Treatment of Autism
Identification and Evaluation of Autism
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Tuesday, October 30, 2007
Monday, October 29, 2007
FDA Clears Genetic Lab Test for Warfarin Sensitivity
The U.S. Food and Drug Administration today cleared for marketing a new genetic test that will help physicians assess whether a patient may be especially sensitive to the blood-thinning drug warfarin (Coumadin), which is used to prevent potentially fatal clots in blood vessels.
One-third of patients receiving warfarin metabolize it quite differently than expected and experience a higher risk of bleeding. Research has shown that some of the unexpected response to warfarin depends on variants of two genes, CYP2C9 and VKORC1. The Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test detects some variants of both genes.
"Today’s action offers physicians the first FDA cleared genetic test for warfarin sensitivity, which is another step in our commitment to personalized medicine,” said Daniel Schultz, M.D., director, FDA’s Center for Devices and Radiological Health. “With this test, physicians may be able to use genetic information along with other clinical information to treat their patients.”
Warfarin can be a difficult drug to use because the optimal dose varies depending on many risk factors, including a patient's diet, age, and the use of other medications. Rapidly achieving the correct dose is important. Patients who receive doses that are higher than needed to correctly thin the blood are at risk of life-threatening bleeding. Those who receive doses that are too low may remain at risk of life-threatening blood clots.
Warfarin is the second most common drug, after insulin, implicated in emergency room visits for adverse drug events.
In August, FDA approved updated labeling for Coumadin, the brand name version of warfarin, explaining that people with variations of the genes CYP2C9 and VKORC1 may respond differently to the drug. Manufacturers of generic warfarin are adding similar information to their products' labeling.
Physicians and other health care professionals who prescribe warfarin regularly check to see if the drug is working properly by ordering a test called the PT or prothrombin time that evaluates the blood's ability to clot properly. The results are measured in seconds and compared with the expected value in healthy people, known as the International Normalized Ratio or INR.
The Nanosphere test is not intended to be a stand-alone tool to determine optimum drug dosage, but should be used along with clinical evaluation and other tools, including INR, to determine the best treatment for patients.
FDA cleared the test based on results of a study conducted by the manufacturer of hundreds of DNA samples as well as on a broad range of published literature. In a three site study, the test was accurate in all cases where the test yielded a result; 8 percent of the tests could not identify which genetic variants were present.
The new test was cleared for use on the Verigene System, a clinical laboratory test system. Both products are manufactured by Nanosphere Inc., Northbrook, Ill.
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One-third of patients receiving warfarin metabolize it quite differently than expected and experience a higher risk of bleeding. Research has shown that some of the unexpected response to warfarin depends on variants of two genes, CYP2C9 and VKORC1. The Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test detects some variants of both genes.
"Today’s action offers physicians the first FDA cleared genetic test for warfarin sensitivity, which is another step in our commitment to personalized medicine,” said Daniel Schultz, M.D., director, FDA’s Center for Devices and Radiological Health. “With this test, physicians may be able to use genetic information along with other clinical information to treat their patients.”
Warfarin can be a difficult drug to use because the optimal dose varies depending on many risk factors, including a patient's diet, age, and the use of other medications. Rapidly achieving the correct dose is important. Patients who receive doses that are higher than needed to correctly thin the blood are at risk of life-threatening bleeding. Those who receive doses that are too low may remain at risk of life-threatening blood clots.
Warfarin is the second most common drug, after insulin, implicated in emergency room visits for adverse drug events.
In August, FDA approved updated labeling for Coumadin, the brand name version of warfarin, explaining that people with variations of the genes CYP2C9 and VKORC1 may respond differently to the drug. Manufacturers of generic warfarin are adding similar information to their products' labeling.
Physicians and other health care professionals who prescribe warfarin regularly check to see if the drug is working properly by ordering a test called the PT or prothrombin time that evaluates the blood's ability to clot properly. The results are measured in seconds and compared with the expected value in healthy people, known as the International Normalized Ratio or INR.
The Nanosphere test is not intended to be a stand-alone tool to determine optimum drug dosage, but should be used along with clinical evaluation and other tools, including INR, to determine the best treatment for patients.
FDA cleared the test based on results of a study conducted by the manufacturer of hundreds of DNA samples as well as on a broad range of published literature. In a three site study, the test was accurate in all cases where the test yielded a result; 8 percent of the tests could not identify which genetic variants were present.
The new test was cleared for use on the Verigene System, a clinical laboratory test system. Both products are manufactured by Nanosphere Inc., Northbrook, Ill.
#
No Long-Term Ill Effects from Repeated Prenatal Corticosteroids for Preterm Labor
Children exposed prenatally to repeated corticosteroid doses for risk of preterm birth show no apparent physical or developmental ill effects after 2 years' follow-up, report two studies in the New England Journal of Medicine.
The studies, comprising some 1500 children, had randomized women at risk for preterm labor to receive either a single course or weekly injections of corticosteroids. When evaluated between ages 2 and 3, the groups showed no differences in measures of growth or neurocognitive development. One study did find an increased frequency of cerebral palsy after repeated corticosteroids, but the difference did not achieve statistical significance.
Both groups of researchers find the results "reassuring," but one group advises against weekly administration, saying the findings "indicate no evident long-term benefit and possible harm [from the cerebral palsy risk]."
An editorialist suggests that, in the absence of longer-term data, repeated courses could be given at lower dosages.
The studies, comprising some 1500 children, had randomized women at risk for preterm labor to receive either a single course or weekly injections of corticosteroids. When evaluated between ages 2 and 3, the groups showed no differences in measures of growth or neurocognitive development. One study did find an increased frequency of cerebral palsy after repeated corticosteroids, but the difference did not achieve statistical significance.
Both groups of researchers find the results "reassuring," but one group advises against weekly administration, saying the findings "indicate no evident long-term benefit and possible harm [from the cerebral palsy risk]."
An editorialist suggests that, in the absence of longer-term data, repeated courses could be given at lower dosages.
HPV Vaccine May Protect Against Additional Strains
The human papilloma virus vaccine (Gardasil) may provide cross-protection against 10 strains of the virus, in addition to the 4 strains it targets, according to an Associated Press story. The vaccine's manufacturer, Merck, presented the data yesterday at the Interscience Conference on Antimicrobial Agents and Chemotherapy.
The vaccine may now protect against 90% of the strains that cause cervical cancer.
Women should still get regular Pap smears because the vaccine does not cover all HPV strains, Michael Segarra, of North Brunswick (New Jersey) Pediatrics, told the AP.
The vaccine may now protect against 90% of the strains that cause cervical cancer.
Women should still get regular Pap smears because the vaccine does not cover all HPV strains, Michael Segarra, of North Brunswick (New Jersey) Pediatrics, told the AP.
West of Scotland Coronary Prevention Study
Long-Term Follow-Up of a Landmark Statin Trial
The benefits of statin therapy lasted 10 years.
The West of Scotland Coronary Prevention Study was the first large randomized trial of statin therapy in people without a history of coronary events (Journal Watch Nov 28 1995). Pravastatin, compared with placebo, was associated with a significantly lower 5-year rate of death from coronary heart disease or nonfatal myocardial infarction (5.5% vs. 7.9%) and a statistically borderline reduction in all-cause mortality (3% vs. 4%). Now, researchers present an additional 10 years of follow-up data. About one third of patients in both groups were taking statins 5 years after the trial ended; no data were available for statin therapy beyond that time point.
At 15 years, the following outcomes were noted in the original pravastatin group compared with the original placebo group:
Significantly lower rate of death from CHD or nonfatal MI (12% vs. 16%)
Significantly lower CHD mortality (5% vs. 6%)
Significantly lower all-cause mortality (19% vs. 21%)
No significant difference in rates of fatal or nonfatal stroke
No significant difference in cancer rates
Comment: This partly industry-supported extended follow-up of a landmark primary prevention trial shows that the benefits of statin therapy were durable, even though only a minority of patients in both groups took statins after conclusion of the trial. The authors attribute their findings to stabilization of existing plaque and slowing of progression of coronary artery disease. Keep in mind that this study population was high-risk to begin with — participants were middle-aged men with a mean LDL cholesterol of 192 mg/dL, and most were current or ex-smokers.
— Allan S. Brett, MD
Published in Journal Watch General Medicine October 11, 2007
Citation(s):
Ford I et al. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med 2007 Oct 11; 357:1477.
The benefits of statin therapy lasted 10 years.
The West of Scotland Coronary Prevention Study was the first large randomized trial of statin therapy in people without a history of coronary events (Journal Watch Nov 28 1995). Pravastatin, compared with placebo, was associated with a significantly lower 5-year rate of death from coronary heart disease or nonfatal myocardial infarction (5.5% vs. 7.9%) and a statistically borderline reduction in all-cause mortality (3% vs. 4%). Now, researchers present an additional 10 years of follow-up data. About one third of patients in both groups were taking statins 5 years after the trial ended; no data were available for statin therapy beyond that time point.
At 15 years, the following outcomes were noted in the original pravastatin group compared with the original placebo group:
Significantly lower rate of death from CHD or nonfatal MI (12% vs. 16%)
Significantly lower CHD mortality (5% vs. 6%)
Significantly lower all-cause mortality (19% vs. 21%)
No significant difference in rates of fatal or nonfatal stroke
No significant difference in cancer rates
Comment: This partly industry-supported extended follow-up of a landmark primary prevention trial shows that the benefits of statin therapy were durable, even though only a minority of patients in both groups took statins after conclusion of the trial. The authors attribute their findings to stabilization of existing plaque and slowing of progression of coronary artery disease. Keep in mind that this study population was high-risk to begin with — participants were middle-aged men with a mean LDL cholesterol of 192 mg/dL, and most were current or ex-smokers.
— Allan S. Brett, MD
Published in Journal Watch General Medicine October 11, 2007
Citation(s):
Ford I et al. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med 2007 Oct 11; 357:1477.
Initiating Insulin in Type 2 Diabetes – The "4-T" Trial
First-year comparisons among prandial, biphasic, and basal insulins reveal tradeoffs in efficacy and safety.
We now have a variety of options for initiating insulin in type 2 diabetic patients. In this trial — dubbed "Treating to Target in Type 2 Diabetes," or "4-T" — U.K. researchers compared three options.
The study included 708 adults with type 2 diabetes and hemoglobin A1c between 7% and 10% (mean, 8.5%) despite treatment with sulfonylurea plus metformin. Patients with recurrent major hypoglycemia were excluded. Patients continued oral agents initially and were randomized to receive twice-daily biphasic insulin aspart 30 (NovoMix 30), thrice-daily prandial insulin aspart (NovoRapid), or once-daily (twice if required) basal insulin detemir (Levemir). A protocol specified dose titration, glucose monitoring, and follow-up visits. Novo Nordisk supported the trial.
During 1 year of follow-up, the following outcomes occurred:
Mean fall in HbA1c was significantly greater in the biphasic and prandial groups (about 1.3%) than in the basal group (0.8%).
The proportion of patients with HbA1c 6.5% was significantly greater in the biphasic (17%) and prandial (24%) groups than in the basal group (8%). Better glycemic control with biphasic and prandial insulins occurred primarily among patients whose baseline HbA1c exceeded 8.5%.
Symptomatic hypoglycemia was more common with prandial than biphasic insulin, and with biphasic than basal insulin.
Patients in the basal group gained less weight than those in the other two groups.
Comment: Biphasic or prandial insulin, added to two-drug oral therapy, was more effective than basal insulin in achieving optimal glycemic control, but at the expense of more hypoglycemia and weight gain. Weighing these tradeoffs — along with the greater ease of once-daily insulin injections — the authors and editorialists offer the reasonable conclusion that once-daily basal insulin is probably the best initial approach for initiating insulin in type 2 diabetic patients. If good glycemic control is not achieved with a simple basal regimen, more complex regimens can be introduced later; indeed, more complex regimens will be examined in the next 2 years of this trial. Finally, the editorialists state a preference for glargine (Lantus) as a basal insulin (because it appears to have less of a peak and is slightly longer-acting than detemir), and they believe that sulfonylureas should be stopped when insulin is begun (because their mechanism of action is not synergistic with insulin).
— Allan S. Brett, MD
Published in Journal Watch General Medicine October 23, 2007
Citation(s):
Holman RR et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007 Oct 25; 357:1716. (http://dx.doi.org/10.1056/NEJMoa075392)
Original article (Subscription may be required)
Medline abstract (Free)
McMahon GT and Dluhy RG. Intention to treat – Initiating insulin and the 4-T study. N Engl J Med 2007 Oct 25; 357:1759. (http://dx.doi.org/10.1056/NEJMe078196)
Original article (Subscription may be required)
Medline abstract (Free)
We now have a variety of options for initiating insulin in type 2 diabetic patients. In this trial — dubbed "Treating to Target in Type 2 Diabetes," or "4-T" — U.K. researchers compared three options.
The study included 708 adults with type 2 diabetes and hemoglobin A1c between 7% and 10% (mean, 8.5%) despite treatment with sulfonylurea plus metformin. Patients with recurrent major hypoglycemia were excluded. Patients continued oral agents initially and were randomized to receive twice-daily biphasic insulin aspart 30 (NovoMix 30), thrice-daily prandial insulin aspart (NovoRapid), or once-daily (twice if required) basal insulin detemir (Levemir). A protocol specified dose titration, glucose monitoring, and follow-up visits. Novo Nordisk supported the trial.
During 1 year of follow-up, the following outcomes occurred:
Mean fall in HbA1c was significantly greater in the biphasic and prandial groups (about 1.3%) than in the basal group (0.8%).
The proportion of patients with HbA1c 6.5% was significantly greater in the biphasic (17%) and prandial (24%) groups than in the basal group (8%). Better glycemic control with biphasic and prandial insulins occurred primarily among patients whose baseline HbA1c exceeded 8.5%.
Symptomatic hypoglycemia was more common with prandial than biphasic insulin, and with biphasic than basal insulin.
Patients in the basal group gained less weight than those in the other two groups.
Comment: Biphasic or prandial insulin, added to two-drug oral therapy, was more effective than basal insulin in achieving optimal glycemic control, but at the expense of more hypoglycemia and weight gain. Weighing these tradeoffs — along with the greater ease of once-daily insulin injections — the authors and editorialists offer the reasonable conclusion that once-daily basal insulin is probably the best initial approach for initiating insulin in type 2 diabetic patients. If good glycemic control is not achieved with a simple basal regimen, more complex regimens can be introduced later; indeed, more complex regimens will be examined in the next 2 years of this trial. Finally, the editorialists state a preference for glargine (Lantus) as a basal insulin (because it appears to have less of a peak and is slightly longer-acting than detemir), and they believe that sulfonylureas should be stopped when insulin is begun (because their mechanism of action is not synergistic with insulin).
— Allan S. Brett, MD
Published in Journal Watch General Medicine October 23, 2007
Citation(s):
Holman RR et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007 Oct 25; 357:1716. (http://dx.doi.org/10.1056/NEJMoa075392)
Original article (Subscription may be required)
Medline abstract (Free)
McMahon GT and Dluhy RG. Intention to treat – Initiating insulin and the 4-T study. N Engl J Med 2007 Oct 25; 357:1759. (http://dx.doi.org/10.1056/NEJMe078196)
Original article (Subscription may be required)
Medline abstract (Free)
Tuesday, October 23, 2007
Thimerosal Exposure and Long-Term Neuropsychological Outcomes
Pre- and postnatal thimerosal exposure was not linked with neuropsychological deficits.
In 1999, the AAP and the U.S. Public Health Service suggested that vaccine manufacturers remove thimerosal preservatives from vaccines to minimize potential mercury toxicity to the developing brain. In this study, investigators examined pre- and postnatal mercury exposure and neuropsychological outcomes in 1047 children at age 7 to 10 years at four HMOs.
Data were collected from complete vaccination records, maternal interviews, and 3-hour neuropsychological assessments of 42 motor and developmental tasks. Estimates of mercury exposure included mothers’ pre- and postnatal exposure to immunoglobulin and vaccines and prenatal fish consumption. Overall, no consistent association was found between pre- or postnatal thimerosal exposure and neuropsychological outcome. A few positive and negative sex-specific associations were noted.
Comment: These results are reassuring for parents whose children were immunized before thimerosal was removed from vaccines. The small potpourri of associations probably reflects the large number of outcomes examined, because no plausible biologic explanation exists for both positive and negative effects. This study did not address a link between thimerosal and autism, but those findings will be reported by the CDC in a separate study. For now, we can reassure parents that mercury has been removed from vaccines, that no clear adverse outcomes have been associated with thimerosal exposure, and that we will continue to assess vaccine safety.
— Peggy Sue Weintrub, MD
Published in Journal Watch Pediatrics and Adolescent Medicine September 26, 2007
Citation(s):
Thompson WW et al. Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. N Engl J Med 2007 Sep 27; 357:1281.
In 1999, the AAP and the U.S. Public Health Service suggested that vaccine manufacturers remove thimerosal preservatives from vaccines to minimize potential mercury toxicity to the developing brain. In this study, investigators examined pre- and postnatal mercury exposure and neuropsychological outcomes in 1047 children at age 7 to 10 years at four HMOs.
Data were collected from complete vaccination records, maternal interviews, and 3-hour neuropsychological assessments of 42 motor and developmental tasks. Estimates of mercury exposure included mothers’ pre- and postnatal exposure to immunoglobulin and vaccines and prenatal fish consumption. Overall, no consistent association was found between pre- or postnatal thimerosal exposure and neuropsychological outcome. A few positive and negative sex-specific associations were noted.
Comment: These results are reassuring for parents whose children were immunized before thimerosal was removed from vaccines. The small potpourri of associations probably reflects the large number of outcomes examined, because no plausible biologic explanation exists for both positive and negative effects. This study did not address a link between thimerosal and autism, but those findings will be reported by the CDC in a separate study. For now, we can reassure parents that mercury has been removed from vaccines, that no clear adverse outcomes have been associated with thimerosal exposure, and that we will continue to assess vaccine safety.
— Peggy Sue Weintrub, MD
Published in Journal Watch Pediatrics and Adolescent Medicine September 26, 2007
Citation(s):
Thompson WW et al. Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. N Engl J Med 2007 Sep 27; 357:1281.
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