Parcopa brands) as needed for first-line therapy. “This is going to be effective in 99.9% of patients, barring side effects like nausea,” he said. He recommends a DA agonist and a sedative as second- and third-line treatment, respectively. Drugs that can aggravate RLS include neuroleptics and antiemetics, as well as SSRIs and tricyclic antidepressants (except for bupropion and trazodone) and antihistamines.

A disadvantage of the DA agonists is that they take 2 hours to reach peak dose effect (3 hours if taken with a meal or after symptom onset), compared with 30–60 minutes for opiates. Thus dopamine agonists are most useful for situations such as airplane flights, he said, but less practical for nighttime RLS. Dr. Earley favors levodopa for occasional nonpainful RLS. “If you have any doubts about whether this is RLS or not RLS, you can use the levodopa”-carbidopa combination (carbidopa 25 mg/levodopa 100 mg) of half to 11/2 tablets for 3 days. “If they get no real benefits from that, this is not RLS—at least not the RLS that I know.”

The DA agonists do have other disadvantages besides their delayed effect, Dr. Earley noted. They can cause compulsive behaviors—though this has been observed more in patients with Parkinson's disease than with RLS. They also can cause hypersomnia. “It's almost like narcolepsy,” he said. Moreover, DA agonists risk the phenomenon of augmentation, whereby an increase in dosage leads to an increase in symptoms, so that a patient is treated effectively for a time period in which RLS occurs (e.g., bedtime), but then the RLS begins to occur either before or after the treated period. “Augmentation is the single biggest reason why you have to stop this drug,” Dr. Earley warned. He consulted on the case of a woman whose RLS progressed over the course of 2 years from initially requiring one dose of Sinemet nightly “to taking Sinemet every hour on the hour, and she was only getting 2 or 3 hours of sleep.”

He advised that when patients taking a DA agonist for sleep complain of RLS symptoms before or after bedtime, the physician should not prescribe additional drug. As long as the patient can sleep without RLS awakening them or interfering with their falling asleep, RLS symptoms at other times of the day are not worth medicating. They are free to walk around in the evenings and the primary lifestyle problem of RLS interference with sleep is still under control, he said.

Notably, opiates do not pose augmentation risk, he said. With opiates, “you're going to get about 85% of them up walking away relatively happy.” Options in this drug category are codeine, propoxyphene, controlled-release oxycodone, methadone, and the fentanyl patch. Dr. Earley observed that methadone is by far the least expensive, at approximately $.05 per dose.

Iron deficiency has been implicated as a possible cause of RLS, he noted. “I check ferritins in everybody,” he said. Deficiency is defined as less than 18 ng/mL or iron saturation less than 16%. He recommends ferrous sulfate 325 mg plus 200 mg vitamin C or orange juice, to be given on an empty stomach in the absence of calcium or milk.

BALTIMORE — In the decision of which drug to prescribe a patient with restless legs syndrome, the frequency and painfulness of symptoms are crucial to making the correct choice, Dr. Christopher J. Earley said at a neurology meeting sponsored by Johns Hopkins University.

“For [75%]-80%, depending on the population that you deal with, pain is not what they experience,” said Dr. Earley, a neurologist at Johns Hopkins. A far greater portion instead describe their RLS as uncomfortable, he said. But for those with painful RLS, that pain must be treated. “So I tend to use the antiseizure medications [e.g., gabapentin, lamotrigine, pregabalin] or the opiates as my first line of treatment, as opposed to the dopamine [DA] agents, when I'm dealing with painful symptoms,” he said. If it's partially responsive… then I will consider the dopamine agonists. If I really get desperate… I might consider sedation.”

For painless nightly RLS, he advises a DA agonist as first-line therapy, opiates as a second-line choice, and sedatives as third-line treatment. Frequent painless RLS (2–3 nights per week) warrants a sedative first, followed by opiates and, if those fail, levodopa. For occasional RLS (less than twice per week), he advises either a half or whole tablet of carbidopa 25 mg/levodopa 100 mg (available as Sinemet and Parcopa brands) as needed for first-line therapy. “This is going to be effective in 99.9% of patients, barring side effects like nausea,” he said. He recommends a DA agonist and a sedative as second- and third-line treatment, respectively. Drugs that can aggravate RLS include neuroleptics and antiemetics, as well as SSRIs and tricyclic antidepressants (except for bupropion and trazodone) and antihistamines.

A disadvantage of the DA agonists is that they take 2 hours to reach peak dose effect (3 hours if taken with a meal or after symptom onset), compared with 30–60 minutes for opiates. Thus dopamine agonists are most useful for situations such as airplane flights, he said, but less practical for nighttime RLS. Dr. Earley favors levodopa for occasional nonpainful RLS. “If you have any doubts about whether this is RLS or not RLS, you can use the levodopa”-carbidopa combination (carbidopa 25 mg/levodopa 100 mg) of half to 11/2 tablets for 3 days. “If they get no real benefits from that, this is not RLS—at least not the RLS that I know.”

The DA agonists do have other disadvantages besides their delayed effect, Dr. Earley noted. They can cause compulsive behaviors—though this has been observed more in patients with Parkinson's disease than with RLS. They also can cause hypersomnia. “It's almost like narcolepsy,” he said. Moreover, DA agonists risk the phenomenon of augmentation, whereby an increase in dosage leads to an increase in symptoms, so that a patient is treated effectively for a time period in which RLS occurs (e.g., bedtime), but then the RLS begins to occur either before or after the treated period. “Augmentation is the single biggest reason why you have to stop this drug,” Dr. Earley warned. He consulted on the case of a woman whose RLS progressed over the course of 2 years from initially requiring one dose of Sinemet nightly “to taking Sinemet every hour on the hour, and she was only getting 2 or 3 hours of sleep.”

He advised that when patients taking a DA agonist for sleep complain of RLS symptoms before or after bedtime, the physician should not prescribe additional drug. As long as the patient can sleep without RLS awakening them or interfering with their falling asleep, RLS symptoms at other times of the day are not worth medicating. They are free to walk around in the evenings and the primary lifestyle problem of RLS interference with sleep is still under control, he said.

Notably, opiates do not pose augmentation risk, he said. With opiates, “you're going to get about 85% of them up walking away relatively happy.” Options in this drug category are codeine, propoxyphene, controlled-release oxycodone, methadone, and the fentanyl patch. Dr. Earley observed that methadone is by far the least expensive, at approximately $.05 per dose.

Iron deficiency has been implicated as a possible cause of RLS, he noted. “I check ferritins in everybody,” he said. Deficiency is defined as less than 18 ng/mL or iron saturation less than 16%. He recommends ferrous sulfate 325 mg plus 200 mg vitamin C or orange juice, to be given on an empty stomach in the absence of calcium or milk.

LAS VEGAS — Patients who present with localized erythema near the site of a tick bite should not necessarily be referred for laboratory tests, Dr. Jana Hercogova said at a dermatology seminar sponsored by Skin Disease Education Foundation.

In fact, a tick bite followed by a local skin reaction should simply be examined in 1 week and, if the redness persists, treated with antibiotics, said Dr. Hercogova of Charles University, Prague.

In the absence of persistent redness, if tests come back positive for Lyme disease, she recommended treating the patient with doxycycline or penicillin, depending upon whether Ehrlichia coinfection is present.

Physicians should also be familiar with macular and annular erythema migrans, she noted, adding that patients with morphea should also be tested for Borrelia infection. However, she cautioned, “we should treat the patient without [serologic] evidence if we see a clinically clear case.”

Dr. Hercogova added that physicians treating pregnant women should consider the gestational age when choosing treatment. In the first trimester, she advised using penicillin G 20 million U/day for 2 days, with oral antibiotics as an option for the following 2 weeks. If infection is suspected to have begun in the second or third trimester, she said she uses only oral antibiotics—mainly penicillin derivatives.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.

LAS VEGAS — Patients who present with localized erythema near the site of a tick bite should not necessarily be referred for laboratory tests, Dr. Jana Hercogova said at a dermatology seminar sponsored by Skin Disease Education Foundation.

In fact, a tick bite followed by a local skin reaction should simply be examined in 1 week and, if the redness persists, treated with antibiotics, said Dr. Hercogova of Charles University, Prague.

In the absence of persistent redness, if tests come back positive for Lyme disease, she recommended treating the patient with doxycycline or penicillin, depending upon whether Ehrlichia coinfection is present.

Physicians should also be familiar with macular and annular erythema migrans, she noted, adding that patients with morphea should also be tested for Borrelia infection. However, she cautioned, “we should treat the patient without [serologic] evidence if we see a clinically clear case.”

Dr. Hercogova added that physicians treating pregnant women should consider the gestational age when choosing treatment. In the first trimester, she advised using penicillin G 20 million U/day for 2 days, with oral antibiotics as an option for the following 2 weeks. If infection is suspected to have begun in the second or third trimester, she said she uses only oral antibiotics—mainly penicillin derivatives.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.

LAS VEGAS — Patients who present with localized erythema near the site of a tick bite should not necessarily be referred for laboratory tests, Dr. Jana Hercogova said at a dermatology seminar sponsored by Skin Disease Education Foundation.

In fact, a tick bite followed by a local skin reaction should simply be examined in 1 week and, if the redness persists, treated with antibiotics, said Dr. Hercogova of Charles University, Prague.

In the absence of persistent redness, if tests come back positive for Lyme disease, she recommended treating the patient with doxycycline or penicillin, depending upon whether Ehrlichia coinfection is present.

Physicians should also be familiar with macular and annular erythema migrans, she noted, adding that patients with morphea should also be tested for Borrelia infection. However, she cautioned, “we should treat the patient without [serologic] evidence if we see a clinically clear case.”

Dr. Hercogova added that physicians treating pregnant women should consider the gestational age when choosing treatment. In the first trimester, she advised using penicillin G 20 million U/day for 2 days, with oral antibiotics as an option for the following 2 weeks. If infection is suspected to have begun in the second or third trimester, she said she uses only oral antibiotics—mainly penicillin derivatives.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.

A treatment protocol used at the University of Pittsburgh Medical Center has nearly cut in half the number of severe hypoglycemic events experienced by inpatients with diabetes.

“There was a lack of a standardized approach to the treatment of hypoglycemia in the hospital” before the protocol was developed, according to Dr. Mary T. Korytkowski, professor of medicine in the division of endocrinology at the university and head of the hospital's Diabetes Patient Safety Committee (DPSC), which developed the protocol in 2001.

The committee includes physicians, nurses, nutritionists, a patient-safety representative, a quality-improvement specialist, and a pharmacist. It was formed in response to concerns first raised by the hospital's “Condition-C” (for “condition crisis”) rapid-response team. A rapid-response team is a specially designated group of nurses and other clinicians who immediately respond to acute patient problems at a hospital.

Rapid responders at UPMC had noticed that some diabetes patients it had treated experienced a change in consciousness, which occurred after their blood glucose level had significantly dropped, Dr. Korytkowski said.

“There was no standard approach for treating low blood sugar,” she explained. “Where some nurses might go and get juice for a patient, others might call the physician … and wait for the physician to respond and prescribe treatment before actually giving something. So there would be a delay, which could take what would be an otherwise mild reaction and have it turn into a more severe reaction.”

To prevent severe hypoglycemia episodes and to develop a consistent response to milder cases as well, the DPSC developed the protocol for use when a patient's blood glucose drops below 70 mg/dL (see box).

To see how well the protocol was working, Dr. Korytkowski and her colleagues examined the non-critical care patient data for 1 month in 2001, before implementation of the protocol, and for the same month in 2004, following implementation, counting nadir blood glucose in each 4-hour period to avoid overcounting of events. They found there had been a 48% decrease in severe hypoglycemic events (blood glucose less than 40 mg/dL), a 38% drop in moderate hypoglycemic events (blood glucose 40–49 mg/dL), and an 8% reduction in mild hypoglycemic events (blood glucose 50–69 mg/dL). They observed a 43% decline in combined moderate and severe hypoglycemic events.

Moreover, since the introduction of the hypoglycemia protocol in 2001, the number of hypoglycemic events treated by the hospital's rapid-response team has dropped from a high of 29 episodes per 1,000 patient-days/month to 22 episodes per 1,000 patient-days/month, according to Dr. Korytkowski. She and her colleagues plan to publish these results in the near future.

“It's hard to attribute it directly to the hypoglycemia treatment protocol … but we've tracked the frequency of events, and it does look like there's a decrease in the amount of time people spend with severe low blood sugar,” she said. The frequency of bedside glucose monitoring has also increased, and the number of instances requiring the care of the rapid-response team has dropped.

The initial version of the protocol took 6 months to develop and was examined and commented on by departments throughout the hospital. It was approved by each department as well as by the medical executive committee.

The protocol eventually expanded to include orders for insulin, postsurgical guidelines for diabetic patients, a protocol for hyperglycemia in critical care units, and others. “I think that developing the protocol for hypoglycemia unmasked some of the other issues that were related to diabetes management,” she said.

The patient safety committee reviews all cases of hypoglycemia that activate the rapid-response team but considers those for which blood glucose drops to less than 40 mg/dL (regardless of mental state) to be severe.

Dr. Michael DeVita, associate medical director for quality and safety at UPMC, noted that the hospital had seen “a series of poorly managed patients” when it came to hypoglycemia in patients with diabetes. Now, thanks to the use of the protocol, “We have much better glycemic management,” he said. “I'd rather be hospitalized here for diabetes than anywhere in the country.”

He emphasized that it is not the glucose level that triggers the rapid-response team in hypoglycemia cases. “We're looking for changes in respiration, consciousness, blood pressure, pulse. … Those are very similar criteria to others that have been described in the literature.”

“It's a really unusual thing nowadays [at the medical center] to have an event due to hypoglycemia,” Dr. DeVita said. “We still have the occasional one, but it's nothing like what it had been. … The old [rate] is one event per unit per day of low blood sugar—and now we're seeing one event per six units per day. It's a big drop.”

The hospitalwide collaboration in the protocol has been crucial to its success, he added. For example, “they're even working out the relationship between insulin dosing and distribution of meals—two completely different areas and responsibilities of the hospital, and yet they've coordinated medication and food delivery to make it safer for patients.”

Proceedings from a recent conference chaired by Dr. DeVita on rapid-response teams are available online at www.metconference.com

Nurses Key to Consistency, Monitoring

The UPMC hypoglycemia treatment protocol need not be administered by a physician but can be initiated by the bedside nurse, Dr. Korytkowski noted. For all patients covered by the protocol, the responder is required to contact a physician and to recheck glucose 15 minutes after the initial treatment.

In each of three categories of blood glucose and patient consciousness level, the protocol lists treatment options and required steps. For example, for alert patients with blood glucose less than 50 mg/dL, the initial options are to give the patient an 8-ounce glass of milk, to give two tubes of glucose gel if the patient can swallow thick liquids, or if the patient can't take anything by mouth, to give 50 mL 50% dextrose solution intravenously (1 ampule). Intravenous dextrose 5% in water can be started at 100 mL/hour for a prolonged episode.

In patients with blood glucose near the upper end of the 70-mg/dL limit who are still conscious, the treatment may be “as simple as a glass of orange juice,” Dr. Korytkowski said. For other patients, the treatment might be intravenously administered glucose.

A treatment protocol used at the University of Pittsburgh Medical Center has nearly cut in half the number of severe hypoglycemic events experienced by inpatients with diabetes.

“There was a lack of a standardized approach to the treatment of hypoglycemia in the hospital” before the protocol was developed, according to Dr. Mary T. Korytkowski, professor of medicine in the division of endocrinology at the university and head of the hospital's Diabetes Patient Safety Committee (DPSC), which developed the protocol in 2001.

The committee includes physicians, nurses, nutritionists, a patient-safety representative, a quality-improvement specialist, and a pharmacist. It was formed in response to concerns first raised by the hospital's “Condition-C” (for “condition crisis”) rapid-response team. A rapid-response team is a specially designated group of nurses and other clinicians who immediately respond to acute patient problems at a hospital.

Rapid responders at UPMC had noticed that some diabetes patients it had treated experienced a change in consciousness, which occurred after their blood glucose level had significantly dropped, Dr. Korytkowski said.

“There was no standard approach for treating low blood sugar,” she explained. “Where some nurses might go and get juice for a patient, others might call the physician … and wait for the physician to respond and prescribe treatment before actually giving something. So there would be a delay, which could take what would be an otherwise mild reaction and have it turn into a more severe reaction.”

To prevent severe hypoglycemia episodes and to develop a consistent response to milder cases as well, the DPSC developed the protocol for use when a patient's blood glucose drops below 70 mg/dL (see box).

To see how well the protocol was working, Dr. Korytkowski and her colleagues examined the non-critical care patient data for 1 month in 2001, before implementation of the protocol, and for the same month in 2004, following implementation, counting nadir blood glucose in each 4-hour period to avoid overcounting of events. They found there had been a 48% decrease in severe hypoglycemic events (blood glucose less than 40 mg/dL), a 38% drop in moderate hypoglycemic events (blood glucose 40–49 mg/dL), and an 8% reduction in mild hypoglycemic events (blood glucose 50–69 mg/dL). They observed a 43% decline in combined moderate and severe hypoglycemic events.

Moreover, since the introduction of the hypoglycemia protocol in 2001, the number of hypoglycemic events treated by the hospital's rapid-response team has dropped from a high of 29 episodes per 1,000 patient-days/month to 22 episodes per 1,000 patient-days/month, according to Dr. Korytkowski. She and her colleagues plan to publish these results in the near future.

“It's hard to attribute it directly to the hypoglycemia treatment protocol … but we've tracked the frequency of events, and it does look like there's a decrease in the amount of time people spend with severe low blood sugar,” she said. The frequency of bedside glucose monitoring has also increased, and the number of instances requiring the care of the rapid-response team has dropped.

The initial version of the protocol took 6 months to develop and was examined and commented on by departments throughout the hospital. It was approved by each department as well as by the medical executive committee.

The protocol eventually expanded to include orders for insulin, postsurgical guidelines for diabetic patients, a protocol for hyperglycemia in critical care units, and others. “I think that developing the protocol for hypoglycemia unmasked some of the other issues that were related to diabetes management,” she said.

The patient safety committee reviews all cases of hypoglycemia that activate the rapid-response team but considers those for which blood glucose drops to less than 40 mg/dL (regardless of mental state) to be severe.

Dr. Michael DeVita, associate medical director for quality and safety at UPMC, noted that the hospital had seen “a series of poorly managed patients” when it came to hypoglycemia in patients with diabetes. Now, thanks to the use of the protocol, “We have much better glycemic management,” he said. “I'd rather be hospitalized here for diabetes than anywhere in the country.”

He emphasized that it is not the glucose level that triggers the rapid-response team in hypoglycemia cases. “We're looking for changes in respiration, consciousness, blood pressure, pulse. … Those are very similar criteria to others that have been described in the literature.”

“It's a really unusual thing nowadays [at the medical center] to have an event due to hypoglycemia,” Dr. DeVita said. “We still have the occasional one, but it's nothing like what it had been. … The old [rate] is one event per unit per day of low blood sugar—and now we're seeing one event per six units per day. It's a big drop.”

The hospitalwide collaboration in the protocol has been crucial to its success, he added. For example, “they're even working out the relationship between insulin dosing and distribution of meals—two completely different areas and responsibilities of the hospital, and yet they've coordinated medication and food delivery to make it safer for patients.”

Proceedings from a recent conference chaired by Dr. DeVita on rapid-response teams are available online at www.metconference.com

Nurses Key to Consistency, Monitoring

The UPMC hypoglycemia treatment protocol need not be administered by a physician but can be initiated by the bedside nurse, Dr. Korytkowski noted. For all patients covered by the protocol, the responder is required to contact a physician and to recheck glucose 15 minutes after the initial treatment.

In each of three categories of blood glucose and patient consciousness level, the protocol lists treatment options and required steps. For example, for alert patients with blood glucose less than 50 mg/dL, the initial options are to give the patient an 8-ounce glass of milk, to give two tubes of glucose gel if the patient can swallow thick liquids, or if the patient can't take anything by mouth, to give 50 mL 50% dextrose solution intravenously (1 ampule). Intravenous dextrose 5% in water can be started at 100 mL/hour for a prolonged episode.

In patients with blood glucose near the upper end of the 70-mg/dL limit who are still conscious, the treatment may be “as simple as a glass of orange juice,” Dr. Korytkowski said. For other patients, the treatment might be intravenously administered glucose.

A treatment protocol used at the University of Pittsburgh Medical Center has nearly cut in half the number of severe hypoglycemic events experienced by inpatients with diabetes.

“There was a lack of a standardized approach to the treatment of hypoglycemia in the hospital” before the protocol was developed, according to Dr. Mary T. Korytkowski, professor of medicine in the division of endocrinology at the university and head of the hospital's Diabetes Patient Safety Committee (DPSC), which developed the protocol in 2001.

The committee includes physicians, nurses, nutritionists, a patient-safety representative, a quality-improvement specialist, and a pharmacist. It was formed in response to concerns first raised by the hospital's “Condition-C” (for “condition crisis”) rapid-response team. A rapid-response team is a specially designated group of nurses and other clinicians who immediately respond to acute patient problems at a hospital.

Rapid responders at UPMC had noticed that some diabetes patients it had treated experienced a change in consciousness, which occurred after their blood glucose level had significantly dropped, Dr. Korytkowski said.

“There was no standard approach for treating low blood sugar,” she explained. “Where some nurses might go and get juice for a patient, others might call the physician … and wait for the physician to respond and prescribe treatment before actually giving something. So there would be a delay, which could take what would be an otherwise mild reaction and have it turn into a more severe reaction.”

To prevent severe hypoglycemia episodes and to develop a consistent response to milder cases as well, the DPSC developed the protocol for use when a patient's blood glucose drops below 70 mg/dL (see box).

To see how well the protocol was working, Dr. Korytkowski and her colleagues examined the non-critical care patient data for 1 month in 2001, before implementation of the protocol, and for the same month in 2004, following implementation, counting nadir blood glucose in each 4-hour period to avoid overcounting of events. They found there had been a 48% decrease in severe hypoglycemic events (blood glucose less than 40 mg/dL), a 38% drop in moderate hypoglycemic events (blood glucose 40–49 mg/dL), and an 8% reduction in mild hypoglycemic events (blood glucose 50–69 mg/dL). They observed a 43% decline in combined moderate and severe hypoglycemic events.

Moreover, since the introduction of the hypoglycemia protocol in 2001, the number of hypoglycemic events treated by the hospital's rapid-response team has dropped from a high of 29 episodes per 1,000 patient-days/month to 22 episodes per 1,000 patient-days/month, according to Dr. Korytkowski. She and her colleagues plan to publish these results in the near future.

“It's hard to attribute it directly to the hypoglycemia treatment protocol … but we've tracked the frequency of events, and it does look like there's a decrease in the amount of time people spend with severe low blood sugar,” she said. The frequency of bedside glucose monitoring has also increased, and the number of instances requiring the care of the rapid-response team has dropped.

The initial version of the protocol took 6 months to develop and was examined and commented on by departments throughout the hospital. It was approved by each department as well as by the medical executive committee.

The protocol eventually expanded to include orders for insulin, postsurgical guidelines for diabetic patients, a protocol for hyperglycemia in critical care units, and others. “I think that developing the protocol for hypoglycemia unmasked some of the other issues that were related to diabetes management,” she said.

The patient safety committee reviews all cases of hypoglycemia that activate the rapid-response team but considers those for which blood glucose drops to less than 40 mg/dL (regardless of mental state) to be severe.

Dr. Michael DeVita, associate medical director for quality and safety at UPMC, noted that the hospital had seen “a series of poorly managed patients” when it came to hypoglycemia in patients with diabetes. Now, thanks to the use of the protocol, “We have much better glycemic management,” he said. “I'd rather be hospitalized here for diabetes than anywhere in the country.”

He emphasized that it is not the glucose level that triggers the rapid-response team in hypoglycemia cases. “We're looking for changes in respiration, consciousness, blood pressure, pulse. … Those are very similar criteria to others that have been described in the literature.”

“It's a really unusual thing nowadays [at the medical center] to have an event due to hypoglycemia,” Dr. DeVita said. “We still have the occasional one, but it's nothing like what it had been. … The old [rate] is one event per unit per day of low blood sugar—and now we're seeing one event per six units per day. It's a big drop.”

The hospitalwide collaboration in the protocol has been crucial to its success, he added. For example, “they're even working out the relationship between insulin dosing and distribution of meals—two completely different areas and responsibilities of the hospital, and yet they've coordinated medication and food delivery to make it safer for patients.”

Proceedings from a recent conference chaired by Dr. DeVita on rapid-response teams are available online at www.metconference.com

Nurses Key to Consistency, Monitoring

The UPMC hypoglycemia treatment protocol need not be administered by a physician but can be initiated by the bedside nurse, Dr. Korytkowski noted. For all patients covered by the protocol, the responder is required to contact a physician and to recheck glucose 15 minutes after the initial treatment.

In each of three categories of blood glucose and patient consciousness level, the protocol lists treatment options and required steps. For example, for alert patients with blood glucose less than 50 mg/dL, the initial options are to give the patient an 8-ounce glass of milk, to give two tubes of glucose gel if the patient can swallow thick liquids, or if the patient can't take anything by mouth, to give 50 mL 50% dextrose solution intravenously (1 ampule). Intravenous dextrose 5% in water can be started at 100 mL/hour for a prolonged episode.

In patients with blood glucose near the upper end of the 70-mg/dL limit who are still conscious, the treatment may be “as simple as a glass of orange juice,” Dr. Korytkowski said. For other patients, the treatment might be intravenously administered glucose.