The FDA has requested that the labels for all sedative/hypnotic drug products include stronger wording regarding possible severe adverse events. Risks include anaphylaxis and angioedema, as well as behaviors such as driving, making phone calls, and preparing and eating food while asleep. The FDA has called on drug manufacturers to send letters to health care providers to notify them of the new warnings, and also to develop Patient Medication Guides to inform consumers about risks and advise them of precautions that can be taken. Clinical studies focusing on the frequency with which sleep-driving and other complex behaviors occur in association with each individual medication were also recommended.

Caregivers of patients with amyotrophic lateral sclerosis (ALS) frequently experience a significant increase of burden and depression, according to a longitudinal study of 31 ALS patient-caregiver couples that was published in the March 20 Neurology. Nine months after baseline interviews, patients’ mean McGill Quality-of-Life scores improved slightly (from 6.8 to 7); mean ALS patient Zung Depression Scale (ZDS) scores also increased slightly (from 43.2 to 45.7), although they remained in the “not depressed” range, noted the researchers. Meanwhile, caregiver quality of life decreased over the nine-month period, albeit insignificantly. However, significant increases were observed in caregiver depression (mean ZDS scores, 38.9 at baseline and 42.2 at follow-up) and caregiver burden (mean Caregiver Burden Inventory, 50.3 at baseline and 55.8 at follow-up).

Greater than normal RAMP1 protein expression may cause amplified responsiveness of receptors for neuronal calcitonin gene-related peptide (CGRP) in the brains of migraineurs, according to research in the March 7 Journal of Neuroscience. Injections of CGRP in mice engineered to express human RAMP1 led to a neurogenic inflammation response 2.2 times the normal level, said the authors. An in vitro portion of the study indicated that increased RAMP1 caused CGRP receptors to react to much lower concentrations of CGRP than usual. The results suggest that differences in RAMP1 genes leading to increased levels of the resultant protein may exist in migraineurs, possibly explaining why some people are susceptible to migraines and others are not.

The use of atorvastatin calcium tablets to reduce the risk of nonfatal heart attacks, fatal and nonfatal strokes, certain types of heart surgery, and chest pain in patients with heart disease has been approved by the FDA. It is also the first cholesterol-lowering medication approved to reduce the risk of hospitalization for heart failure. The five-year Treating to New Targets trial, which included 10,000 patients with heart disease and elevated LDL cholesterol levels, indicated that those receiving 80 mg atorvastatin calcium had significant reductions in risk of major cardiovascular events and of hospitalization for heart failure, compared with patients taking a 10-mg dose (22% and 26%, respectively). Adverse events and discontinuations were reported to be more serious with the 80-mg dose than with the 10-mg dose, though overall frequency of treatment-related adverse events did not differ.

Stroke patients admitted to the hospital during the weekend have an increased risk for death compared with those admitted on a weekday, according to research published in the April Stroke. Seven-day stroke mortality was 7.6% for 26,676 patients who were admitted to a hospital for ischemic stroke between April 2003 and May 2004. However, the rate was higher for nearly one quarter of the cohort admitted on a weekend (8.5% versus 7.4%). Mortality showed a similar “weekend effect” in urban versus rural hospitals and when the primary physician was a general practitioner versus a specialist, the authors reported. The odds ratio for early mortality in weekend admissions was 1.14 after adjustment for age, sex, comorbidities, and medical complications.

Inhibition of fibrinogen-triggered inflammation in the brain may halt the destruction of myelin sheaths as observed in multiple sclerosis (MS), reported researchers in the March 19 Journal of Experimental Medicine. They observed fewer resultant inflammatory lesions and less severe MS symptoms in mice with a mutant form of fibrinogen that is incapable of binding to Mac-1 and thus disrupts microglia activation, potentially leading to myelin destruction. Pharmacologic administration of a fibrinogen–Mac-1 inhibitor similarly attenuated the microglia activation, the authors reported. Because the observed interaction did not affect the procoagulant properties of fibrinogen, the investigators suggested that this may “represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation.”

The FDA has given marketing clearance to Xpert EV, a rapid test for viral meningitis. The test identifies infection from Entero­virus, a genus of viruses responsible for 90% of viral meningitis infections, in less than three hours; current diagnostic tests can take nearly a week, stated the FDA. Accuracy of Xpert EV was confirmed by a multisite study of 255 patient samples. The test had a 96% positive predictive value and a negative predictive value of 97%. Administrators at the FDA stated that the test could minimize delays in the treatment of patients and would prevent unnecessary antibiotic treatment in patients with viral meningitis, which typically resolves in two weeks without medical intervention.

In patients with Alzheimer’s disease, a lifetime history of depression corresponds with increases in Alzheimer’s disease–related neuropathologic changes within the hippocampus, according to the February Archives of General Psychiatry. In a postmortem study, investigators compared the brains of 52 patients with Alzheimer’s disease who did not have a history of major depression with the brains of 50 Alzheimer’s disease patients who did have a history of major depression. The brains of patients with a history of depression revealed higher levels of plaque and tangle formation within the hippocampus than did the brains of patients without a history of depression. The researchers noted that these changes "are more pronounced in patients with Alzheimer’s disease and suffering from depression early on in the disease process."

Researchers have identified 34 single nucleotide polymorphisms that may be linked to sporadic amyotrophic lateral sclerosis (ALS), according to preliminary results of a genome-wide association study published in the April Lancet Neurology. More than 300 million genotypes were produced in 276 patients with sporadic ALS and in 271 neurologically normal control participants. No single locus was definitively associated with an increased risk of ALS, although potentially associated candidate single-nucleotide polymorphisms were identified. The investigators recommended further study of the mutations.

Researchers have identified a gene mutation that appears to be an important cause of familial and sporadic Parkinson’s disease in Ashkenazi Jewish patients, according to findings published in the January 26 New England Journal of Medicine. DNA was extracted from white cells or buccal cells in 120 Ashkenazi Jewish patients with Parkinson’s disease and in 317 Ashkenazi Jewish controls without Parkinson’s disease. The mutation G2019S in the leucine-rich repeat kinase 2 gene was detected in 22 patients (18.3%) with Parkinson’s disease and in four members (1.3%) of the control group. In addition, the mutation was present in 11 of 37 participants (29.7%) who had at least one affected first-degree, second-degree, or third-degree relative with Parkinson’s disease, and in 11 of 83 participants (13.3%) with no family history of Parkinson’s disease.

Neural stem cells transplanted into the brains of newborn mice with Sandhoff’s disease appeared to delay disease onset, preserve motor function, reduce pathology, and prolong survival, as reported online March 11 in Nature Medicine. Additionally, brain b-hexosaminidase levels were increased, ganglioside storage was reduced, and microgliosis was diminished. The authors asserted that the “small degree of neuronal replacement alone could not account for the improvement.” Efficacy was also established with both human neural stem cells isolated directly from the CNS and those derived secondarily from embryonic stem cells. These potential therapeutic actions of neural stem cells may help in formulating strategies for the treatment of neurodegenerative conditions, including Tay-Sachs disease, Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis.

The FDA has approved additional label changes for the drug tolcapone, a catechol-O-methyltransferase inhibitor used to treat patients with Parkinson’s disease. A new patient acknowledgment form, which outlines possible adverse effects, including liver damage, is designed to “allow for more constructive and balanced discussions between the physician and the patient,” according to Valeant Pharmaceuticals, which produces the drug. The form, revised from a patient consent form, follows a February 2006 label change, which resulted from serum analysis of patients treated with tolcapone. It found that the liver monitoring requirements were “unnecessarily restrictive.”

Moderate to severe migraine may be treated most effectively with a combination therapy, as reported in the April 4 JAMA. In two replicate studies, 1,461 (study 1) and 1,495 (study 2) migraineurs were randomized to receive 85 mg sumatriptan monotherapy, 500 mg naproxen sodium monotherapy, a single tablet of the two drug therapies together, or placebo; participants were instructed to take the tablet after onset of moderate to severe migraine. Two hours after dosing, the combination therapy was superior to placebo in both studies in headache relief (study 1, 65% versus 28%; study 2, 57% versus 29%), absence of photophobia (study 1, 58% versus 26%; study 2, 50% versus 32%), and absence of phonophobia (study 1, 61% versus 38%; study 2, 56% versus 34%); absence of nausea was higher with combination therapy than placebo in study 1, though the two groups did not differ in study 2. Two- to 24-hour sustained pain-free response was also superior for combination therapy when compared with either monotherapy or placebo. Additionally, the adverse effect profile for sumatriptan–naproxen sodium was acceptable and well tolerated, reported the authors.

Three proteins may serve as objective biomarkers to help identify patients with amyotrophic lateral sclerosis (ALS), according to a report in the February 15 online Neurology. Investigators analyzed CSF from patients diagnosed with ALS, patients with other neurologic disorders, and healthy controls. Findings revealed that CSF from patients with ALS had significantly lower concentrations of three proteins than did that of healthy participants. In addition, the combination of these three proteins correctly identified patients with ALS with 95% accuracy, 91% sensitivity, and 97% specificity. The investigators noted that the three proteins could conceivably "serve as surrogate markers for disease progression," and, if well validated, "may facilitate therapeutic trials in ALS."

Persons with mild cognitive impairment (MCI) without comorbidities are often in the earliest stages of dementia, according to a study in the March Archives of Neurology. Researchers from the Cardiovascular Health Study Cognition Study found that 51% of 136 participants diagnosed with MCI progressed to dementia, while 18% returned to normal (mean follow-up, 3.2 years). Among participants with comorbidities that could account for impairment, there was a lesser rate of dementia conversion (48%) and a greater rate of returning to normal (27%) than in those lacking possibly explanatory comorbidities (56% and 8%, respectively), although the authors described the differences as “slight.” Additionally, “the absence of a memory deficit does not attenuate the risk of converting to dementia,” stated the authors, as similar rates of conversion to dementia were observed in participants with a broad range of cognitive deficits (54% with memory impairment versus 50% without).           

NR