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 Enduring cold temperatures alters fat cell epigenetics
19.04.2018 | University of Tokyo

nachricht Full of hot air and proud of it
18.04.2018 | University of Pittsburgh

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

Im Focus: The Future of Ultrafast Solid-State Physics

In an article that appears in the journal “Review of Modern Physics”, researchers at the Laboratory for Attosecond Physics (LAP) assess the current state of the field of ultrafast physics and consider its implications for future technologies.

Physicists can now control light in both time and space with hitherto unimagined precision. This is particularly true for the ability to generate ultrashort...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Diamond-like carbon is formed differently to what was believed -- machine learning enables development of new model

19.04.2018 | Materials Sciences

Electromagnetic wizardry: Wireless power transfer enhanced by backward signal

19.04.2018 | Physics and Astronomy

Ultrafast electron oscillation and dephasing monitored by attosecond light source

19.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>