Epileptic Seizures May Lead to Reduced Medication Entry to the Brain, Say Researchers

Researchers have found that one of the body’s own neurotransmitters released during epileptic seizures, glutamate, could lead to reduced medication entry into the brain. This may explain why approximately 30% of patients with epilepsy do not respond to anti-epileptic medications.

The study was conducted by researchers at the National Institute of Environmental Health Sciences (NIEHS) using a rodent model of epilepsy.

"Our work identifies the mechanism by which seizures increase production of a drug transport protein in the blood brain barrier, known as P-glycoprotein, and suggests new therapeutic targets that could reduce resistance," said David Miller, Ph.D., a principal investigator in the NIEHS Laboratory of Pharmacology and co-author on the paper.

The blood-brain barrier (BBB), which resides in brain capillaries, is a limiting factor in treatment of many central nervous system disorders. It is altered in epilepsy so that it no longer permits free passage of administered antiepileptic drugs into the brain. Miller explained that P-glycoprotein forms a functional barrier in the BBB that protects the brain by limiting access of foreign chemicals.

"The problem is that the protein does not distinguish well between neurotoxicants and therapeutic drugs, so it can often be an obstacle to the treatment of a number of diseases, including brain cancer," Miller said. Increased levels of P-glycoprotein in the BBB has been suggested as one probable cause of drug resistance in epilepsy.

Using isolated brain capillaries from mice and rats and an animal model of epilepsy, the researchers found that glutamate, a neurotransmitter released when neurons fire during seizures, turns on a signaling pathway that activates cyclooxygenase-2 (COX-2), causing increased synthesis of P-glycoprotein in these experiments. Increased transporter expression was abolished in COX-2 knockout mice or by COX-2 inhibitors. It has yet to be shown in animals or patients that targeting COX-2 will reduce seizure frequency or increase the effectiveness of anti-epileptic drugs.

"These findings provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders," said Bjoern Bauer, Ph.D., lead author on the publication. "Targeting blood-brain barrier signals that increase P-glycoprotein expression rather than the transporter itself suggests a promising way to improve the effectiveness of drugs that are used to treat epilepsy, though more research is needed before new therapies can be developed."

The study appears in the May, 2008 issue of Molecular Pharmacology.

Antiepileptic Drugs May Increase Suicidal Thoughts, Says FDA

The U.S. Food and Drug Administration (FDA) today issued new information to health care professionals to alert them about an increased risk of suicidal thoughts and behaviors (suicidality) in patients who take drugs called antiepileptics to treat epilepsy, bipolar disorder, migraine headaches, and other conditions.

An FDA analysis of suicidality reports from placebo-controlled studies of 11 antiepileptic drugs shows that patients taking these drugs have about twice the risk of suicidal thoughts and behaviors (0.43 percent), compared with patients receiving placebo (0.22 percent). This risk corresponds to an estimated 2.1 per 1,000 more patients in the drug treatment groups who experienced suicidality than in the placebo groups.

"We want health care professionals to have the most up to date drug safety information," said Russell Katz, M.D., director of the Division of Neurology Products in FDA’s Center for Drug Evaluation and Research. "This is an example of FDA working with drug manufacturers throughout products’ lifecycles to keep health care professionals informed of new safety data."

Patients who are currently taking antiepileptic medicines should not make any changes without first talking to their health care provider. Health care providers should notify patients, their families, and caregivers of the potential for an increase in the risk of suicidal thoughts or behaviors so that patients may be closely observed for notable changes in behavior.

Following a preliminary analysis of data from several antiepileptic drugs that suggested an increased risk of suicidality, in March 2005 FDA requested this type of data from manufacturers of marketed antiepileptic drugs for which there were adequately designed controlled clinical trials. FDA received and reviewed data from 199 placebo-controlled studies of 11 drugs.

The analysis included 27,863 patients in drug treatment groups and 16,029 patients in placebo groups. There were four suicides among patients in the drug treatment groups and none among patients in placebo groups. There were 105 reports of suicidal thoughts or behaviors in the drug-treated patients and 35 reports in placebo-treated patients.

The higher risk of suicidal thoughts and behaviors was observed at one week after starting a drug and continued to at least 24 weeks. The results were generally consistent among all the different drug products studied and were seen in all demographic subgroups. There was no clear pattern of risk across age groups.

Antiepileptic drugs in the analyses included the following:

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
  • Felbamate (marketed as Felbatol)
  • Gabapentin (marketed as Neurontin)
  • Lamotrigine (marketed as Lamictal)
  • Levetiracetam (marketed as Keppra)
  • Oxcarbazepine (marketed as Trileptal)
  • Pregabalin (marketed as Lyrica)
  • Tiagabine (marketed as Gabitril)
  • Topiramate (marketed as Topamax)
  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
  • Zonisamide (marketed as Zonegran)

Some of these drugs are also available in generic form.

Although only the drugs listed above were part of the analysis, the FDA expects that all medications in the antiepileptic class share the increased risk of suicidality.

FDA will be working with manufacturers of marketed antiepileptic drugs to include this new information in the labeling for these products. The agency anticipates that labeling changes will be applied broadly to the entire class of drugs. FDA is also planning to discuss these data at an upcoming advisory committee meeting.

Source: FDA, January 31, 2008

Epilepsy Drug Topamax Helps Alcoholism Treatment

A drug called Topamax (topiramate) has been found to help alcoholics quit drinking excessively, according to a University of Virginia study. The drug is not FDA approved for treatment of alcoholism, but has been prescribed off-label by doctors to treat the condition.

Topiramate (brand name Topamax) is an anticonvulsant drug produced by Ortho-McNeil Neurologics, a division of Johnson & Johnson. The drug is FDA-approved for treatment of epilepsy and for the prevention of migraines.

To test the drug’s efficacy in treating alcoholism, researchers conducted a 14-week study of 317 alcoholics. Half of the participants were given a placebo and the other half were given Topamax.

The study found that participants on Topamax reduced their alcohol intake from 11 drinks per day on average, to just 3.5 drinks per day. Furthermore, while only abstaining from drinking 3 days per month at the start of the study, by the end of the study they were abstaining from drinking about 15 days per month.

The placebo group also drank less during the study. However, by the end of the study, they abstained from drinking 10 days per month and consumed six drinks per day on average.

The most common side effects of Topamax include a change in taste (carbonated beverages, especially diet sodas and beer, taste particularly bad) and feelings of pins and needles in the head and extremities. Less common side effects include cognitive deficiency (particularly word-finding difficulty); grogginess; lethargy; renal stones, impairment of fine motor skills; vision abnormality and transient or permanent vision loss; weight loss; breast pain; abdominal pain; intense sweating; menstrual disorder; taste changes; pharyngitis; sinusitis; diplopia; rash; leukopenia; fatigue; dizziness; insomnia; anxiety; depression; paresthesia; diarrhea; nausea; dyspepsia; constipation; dry-mouth; dysmenorrhea.

Sources:

  • New Scientist October 10, 2007
  • FDA