Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
Condition: Epilepsy
MeSH terms: Epilepsy
Intervention: phenytoin; phenytoin and probenecid
Intervention description: intravenous phenytoin (15 mg/kg) single dose; intravenous phenytoin (15 mg/kg) single dose and oral probenecid 2000 mg single dose
Intervention MeSH terms: Probenecid; Phenytoin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 8.0
Sex: Male
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: pharmacoresistance; healthy volunteers

Summary:

      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.
    

Eligibility 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