Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy

This study has been terminated.
(Investigators decided not to continue)
Sponsor:
Information provided by (Responsible Party):
Jim McAuley, The Ohio State University
ClinicalTrials.gov Identifier:
NCT00610532
First received: January 28, 2008
Last updated: May 13, 2013
Last verified: May 2013
  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 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluating Transporter Protein Inhibitors in Patients With Epilepsy

Resource links provided by NLM:


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 ]

Enrollment: 8
Study Start Date: March 2006
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
intravenous phenytoin alone
Drug: phenytoin
intravenous phenytoin (15 mg/kg) single dose
Experimental: B
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
United States, Ohio
The Ohio State University
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Jim McAuley
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: Jim McAuley, Associate Professor, The Ohio State University
ClinicalTrials.gov Identifier: NCT00610532     History of Changes
Other Study ID Numbers: 2005H0170
Study First Received: January 28, 2008
Results First Received: December 6, 2012
Last Updated: May 13, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Ohio State University:
pharmacoresistance
healthy volunteers

Additional relevant MeSH terms:
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Phenytoin
Probenecid
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Uricosuric Agents
Gout Suppressants
Antirheumatic Agents
Renal Agents

ClinicalTrials.gov processed this record on September 16, 2014