References on the Administration of Anticonvulsive Agents Using ALZET^® Osmotic Pumps

(For additional anticonvulsants please refer to benzodiazepines list: BENZ)

1. Carbamazepine

Q0269 Cain,S.M., Ruest,T., Pimlott,S., Patterson,J., Duncan,R., Dewar,D., Sills,G.J. High resolution micro-SPECT scanning in rats using 125I beta-CIT: Effects of chronic treatment with carbamazepine. Epilepsia 2009; 50(-8-):1962-1970. >>> Carbamazepine; DMSO; propylene glycol; ethyl alcohol; acetone; SC; Rat; 2ML2; 14 days; Controls received mp w/ vehicle; animal info (adult, male, Sprague-Dawley, 160-270 g); functionality of mp verified by serum drug levels; 42% DMSO used; identified 3 mg/kg/day as the highest dose that could be reliably administered via minipumps over a 14-day period at 37 degrees Celsius, pg. 1969.

P5195 Doheny,H.C., Jefferys,J.G.R., Whittington,M.A., Patsalos,P.N. A comparison of the efficacy of carbamazepine and the novel anti-epileptic drug levetiracetam in the tetanus toxin model of focal complex partial epilepsy. British Journal of Pharmacology 2002/3; 135(-6-):1425-1434. >>> Carbamazepine; levetiracetam; DMSO; Propylene glycol; ethanol, saline; IP; Rat; 7 days; Controls received mp/ vehicle; functionality verified by drug serum levels; dose-response (text p.1428); carbamazepine was dissolved in 42.5% DMSO/42% Propylene glycol/15% ethanol. Levitiracetam was dissolved in saline; 2-day recovery period given using coiled PE-40 tubing; epilepsy; anticonvulsant.

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2. Deprenyl

P9373 Chenu,F., El Mansari,M., Blier,P. Long-term administration of monoamine oxidase inhibitors alters the firing rate and pattern of dopamine neurons in the ventral tegmental area. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY 2009; 12(-4-):475-485. >>> Clorgyline; phenelzine; deprenyl; SC; Rat; 2, 21 days; Controls received mp w/ saline; enzyme inhibitor (MAO, monoamine oxidase); animal info (male, Sprague Dawley, 250-300 g.).

P5438 Mejia,J.M., Ervin,F.R., Baker,G.B., Palmour,R.M. Monoamine oxidase inhibition during brain development induces pathological aggressive behavior in mice. Biological Psychiatry 2002; 52(-8-):811-822. >>> Chlorgyline; Deprenyl; Saline; SC; Mice (pregnant); 2002; 2004; 6 weeks; Controls received mp w/ vehicle; teratology; enzyme inhibitors (monoamine oxidase inhibitors); 2002 pumps were replaced w/ 2004 pumps after 2 weeks to complete a 6 week infusion; agents infused singly or concommitant in the same pump.

P4227 Loscher,W., Lehmann,H. Anticonvulsant efficacy of L-deprenyl (selegiline) during chronic treatment in mice: continuous versus discontinuous administration. Neuropharmacology 1998; 37(--):1587-1593. >>> Deprenyl, L-; Water, distilled; SC; mice; 2002; 2004; 2,4 weeks; controls received mp w/saline; functionality of mp verified by residual volume; comparison of daily i.p. injections vs. mp; good methods (p. 1588); anticonvulsant; also called selegiline.

P3400 Carrillo,M.C., Kanai,S., Sato,Y., Nokubo,M., Ivy,G.O., Kitani,K. The optimal dosage of (-) deprenyl for increasing superoxide dismutase activities in several brain regions decreases with age in male Fischer 344 rats. Life Sci. 1993; 52(--):1925-1934. >>> Deprenyl; Saline; SC; rat; 3 weeks; controls received mp w/saline; dose-response.

P3067 Mousseau,D.D., McManus,D.J., Baker,G.B., Juorio,A.V., Dewhurst,W.G., Greenshaw,A.J. Effects of age and chronic antidepressant treatment on [3H]tryptamine and [3H]dihydroalprenolol binding to rat cortical membranes. Cell.Molec.Neuro. 1993; 13(-1-):3-13. >>> Imipramine HCl; Desipramine HCl; Clomipramine HCl; Tranylcypromine HCl; Phenelzine sulfate; Clorgyline HCl; Deprenyl HCl; SC; rat; 2002; 2ML4; 14,28 days; antidepressant; controls received mp with vehicle; drug concentrations determined from Greenshaw program.

P2971 Sherry-McKenna,R.L., Wong,J.T.F., Paetsch,P.R., Baker,G.B., Mousseau,D.D., McKenna,K.F., Coutts,R.T., Greenshaw,A.J. Monoamine oxidase inhibitors: effects on tryptophan concentrations in the rat brain. J.Neural Transm. 1994; 41(--):155-163. >>> Phenelzine; Tranylcypromine, 4-methoxy-; Acetylphenelzine, N2-; Tranylcypromine, 4-fluoro-; Tranylcypromine; Deprenyl; SC; IP; rat; 28 days; antidepressant; controls received mp with vehicle; comparison of TCP and PLZ ip injections vs. mp.

P2709 de Yebenes,J.G., Fahn,S., Lovelle,S., Jackson-Lewis,V., Jorge,P., Mena,M.A., Reiriz,J., Bustos,J.C., Magarinos,C., Martinez,A. Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson's disease. Movement Disorders 1987; 2(-3-):143-158. >>> Dopamine; Pargyline; Deprenyl; Lisuride; Pergolide; HCl; Sodium metabisulfate; CSF/CNS; rat; 2001; 6,7 days; controls received mp with vehicles; replacement therapy (lesion in dopamine pathway); stability verified for 1 week by measuring dopamine concentrations and its metabolites at varying time intervals with HPLC; concomitant dopamine infusion w/ pargyline and w/ deprenyl; antihypertensive; neurodegenerative (Parkinson's disease).

P2496 Paetsch,P.R., Greenshaw,A.J. Down-regulation of b-adrenergic and dopaminergic receptors induced by 2-phenylethylamine. Cell.Molec.Neuro. 1993; 13(-3-):203-215. >>> Phenylethylamine HCl, 2-; Deprenyl HCl; SC; Rat; 2002; 2ML2; 28 days; Pumps replaced after 14 days; multiple pumps per animal (2); antidepressant.

P2407 Paetsch,P.R., Baker,G.B., Greenshaw,A.J. Induction of functional down-regulation of beta-adrenoceptors in rats by 2-phenylethylamine. J.Pharm.Pharmacol. 1993; 82(-1-):22-24. >>> Phenelzine sulfate; Phenylethylamine HCl, 2-; Deprenyl HCl; Saline; SC; Rat; 2002; 2ML2; 21, 22 days; Antidepressant; controls received mp w/ vehicle; multiple pumps per animal (2).

P1313 de Yebenes,J.G., Fahn,S., Jackson-Lewis,V., Jorge,P., Mena,M.A., Reiriz,J. Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson's disease. J.Neural Transm. 1988; 27(--):141-160. >>> Deprenyl; Dopamine; Lisuride; Pargyline; Pergolide; HCl; Sodium metabisulfite; Water; CSF/CNS; rat; 2001; 6, 7 days; mp connected to cannula; stability of DA verified in several vehicles, p 146; concomitant DA infusion with pargyline; DA infusion with deprenyl; replacement therapy (dopamine deficiency); stability verified in vitro; antihypertensive; neurodegenerative (Parkinson's disease).

P1096 O'Regan,D., Kwok,R.P.S., Yu,P.H., Bailey,B.A., Greenshaw,A.J., Boulton,A.A. A behavioural and neurochemical analysis of chronic and selective monoamine oxidase inhibition. Psychopharmacology 1987; 92(--):42-47. >>> Deprenyl HCl; Clonidine HCl; Clorgyline HCl; Saline; SC; rat; 2002; 13 days; controls received mp w/vehicle; hypothalmic electrodes implanted for self-stimulation to further access agents effects; antihypertensive.

P0211 Cohen,R.M., Campbell,I.C., Yamaguchi,I., Pickar,D., Kopin,I.J., Murphy,D.L. Cardiovascular changes in response to selective monoamine oxidase inhibition in the rat. Eur.J.Pharmacol. 1982; 80(--):155-160. >>> Deprenyl, 1-; Clorgyline; Saline; SC; rat; 21-24 days; mp model not stated; comparison of ip injection vs. infusion.

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3. Levetiracetam

Q0813 Sugaya,Y., Maru,E., Kudo,K., Shibasaki,T., Kato,N. Levetiracetam suppresses development of spontaneous EEG seizures and aberrant neurogenesis following kainate-induced status epilepticus. Brain Research 2010; 1352(-;-):187-199. >>> Levetiracetam; Saline; CSF/CNS; Rat; 2004; 28 days; Controls received mp w/ vehicle; animal info (male, Sprague-Dawley, 8 wks old); 15 ul saline allowed for 3-day delayed delivery followed by 25-day levetiracetam delivery; "A preliminary study in which a mini-pump was filled with bromophenol blue instead of levetiracetam, confirmed that the pumped drug solution was constantly separated from the predrug saline for 3 days at 37°C." pg 196.

P9736 Elzayat,E.A., Campeau,L., Karsenty,G., Blok,B., Padjen,A.L., Corcos,J. Effect of Antiepileptic Agent, Levetiracetam, on Urodynamic Parameters and Neurogenic Bladder Overactivity in Chronically Paraplegic Rats. UROLOGY 2009; 73(-4-):922-927. >>> Levetiracetam; Saline, normal; SC; Rat; 2ML1; 2ML2; 1, 2 weeks; Controls received no spinal cord transection; dose-response (Fig 2A); animal info (female, Sprague Dawley, 225-275 g, spinal cord transection).

P9181 Van Vliet,E.A., Van Schaik,R., Edelbroek,P.M., da Silva,F.H.L., Wadman,W.J., Gorter,J.A. Development of tolerance to levetiracetam in rats with chronic epilepsy. Epilepsia 2008; 49(-7-):1151-1159. >>> Levetiracetam; Water, distilled; SC; Rat; 2ML1; 2 weeks; Functionality of mp verified; pumps replaced after 1 week; tolerance; animal info (male, Sprague Dawley, adult, 500-700 g.); "flow rate of each pump was verified after removal and corresponded to the range given by the manufacturer indicating that all minipumps functioned properly." pg. 1156.

P8935 Margineanu,D.G., Matagne,A., Kaminski,R.M., Klitgaard,H. Effects of chronic treatment with levetiracetam on hippocampal field responses after pilocarpine-induced status epilepticus in rats. Brain Research Bulletin 2008; 77(-5-):282-285. >>> Levetiracetam; SC; Rat; 3 weeks; 21 days; Controls received mp w/ vehicle; functionality of mp verified by drug plasma levels; dose-response (table 1, pg. 283); animal info (male, Sprague Dawley, 220-250 g.); epilepsy; "chronic treatment with levetiracetam completely inhibits the development of hippocampal hyperexcitability following pilocarpine-induced (status epilepticus)".

P5195 Doheny,H.C., Jefferys,J.G.R., Whittington,M.A., Patsalos,P.N. A comparison of the efficacy of carbamazepine and the novel anti-epileptic drug levetiracetam in the tetanus toxin model of focal complex partial epilepsy. British Journal of Pharmacology 2002/3; 135(-6-):1425-1434. >>> Carbamazepine; levetiracetam; DMSO; Propylene glycol; ethanol, saline; IP; Rat; 7 days; Controls received mp/ vehicle; functionality verified by drug serum levels; dose-response (text p.1428); carbamazepine was dissolved in 42.5% DMSO/42% Propylene glycol/15% ethanol. Levitiracetam was dissolved in saline; 2-day recovery period given using coiled PE-40 tubing; epilepsy; anticonvulsant.

P5035 Glien,M., Brandt,C., Potschka,H., Loscher,W. Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy. Epilepsia 2002; 43(-4-):350-357. >>> Levetiracetam; Water, distilled; SC; rat; 2ML1; 6 weeks; anticonvulsant; controls received mp w/ vehicle; functionality of mp verified by residual aspiration, plasma levels; pumps replaced every week; good methods (priming, filling p. 352-53); rats received 2-week saline infusion (pre-drug control period) then 2 week levetiracetam infusion then another 2-week saline infusion.

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4. Phenobarbital

P0494 Hock,F.J., Beyhl,F.E. A novel method for the administration of the enzyme inducer phenobarbital to rats via an osmotic minipump. IRSC Med.Sci.: Biochem. 1984; 12(-8-):661-. >>> Phenobarbital; SC; rat; 2002; 8 days; Comparison of phenobarb. consumed po in drinking water vs. mp infusion; author states advantages of mp use.

P0447 Davis,T.P., Schoemaker,H., Culling,A.J. Centrally acting drugs alter in vitro B-endorphin processing in the rat. Eur.J.Pharmacol. 1984; 100(--):249-251. >>> Chlorpromazine; haloperidol; phenobarbital; promethazine; SC; Rat; 2001; 8 days; Comparison of agents effects.

P0401 Kuhnz,W., Zierer,R., Nau,H. A new method for kinetic studies of drug interactions in experimental animals during steady state: controlled-rate application of valproic acid, phenobarbital and their combinations via implanted osmotic minipumps in the mouse. Arzneimittelforschung 1983; 33(-11-):1579-1582. >>> Phenobarbital, sodium; Valproate, sodium; Water; SC; mice (pregnant); 2001; 2002; 1 and 2 weeks; no stress see p. 1580, 1582; 1-2 pumps/animal; VPA and PB used singly and in combination in mp.

P0311 Kapetanovic,I.M., Sweeney,D.J., Rapoport,S.I. Phenobarbital pharmacokinetics in rat as a function of age. Drug Metab.Disp. 1982; 10(-6-):586-589. >>> Phenobarbital; Water; IP; rat; 5 days; bolus injec. vs. mp infusion.

P0036 Tabakoff,B., Ritzmann,R.F., Oltmans,G.A. The effect of selective lesions of brain noradrenergic systems on the development of barbiturate tolerance in rats. Brain Research 1979; 176(--):327-336. >>> Phenobarbital, sodium; Propylene glycol; Water; CSF/CNS; rat; 3 days; some groups given 6-OHDA or vehicle of ascorbic acid in Artificial CSF prior to infusion.

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5. Promethazine

P0447 Davis,T.P., Schoemaker,H., Culling,A.J. Centrally acting drugs alter in vitro B-endorphin processing in the rat. Eur.J.Pharmacol. 1984; 100(--):249-251. >>> Chlorpromazine; haloperidol; phenobarbital; promethazine; SC; Rat; 2001; 8 days; Comparison of agents effects.

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6. Tiagabine

P4724 Cleton,A, Altorf,B.A, Voskuyl,R.A, Danhof,M. Pharmacokinetic-pharmacodynamic modelling of tiagabine CNS effects upon chronic treatment in rats: lack of change in concentration-EEG effect relationship.. European Journal of Pharmacology 2000; 12(--):141-150. >>> Tiagabine;; Saline;; IV (jugular);; rat;; 2ML2;; 14 days;; Controls received mp w/ vehicle; functionality of mp verified by plasma levels; dose-response (graph p. 145); comparison of IV injections vs. mp; Tiagabine is a GABA uptake inhibitor; seizure prevention; Epilepsy;.

P3415 Halonen,T., Nissinen,J., Jansen,J.A., Pitkanen,A. Tiagabine prevents seizures, neuronal damage and memory impairment in experimental status epilepticus. Eur.J.Pharmacol. 1996; 299(--):69-81. >>> Tiagabine; Propylene glycol; SC; rat; 2ML1; 7 days; functionality of mp verified by in vitro testing and residual volumes; dose-response; half-life (p. 70); compound stable for one week (see p. 78); stability.

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7. Valproic Acid

P9619 Kitazoe,K., Abe,M., Hiasa,M., Oda,A., Amou,H., Harada,T., Nakano,A., Takeuchi,K., Hashimoto,T., Ozaki,S., Matsumoto,T. Valproic acid exerts anti-tumor as well as anti-angiogenic effects on myeloma. International Journal of Hematology 2009; 89(-1-):45-57. >>> Valproic acid; PBS; SC; Mice (SCID); 2002; 14 days; Controls received mp w/vehicle; cancer (myeloma); animal info (8-10 wks old, female).

P9073 Shu,Q., Antalffy,B., Su,J.M., Adesina,A., Ou,C.N., Pietsch,T., Blaney,S.M., Lau,C.C., Li,X.N. Valproic Acid prolongs survival time of severe combined immunodeficient mice bearing intracerebellar orthotopic medulloblastoma xenografts. Clin.Cancer Res. 2006/8/1; 12(-15-):4687-4694. >>> Valproic acid; Sodium chloride; SC; Mice (SCID); 2001; 14 days; Controls received no treatment; pumps replaced after 7 days; animal info (6-10 wks old, Rag 2).

P8386 Serralta,A., Barcia,J.A., Ortiz,P., Duran,C., Hernandez,M.E., Alos,M. Effect of intracerebroventricular continuous infusion of valproic acid versus single i.p. and i.c.v. injections in the amygdala kindling epilepsy model. Epilepsy Research 2006; 70(-1-):15-26. >>> Valproic acid; Saline; CSF/CNS; Rat; 2001; 2002; 7 days; Controls received no treatment; dose-response (fig. 1); comparison of icv, IP injections vs. mp; no stress (see pg. 22); toxicology; multiple pumps per animal (2); animal info (male, Wistar, amygdala-kindled epilepsy, 380-420g.); mp primed 1 hr. in 37.5 celsius saline; evans blue dye used to confirm cannula placement, "chronic i.c.v. VPA infusion affords protection against kindled seizures accompanied by less ataxia and sedation" (pg. 24).

P3616 Ohdo,S., Ogawa,N., Nakano,S., Higuchi,S. Influence of feeding schedule on the chronopharmacological aspects of sodium valproate in mice. J.Pharmacol.Exp.Ther. 1996; 278(-1-):74-81. >>> Valproic acid; Saline, sterile physiological; SC; mice; 2001; no duration posted; functionality of mp verified by plasma levels; half-life of less than 1 hour (p. 76); 2 mps implanted concomitantly.

P2820 Song,J.-G. Chronopharmacokinetices of valproic acid in mice following contsant-rate administration by osmotic minipump. Chinese Pharmacological Bulletin 1995; 11(-2-):135-136. >>> Valproic acid; SC; mice; no duration posted; comparison of iv injections vs. mp; article in Chinese w/ abstract in English.

P1335 Paulson,R., Sucheston,M., Hayes,T., Weiss,H., Sachs,L., Oca,M., Kernan,B., Weiss,S. Effects of sodium valproate and oxygen on the CD-1 mouse fetus. J.Craniofac.Genet.Dev.Biol. 1988; 8(--):35-42. >>> Valproic acid; Sodium carbonate; Water; SC; mice (pregnant); 2001; 7 days; dose-response (text, graph); half-life; 2 pumps implanted simultaneously; functionality of mp verified by plasma levels; no stress; toxicology/teratology.

P0886 Loscher,W. Development of tolerance to the anticonvulsant effect of GABAmimetic drugs in genetically epilepsy-prone gerbils. Pharmacol.Biochem.Behav. 1986; 24(--):1007-1013. >>> Aminobutyric acid, Y-acetylenic Y-; Aminooxyacetic acid; Diazepam; THIP; Valproic acid; Saline; SC; rat; 2ML2; 2 weeks; controls received mp w/saline; diazepam too unstable to be used in mp; epilepsy; functionality of mp verified after 14 day exper. period - all 50 mps worked accurately; stability of VPA, THIP, GAG and AOAA.

P0848 Nau,H. Valproic acid teratogenicity in mice after various administration and phenobarbital-pretreatment regimens: the parent drug and not one of the metabolites assayed is implicated as teratogen. Fundam.Appl.Toxicol. 1986; 6(-4-):662-668. >>> Valproic acid; Water; SC; mice; 1 day; teratology; states pump rate at 8 ul/hr; 2 doses of vpa infused; comparison of SC or IP injections or oral dose vs. mp infusion.

P0366 Loscher,W., Nau,H. Distribution of valproic acid and its metabolites in various brain areas of dogs and rats after acute and prolonged treatment. J.Pharmacol.Exp.Ther. 1983; 226(-3-):845-854. >>> Valproic acid; SC; rat; 2ML2; 1, 3, or 14 days; no comment posted.

P0274 Nau,H., Zierer,R. Pharmacokinetics of valproic acid and metabolites in mouse plasma and brain following constant-rate application of the drug and its unsaturated metabolite with an osmotic delivery system. Biopharm.Drug Disp. 1982; 3(--):317-328. >>> Valproic acid; Sodium bicarbonate; Water; SC; mice; 2001; 2002; 1 week; intermittent sc. injec. vs. mp infusion; 1 or 2 pumps/animal; comparison of human vs. animal pharmacokinetics.

P0175 Nau,H., Zierer,R., Spielmann,H., Neubert,D., Gansau,Ch. A new model for embryotoxicity testing: teratogenicity and pharmacokinetics of valproic acid following constant-rate administration in the mouse using human therapeutic drug and metabolite concentrations. Life Sci. 1981; 29(-26-):2803-2813. >>> Valproic acid; Water; SC; mice; 2001; 7 days; 1 or 2 pumps/mouse; comparison of injection vs. infusion and human vs. animal pharmacokinetics.

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8. Vigabatrin

R0242 Loescher,W. The pharmacokinetics of antiepileptic drugs in rats: Consequences for maintaining effective drug levels during prolonged drug administration in rat models of epilepsy. Epilepsia 2007; 48(-7-):1245-1258. >>> Levetiracetam; phenobarbital; phenytoin; valproic acid; vigabatrin; Water, distilled; PEG 300; glycerol; PEG 400; propylene glycol; SC; IP; Rat; mice; gerbils; 2ML1; 2ML2; 1-4,2 weeks; 7 days; Comparison of IV, IP injections vs. food or water delivery vs mp; pumps replaced (every week in one set of experiments); stress/adverse reaction: (see pg. 1255); peritoneal irritation, peritonitis in some of the IP experiments); half-life (p. 1247) table 1 (18 compounds); animal info (epileptic, Sprague-Dawley, Wistar); review; see p. 1254-1255; see table 4 for advantages + disadvantages of different applicatoin routes.

R0177 Pitkanen,A. Efficacy of current antiepileptics neurodegeneration in epilepsy to prevent models. Epilepsy Research 2002; 50(-1-2-):141-160. >>> Vigabatrin; Tiagabine; SC; Rat; 2 months; Neuroprotection; pump use mentioned on p. 147 and 155.

P4904 Halonen,T., Nissinen,J., Pitkanen,A. Chronic elevation of brain GABA levels beginning two days after status epilepticus does not prevent epileptogenesis in rats. Neuropharmacology 2001; 40(--):536-550. >>> Vigabatrin; Saline; SC; rat; 2ML2; 10 weeks; controls received mp w/ vehicle; long-term study, pumps replaced every 2 weeks for 10 weeks; epilepsy; seizures..

P4343 Pitkanen,A., Nissinen,J., Jolkkonen,E., Tuunanen,J., Halonen,T. Effects of vigabatrin treatment on status epilepticus-induced neuronal damage and mossy fiber sprouting in the rat hippocampus. Epilepsy Research 1999; 33(--):67-85. >>> Vigabatrin;; Saline;; SC;; rat;; 2ML1;; 2 months;; controls received mp with vehicle; functionality of mp verified by plasma levels and residual volume; long-term study, pumps replaced every 2 weeks; enzyme inhibitor;.

P4249 Golombek,D.A., Ralph,M.R. Inhibition of GABA transaminase enhances light-induced circadian phase delays but not advances. J.Biol.Rhythms 1994; 9(-3-4-):251-261. >>> Vigabatrin; Saline; IP; hamster; 2002; 14 days; controls received mp w/saline or no treatment; comparison of injections vs. mp; GABA transaminase inhibitor.

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