Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene Variations Explain Drug Dose Required to Control Seizures

29.03.2005


Determining which variants of particular genes patients with epilepsy carry might enable doctors to better predict the dose of drugs necessary to control their seizures, suggest basic findings by researchers at the Duke University Institute for Genome Sciences & Policy (IGSP) and the University College London. Patients often undergo a lengthy process of trial and error to find the dose of anti-epilepsy drugs appropriate for them.



The researchers found that variants of two genes were more likely to be found in patients who required higher dosages of anti-epileptic drugs. The findings suggest that, by incorporating genetic tests into the prescription process, physicians might improve outcomes for patients with epilepsy, said the researchers. A similar approach might also prove useful for other conditions, such as Parkinson’s disease and cancer, in which patients’ drug dosage requirements vary substantially, they added. Rigorous clinical study is required before any such method could be put into practice, the researchers emphasized.

In the March 28, 2005, early edition of Proceedings of the National Academy of Sciences, the investigators report the first clear evidence linking variation in genes involved in the action or metabolism of the anti-epileptic drugs, carbamazepine and phenytoin, to the drugs’ clinical use. The study is the first to emerge from a partnership, aimed at tailoring the treatment of epilepsy to patients’ genetic makeup, between the Department of Clinical and Experimental Epilepsy at the University College London and the Duke Center for Population Genomics and Pharmacogenetics, a center of the IGSP. If the genes’ predictive value is verified in clinical trials, such a "pharmacogenetic" approach might make it possible to safely reduce the time required for patients with epilepsy and their physicians to reach an effective dose of the medications that control seizures, said David Goldstein, Ph.D., director of the IGSP Center at Duke University Medical Center and senior author of the study.


"In medicine today, physicians must rely on a one-size-fits-all approach when making decisions about which drug to use and in what dose," Goldstein said. "This study makes clear that such an approach is not sufficient. People with epilepsy are genetically different from one another, and some of those differences affect their responses to drugs in a predictable manner. "We are beginning to understand how genetics can be applied to medicine in such a way as to reduce trial and error and improve quality of life for patients," he added.

Epilepsy and seizures affect 2.5 million Americans of all ages, with approximately 181,000 new cases diagnosed each year. Phenytoin and carbamazepine are important first-line anti-epileptic drugs that are widely prescribed throughout the world, Goldstein said. Both drugs commonly spur adverse reactions. "Physicians have long recognized that patients with the same condition differ in their responses to the same drugs," said neurologist and epilepsy specialist Sanjay Sisodiya, M.D., leader of the University College London effort and co-author of the study. "This study establishes the principle that genetic differences between patients do influence variation in response to anti-epileptic drugs for patients with epilepsy. "In time, we hope to have a number of such gene variants that together can explain and predict more and more of the variation among patients in drug response, allowing better informed treatment decisions," he continued.

Control of epilepsy with phenytoin can be a difficult and lengthy process because of the wide range of doses required by different patients and the drug’s narrow therapeutic index, explained study co-author Nicholas Wood, Ph.D., of the University College London. The therapeutic index refers to the ratio between a drug’s toxic and therapeutic dose, used as a measure of the drug’s relative safety for a particular treatment. Similarly, appropriate doses of carbamazepine take time to determine because of the drug’s variable affects on patient metabolism and its potential neurologic side effects.

The team identified genes considered to be obvious candidates underlying patients’ drug response, based on their known roles in the metabolism or transport of one or both anti-epileptic drugs. In 425 epileptic patients taking carbamazepine and 281 taking phenytoin, the researchers then searched for an association between clinical use of the drugs and variation in the candidate genes. One variant of a gene known as CYP2C9, which encodes a liver enzyme involved in drug metabolism, showed a significant association with the maximum dose of phenytoin taken by patients with epilepsy.

Moreover, a variant of a second gene, called SCN1A, with activity in the brain, was found significantly more often in patients on the highest doses of both carbamazepine and phenytoin. SCN1A has been implicated in many inherited forms of epilepsy and is the drug target for phenytoin. Given its relationship to both anti-epileptic drugs tested, the SCN1A variant may be of particular importance for understanding patient response to drug treatment, said the researchers, noting that many other anti-epilepsy drugs act on related brain proteins. "The range of doses taken by patients at epilepsy clinics is great," Goldstein said. "For someone at the higher end, it can take months to get their seizures under control. This study uncovers factors that might determine, in advance, which patients will need the higher dose." Before any such pharmacogenetic approaches can be put into practice, they must be explicitly evaluated for clinical utility in improving patient outcomes, Goldstein said.

The new findings provide a direction for a dosing scheme that could be tested in the clinic to assess whether pharmacogenetic diagnostics can improve dosing decisions, he added. In particular, it may be clinically relevant to determine whether physicians can safely increase drug doses more rapidly for some patients. Such a trial might also allow physicians to identify patients who might safely take a smaller dose, thereby minimizing their risk for adverse side effects, he added.

The findings in epilepsy set the stage for scientists to evaluate other conditions in which gene-based diagnostics might help determine the optimum dosage of particular therapies for particular patients, Goldstein said. "For most drugs we know a lot about how and where they act in the body," Goldstein said. "The current results support the idea that known drug targets, transporters and drug metabolizing enzymes are good starting points for understanding variation among patients in drug response."

In Parkinson’s disease, for example, a pharmacogenetic test might assist physicians in prescribing the drug dose that will balance short-term control of tremors with long-term drug side effects that eventually render the disease untreatable, he said. Patients’ genetic makeup might also influence the dose of chemotherapy needed to successfully fight a tumor, while minimizing often intolerable side effects.

Collaborators on the study include Sarah Tate, Chantal Depondt,Gianpiero Cavalleri, Stephanie Schorge, Nicole Soranzo, Maria Thom, Arjune Sen and Simon Shorvon, all of the University College London; Josemir Sander, of the National Society for Epilepsy, U.K. The work was supported by the National Society for Epilepsy and the Medical Research Council.

Kendall Morgan | EurekAlert!
Further information:
http://www.duke.edu

More articles from Life Sciences:

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>