Abstracts

Since CSF drug delivery is clinically useful for antibiotics and antineoplastics, direct delivery of anti-epileptic medication to the CSF may also be useful and improve the tolerability and efficacy of these drugs. We performed a proof-in-principle study of intraventricular gabapentin (GPN) in the rat., Anesthetized Sprague-Dawley rats were implanted with two Alzet model 2001 osmotic pumps, each delivering 1.0 [mu]L/hour for one week. Pumps were connected to left and right intraventricular catheters, with tips in relation to Bregma at: 1.4 mm lateral and 0.8 mm posterior on the right, 2 mm lateral and 1.3 mm posterior on the left, and 2.5 mm below the top of cortex. GPN 80 [mu]g/[mu]L was installed into each pump and delivered at 3.8 mg per day. Half of the animals had pumps filled with isotonic normal saline (control group), and half with GBP. Seizure theshold was tested after five days, by dripping the convulsant liquid anesthetic flurothyl onto tissue paper at 10 [mu]L/minute in a sealed 3.2 L container. A single observer, blinded as to treatment group, recorded the time to first myoclonic twitch, first partial seizure and first tonic-clonic seizure. Seizures were judged behaviorally; no EEG was used as part of this protocol., Of 60 rats used, 6 were lost due to mortality or pump/catheter malfunction. For the surviving 54, time to first tonic-clonic seizure was 295.8 [plusmn] 58.8 s (n=28) for control group, versus 338.0 [plusmn] 89.9 s (n=26) for the rats with GBP in the pump (p=0.049 by two-tailed t-test). The mean time to onset of first myoclonic jerk was 158.7 [plusmn] 20.8 vs. 164.6 [plusmn] 33.5 s (p=n.s.). Effects of flurothyl can be influenced by animal weight; however, regression of time to tonic-clonic seizure versus weight yielded no significant relationship. Serum gabapentin levels obtained immediately after testing the seizure threshold were undetectable ([lt] 1 [mu]g/ml) in every animal. We did not perform quantitative studies of GPN distribution through brain, but methylene blue dye in the pumps distributed into periventricular white matter and also over cortex, especially ipsilaterally., Intraventricular delivery of gabapentin elevates the threshold for generalized tonic-clonic seizures in the rat flurothyl model, but not time to the first myoclonic jerk or first partial seizure. Interpretation is limited, as the degree of penetration and distribution of the GPN into brain cannot be detailed. Unmeasurable serum levels suggest the effect is not systemic. Intraventricular delivery of antiepileptic drugs would be useful for drugs with poor oral absorption or which do not penetrate the blood-brain barrier. Intraventricular administration of drugs that do penetrate into brain after oral ingestion (e.g. GPN) may or may not be useful, depending upon achievable improvements in the therapeutic/toxic ratio and in steady brain levels of drug., (Supported by Medtronic, and by the Maslah Saul MD Chair, the James and Carrie Anderson Epilepsy Laboratory, and the Susan Horngren Fund.)