Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy - Full Text View

Sponsor:	Ohio State University
Information provided by:	Ohio State University
ClinicalTrials.gov Identifier:	NCT00610532

Purpose

The study is being done to understand why some patients with epilepsy (disease of recurrence of seizures) do not respond very well to drug treatment with anticonvulsants.

Despite the availability of many anticonvulsants, about 30% of patients with epilepsy are resistant to them. The cause of the resistance is not clear, but one of the reasons could be an increased amount of proteins in the cells of the body called transporter proteins.

Transporter proteins are a group of proteins that help to defend the body against toxins, including drugs, by pumping them out of the cells. Studies have shown that the number of transporter proteins is higher in the parts of the brain that trigger seizures when compared to other parts of the brain.

Studies in animals have shown that taking an anticonvulsant with an inhibitor (meaning "to stop" or "to reduce") of a transporter protein can increase the concentration of that anticonvulsant inside the brain cells. The main purpose of the study is to determine if taking an anticonvulsant and a transporter protein inhibitor will change the brain concentration of the anticonvulsant.

In this study, a single dose of phenytoin (Dilantin® is a brand name anticonvulsant which has phenytoin as its active ingredient), a commonly used anticonvulsant, will be given once by itself, and then will be given a separate time with a single (i.e. one time only) dose of probenecid. Probenecid, a medicine used commonly to treat gout (a disease of increased uric acid), is known to be an inhibitor of transporter proteins. The study will use electroencephalogram or EEG (recording of brain wave activities) to determine if the EEG pattern when probenecid is given, will be different from the EEG pattern when phenytoin is given alone. This will suggest that probenecid has affected the brain concentration of phenytoin.

Condition	Intervention	Phase
Epilepsy	Drug: phenytoin Drug: phenytoin and probenecid	Phase IV

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Single Blind (Outcomes Assessor), Crossover Assignment
Official Title:	Evaluating Transporter Protein Inhibitors in Patients With Epilepsy

Resource links provided by NLM:

Genetics Home Reference related topics: pyridoxal 5'-phosphate-dependent epilepsy

MedlinePlus related topics: Epilepsy

Drug Information available for: Phenytoin Probenecid Phenytoin sodium

U.S. FDA Resources

Further study details as provided by Ohio State University:

Primary Outcome Measures:

quantitative EEG recordings [ Time Frame: end of each treatment ] [ Designated as safety issue: No ]

Estimated Enrollment:	20
Study Start Date:	March 2006
Estimated Study Completion Date:	November 2010
Estimated Primary Completion Date:	September 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A: Experimental intravenous phenytoin alone	Drug: phenytoin intravenous phenytoin (15 mg/kg) single dose
B: Experimental intravenous phenytoin plus probenecid	Drug: phenytoin and probenecid intravenous phenytoin (15 mg/kg) single dose and oral probenecid 2000 mg single dose

Detailed Description:

About 30% of patients with epilepsy are refractory to medical treatment (pharmacoresistant epilepsy). The cause of which is multifactorial. Multidrug resistance (MDR) causes decreased uptake of medicines in tissues. MDR occurs because of overexpression of a family of transporter proteins that act as a physiological defense mechanism that pumps toxins out of cells. Two groups of transporters, P-glycoprotein (PGP) and multidrug resistance-associated proteins (MRP), are important gatekeepers in the blood brain barrier. PGP and MRP are overexpressed in the brain tissue of pharmacoresistant patients with partial epilepsy and many antiepileptic drugs (AEDs) are substrates for PGP, MRP or both.

It is logical to try to apply these observations to clinical practice. We hope that through co-administration of an inhibitor of transporter proteins, we can increase the CNS concentrations of AEDs, and subsequently improve seizure control. However, before this, it is critical to demonstrate that a transporter protein inhibitor can increase the concentration of AEDs in human brain.

Probenecid is an MRP inhibitor while phenytoin is an MRP substrate. Evaluating whether probenecid can increase the CNS concentration of PHT can potentially be achieved noninvasively by using pharmaco-EEG.

We plan to estimate the effect of probenecid (a transporter protein inhibitor) on the quantitative EEG recordings when it is administered to patients with pharmacoresistant epilepsy and in normal healthy volunteers.

We plan to recruit two groups of 10 subjects each, normal volunteers and patients with pharmacoresistant epilepsy. They will undergo two treatment regimens; EEG recording after administration of intravenous phenytoin only and again after pre-dosing them with probenecid.

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Men with pharmacoresistant partial epilepsy defined as failure of two or more AEDs at a reasonable therapeutic dose
Patient is able to understand and sign a consent form and able to keep a seizure calendar
Patient is older than 18 years of age
Patient is otherwise healthy by laboratory and physical examination

Exclusion Criteria:

Patient is currently taking phenytoin
Patient has a history of an adverse reaction to phenytoin
Patient has a history of gout disease, peptic ulcer disease, blood dyscrasias, or uric acid kidney stones
Patient has an allergy to sulfa drugs or probenecid
Patient has been exposed to probenecid or another known transporter inhibitor (verapamil, progesterone, etc) in the three months prior to enrollment
Patient has a history of renal impairment (creatinine clearance < 50 ml/min)
Patient has a history of diabetes and is taking oral sulfonylurea agents

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00610532

Contacts

Contact: James W McAuley, PhD	614-292-9713	mcauley.5@osu.edu
Contact: Bassel F Shneker, MD	614-293-4974	shneker.1@osu.edu

Locations

United States, Ohio
The Ohio State University	Recruiting
Columbus, Ohio, United States, 43210

Sponsors and Collaborators

Ohio State University

Investigators

Principal Investigator:	James W McAuley, PhD	Ohio State University
Principal Investigator:	Bassel F Shneker, MD	Ohio State University

More Information

No publications provided

Responsible Party:	The Ohio State University ( James W. McAuley, PhD, Associate Professor )
Study ID Numbers:	2005H0170
Study First Received:	January 28, 2008
Last Updated:	September 22, 2009
ClinicalTrials.gov Identifier:	NCT00610532 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Ohio State University:

pharmacoresistance
healthy volunteers

Additional relevant MeSH terms:

Nervous System Diseases
Central Nervous System Diseases
Renal Agents
Brain Diseases
Gout Suppressants
Pharmacologic Actions
Phenytoin

Epilepsy
Uricosuric Agents
Therapeutic Uses
Probenecid
Antirheumatic Agents
Central Nervous System Agents
Anticonvulsants

ClinicalTrials.gov processed this record on November 25, 2009