Terry W. Hood, Edward F. Domino and Harry S. Greenberg- Possible Treatment of Parkinson’s Disease with Intrathecal Medication in the MPTP Model

8/3/2019 Terry W. Hood, Edward F. Domino and Harry S. Greenberg- Possible Treatment of Parkinsons Disease with Intrathe

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Possible Treatment of Parkinsons Diseasewith Intrathecal Medication in theMPTP Model

T E R R Y W . HOOD, E D W A R D F. D O M I N O , A N DH A R R Y S. G R E E N B E R G

Departments of Surgery (Section of Neurosurgery),Pharmacology and NeurologyUniversity of Michigan Medical SchoolAnn Arbor, Michigan 48109

INTRODUCTIONParkinsons disease is a neurological syndrome secondary to diminished levels ofdopa mine in the corpus striatum of the cerebrum . This disease is manifested by theclassic clinical constellation of bradykinesia, rigidity, tremor and postural changes.T he tre atm ent of Parkinsons disease was significantly ad vance d with th e introdu ctionof levodopa, a m etabolic precursor of dopamine. However, afte r five yea rs of levodopatherapy, 50%of patients develop fluctuating motor responses, th e on-off phenome-non, to dru g treatme nt which can be disabling and in m any cases poorly controlled byconservative thera py.2 These fluctuations range from excessive involuntary dyskineticmovements to akinesia. Since plasma levels of levodopa are high during periods ofmobility with dyskinesias and low during episodes of immobility, a constant druginfusion may provide stable plasma dr ug levels an d con trol this clinical problem.Several investigators have used a constant intravenous infusion of levodopa tocontrol the on-off phenomenon in Parkinsons disease patient^.^ Recently continu-ous subcutan eous infusion of the dopa minergic agon ist lisuride has been reported tocontrol fluctuations of motor pe rform anc e in clinical trials. In a n ani ma l model of

Parkinsons disease th e direct infusion into the corpu s str ia tu m of dopam ine has beenreported to reduce apomorphine induced rotation in rats with unilateral substantianigra lesions from 6-hydro~ydopamine.~nitially the intraventricular application ofdopamine was attempted in our laboratory to reverse the symp toms of bradykinesia inth e 1-methy l-Cphen yl- 1,2,5,6 tetrahydropy ridine (M P T P ) model of Parkinsons dis-ease in the rhesus monkey. M P T P is a by produc t of improp er meperidine synthesis an dcauses a permanent parkinsonism syndrome in intravenous drug abusers. Subse-quently this compound has been used extensively in primates to effect th e best anim almodel of Parkinsons disease, both symptomatically and pathologically, developed todate.* However, the use of dopam ine caused ma ny u ndesirable behavioral side effectswhich caused us to look for a better agent. Since levodopa is relatively insoluble, wedecided to look at other possible precursors of dopamine. For th e past two years ourlaboratory has concentrated on th e intraventricular adm inistration of levodopa m ethylester (LD M E ) to reverse the symptom s of bradykinesia induced by M PT P. Addition-ally, we have investigated the regional advantage of the intraventricular route overintravenou s adm inistration. This repo rt will detail our preliminary exp erience with thismodel and discuss the poten tial treatm ent advan tages of intraventricular perfusion inthe treatmen t of on-off phenomenon of Parkinsons disease patients.

200


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HOOD er al.: INTRATHECAL MEDICATION 201ACUTE INTRAVENTRICULAR INFUSION

Ten adult rhesus monkeys were admin istered 1.4 mg/kg M PT P (Aldrich ChemicalCo., Milwaukee, W I) intravenously in divided dosages which resulted in th e develop-ment of severe bradykinesia and marked decrease of spontaneous food intake. Theabsolute amount of MPTP required to develop clinical parkinsonism showed markedindividual variation which correlated primarily with the animals age with youngeranimals requiring more dru g to exhibit the equivalent motor change s of th e treatedolder animals. All animals required supplementary nasogastric tube feedings in theattemp t to m aintain pretreatm ent body weight.Th e animals subsequently underwent placement of a lateral ventricular c annulaconnected to a subgaleal R ickh am reservoir or an Infusaid M odel 400 pum p (InfusaidCorp.. Norwood, MA) placed subcutaneously in the interscapular space. All surgerywas performed using intramuscular ketamine 10 mg/kg and xylazine 2 mg/kganesthesia. Postoperatively the animals received acetamenophen water for analgesia.Th e lnfusaid pum p permitted th e continuous perfusion of artificial cerebrospinal fluidbetween injections of intraventricular levodopa methyl ester which preven ted cathe terocclusion whereas th e R ickham reservoir permitte d frequent C S F samp ling followingdrug injection. Following catheter placement the animals underwent air or positivecontrast ventriculography under intramuscular ketamine 10 mg/kg anesthesia todocument proper catheter p lacement.Prior to LDME injection animals were videotaped for three hours to documentspontan eous motor activity. Daily voluntary food intake by th e animals was recorded.Following the intraventricular injection of L D M E 1 5 mg, anima ls were videotaped foran additional three hours. Sp ontaneous motor activity of th e animals was evaluated bya neurologist in a blinded m anner a nd circling movements were measured. Changes inspontan eous food intake were evalua ted by a review of th e animals daily food intakerecords.C S F dopamine m etabolite studies were performed following th e evaluation ofmotor an d feeding effects of intraventricular L DM E. M PTP -treated rhesus monkeyswith Rickham reservoirs connected to lateral ventricular catheters were placed inmonkey chairs during C S F sampling experiments. Control C S F 1 ml was obtainedimmediately preceding the intraventricular injection of L D M E 15 mg. Following theinjection hourly samples of CSF were obtained for the measurement of the dopaminemetabolites homovanillic acid (H VA ) and dihydroxyphenylacetic acid (D O PA C ) andLD M E using a H PL C system with an electrochemical detector.After the drug trials the animals were euthanized. The brains were immediatelyremoved an d placed in formalin 15%. Aft er adeq uate fixation gross and microscopicexamination were performed.Review of six animals videotaped before and after intraventricular LDMEdocumented a 470% increase in spon taneous circling movemen ts during th e three-hourobservation period after injection (FIGURE ) . Analysis of th e animals movement didnot reveal circling predominantly in one direction. Hourly measurements of move-ments afte r injection were compared to corresponding hours prior to the d rug a nd wereanalyzed statistically using the Students T Test. The increase in spontaneousmovement was statis tically significant (p < 0.05).During the three-hour videotaped observation following intraventricular LDMEthe animals were noted to increase their spontaneous food intake greatly. Analysis ofthis behavioral change revealed a 580% increase of food intake dur ing th e day of th edrug trial compared to the day before (FIG UR E ). Th e measure ment of food intake ofthe day of the drug trial an d the days before and after intraventricular L D M E were


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202 ANNALS NEW YORK ACADEMY OF SCIENCES

FIGURE 1. Increase of movement followingthe acute intraventricular injection of LDMEmeasured as percentage of control movementscounted in the same MFTP rhesus monkeyimmediately before drug trial (n = 6).1 L 1

I 2 3HOURS POSTL- DOPA METHYL ESTER

compared with the Student's T Test a nd the increase of spontaneous food intake wassignificant (p < 0.01).C S F dopamine metabolite studies have been com pleted thus f ar on two animals. A10-fold increase in HVA and DOPAC over baseline values after intraventricularLDME have been documented (FIGURE3). Following intravenous LDME 15 mgminimal increases of CSF HVA and DOPAC were seen and no change of C S Fdopamine metabolites were found following an intraventricular placebo injection ofartificial C S F (FIGUR E ).

DISCUSSIONHypotheses of the etiology of th e "on-off'' phenomenon a re based on the facto rs ofdrug absorption and transport competition causing fluctuations of levodopa plasmalevels as well as a lterations of dopamine recepto r s it e f ~ n c t i o n . ~ " ~ietary intake ofamino acids can interfere with d rug absorption an d transport an d result in unstableblood levels of levodopa. Plasma levels of levodopa rise more rapidly after oraladministration in patients on chronic com pared to those patients initiating treatm ent.Lastly, some authors have proposed that leveodopa therapy results in dopaminereceptor site hypersensitivity which would ex agg erate th e problems of u nstable d ru gplasma levels. Measures used to treat the "on-off" phenomenon have included drugholidays, the administration of frequent, small dosages of levodopa, the use ofdecarboxylase inhibitors to limit peripheral metab olism, dopam inergic agonist thera -

FIGURE 2. Spontaneous food intake measuredby volume of the test animals on the days of th edrug trial and th e days before and after mea-sured in percent of food intake expected of anormal weight matched rhesus monkey(n = 6).

8 DAYBEFORE L-DOPA DAY AFTERTRIAL M~~~~~


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HOOD er al.: INTRATHECAL MEDICATION 203py, and lo w protein diets. These treatment regimens usually provide only limitedcontrol of the symptoms of the on-off phenomenon. More recently time-releasedlevodopa has undergone clinical trials a n d ha s shown limited success.11*2 he use ofconstan t dru g perfusion would be th e obvious extention of these the rap ies and wouldavoid the problems associated with oral administratio n.Clinically the use of an intravenous infusion of levodopa has been reported byseveral authors. This approach would not be practical for chronic treatment sincelevodopa is poorly wate r soluble an d acidic an d req uires larg e volumes of solution forparenteral administration. More recently a report of consta nt subcutan eous infusion ofthe dopaminergic agonist lisuride was published. For a period of 4 to 7 months threepatients received lisuride by a portab le mini-infusion pu m p in addition to oral levodopaand a decarboxylase inhibitor. Although symptomatically improved, the patientsexhibited increased dyskinetic movements.In animal models of Parkinsons disease the intraventricular and direct tissueinfusion routes have been recently r e p ~ r t e d . ~ . ~heoretically the intraventricular routeof drug administration should be particularly advantageous in the treatment of the

n glml 4000300020001 0 0 0

. - . . - . - .baseline hour 1 hour 2 hour 3 hour 4FIGURE 3. Cerebrospinal fluid dopamine metabolites H V A and DOPAC and the test drugLDME in ng/ml measured hourly before and after intraventricular injection of 15 mg.

on-off phenomenon. This route would avoid dr ug absorption and tra nsp ort com peti-tion which in part result in unstable plasma drug levels. Secondly, peripheralmetabolism would not be an issue with direct central nervous system administration.These two hypotheses of the on-off phenomenon w ould not be com pletely avoidedusing a constant subcu taneou s or intravenous dru g infusion. Th e intraventricular routemay provide constant drug perfusion for the entire corpus striatum which would notoccur with direct tissue infusion unless multiple catheters were utilized. However, adiffusion gradient from the ventricular system may become a significant issue whenthis route is used in the larger human brain resulting in differential stimulation ofdopamine receptors. This concern will require human trials to determine if it will beclinically im portant.Direct intrastriatal perfusion of dopamine would require multiple catheters todeliver th e neurotransmitter to the widespread parts of th e corpus striaturn. Placem entof these catheters would have to be precise since the tissue diffusion of dopamine wasvery limited. The necessity of multiple catheters and precise localization would resultin a more hazardous procedure with a higher failure rate.


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204 ANNALS NEW YORK ACADEMY OF SCIENCES

3 5 0 0 -3000

2 5 0 0 -2000 -1500 -1000 -

nglml

Our preliminary data suggest that the acute intraventricular administration ofLDME transiently reverses bradykinesia in the MPTP rhesus monkey model ofparkinsonism. An approximate 10 to 1 regional adv anta ge was seen when compa ringdopam ine m etabolites following adm inistration of identical intraventricular or intrave-nous dosages. This regional advantage is particularly important since implantablepum p systems have a limited capacity a nd t he risk of infection occurs with every pum prefill. Importantly, LDME is freely water soluble and could be infused in small,

500

iIV l h p a methyl ester

I- Ellbll's B solution

baseline hour 1 hou r 2 h o u r 3 hour 4B

a- V l-dopa methyl ester

baseline hour 1 hour 2 hour 3 hour 4FIGURE 4. Cerebrospinal fluid analysis of (A ) H V A and (B) DOPAC in ng/ml measuredhourly following intraventricular ( I ) LDME 15 mg, intravenous ( IV) LDME 15 mg and theintraventricular injection of a placebo, Elliott's B solution.

concentrated volumes which is not possible with levodopa. More clinical experiencewill be necessary to determ ine if L D M E like levodopa is generally better tolerated t ha nmany of the dopam inergic agonists.Additional resea rch is necessary t o determin e if this thera peu tic app roac h will bepractical for patients. T he issue of dru g stability in solution for periods of thre e to fourweeks will have to be resolved. Additionally chro nic efficacy an d toxicity will have tobe determ ined before widespread clinical use will be approved. O ur positive exper ience


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HOOD et al.: INTRATHECAL M EDICATION 205with the in t ravent r icu lar adm inis t ra t ion of LDM E warrants i t s fur th er inves tigat ion int h e a t t e m p t t o find a t he rapy fo r t he p rob l em of on-off phenomenon .

REFERENCESI .

2.3.4.

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6.

7.8.

9.

10.11 .12.

13.14.

HOR NKIEWIC Z,. 1966. Metabolism of brain dopamine in human parkinsonism: Neuro-chemical and clinical aspects. In Biochemistry and Pharmacology of the Basal Ganglia.E. Costa, L. J. Cote & M. D. Yahr. Eds. 171-181. Raven Press. New Y ork, NY .MARSDEN, . D. & J. D. PARKS. 1976. On-off effects in patients with Parkinsonsdisease on chronic levodopa therap y. Lancet 1: 292-296.MCDOW ELL, . H ., J. E . L EE& R. D. SWEET.981. Extrapyra midal disease. In ClinicalNeurology. A. B. Baker & L. H. Baker, Eds. Ha rpe r and Row. Philadelphia, PA .ROSIN,A. J.. D. DEVEREUX,. ENG& D. B. CALNE. 979. Parkinsonism with on-offphenomenon. Intravenous treatm ent with levodopa afte r major abdo minal surgery. Arch.Neurol. 3 6 32-34.OBESO, . A.. M . R. LUQ UIN J. M. MA RTINEZ-LA CE.986. Lisuride infusion pump: Adevice for the treatment of motor fluctuations in Parkinsons disease. Lancet 1: 467-470.HARGRAVES,. W. & W. FREED. 987. Chronic intra striatal dop amine infusions reducemotor abnormalities in an animal model of Parkinsons disease. Presented a t the A nnu alMeeting of the American Association of Neurological Surgeons. May 3-7. Dallas, TX .LANGSTON,. W., P. BALLARD,. W. TETRUD I. IR WIN. 983. Chronic parkinsonism inhumans due to a product of meperidine-analog synthesis. Science 2 1 9 979-980.BURNS,R. S., C. C. CHIUEH , . P. MARKEY,M. H. EBERT,D. M. JACOBOWITZI . J .KOPIN.1983. A primate model of parkinsonism: Selective destruction of dopaminergicneurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine. Proc. Na tl. Acad. Sci. USA 8 0 4546-4550.N u n , J . G., W. R. WOODWARD.. P. HAMMERSTAD,. H. CARTER& J. L. ANDERSON.1984. Th e on-off phenom enon in Parkinsons disease. Relation to levodopa absorptionand tran sport. N. Engl. J. Med. 3 1 0 483-488.KLAWANS, . L., C . GOETZ,P. H. NAU SIEDA W. J. WEINER. 977. Levodopa-induceddopamine receptor hypersensitivity. An n. Neurol. 2 125-1 29.NUTT.J. G., W. R. WOODW ARD J. H . CARTER. 986. Clinical and biochemical studieswith controlled release Sin em et. Neurology 36:1206-121 1.JUNCOS, . L.. G. F AB BR IN I,. M. MOW RADIAN,.SERR ATI, . M. KASK& T.N . CHASE.1987. Controlled release levodopa tre atm ent of m otor fluctuations in Parkinsons disease.J . Neurol. N eurosurg. Psychiatry 5 0 1 9 4 1 9 8 .QU IN N. . , C. D. MARSDEN J. D. PARKES. 1982. Complicated response fluctuations inParkinsons disease: Response to intravenous infusion of levodopa. Lan cet 2: 412-41 5 .HOOD,T. W., E. F. DOMINO H. S. GR EENB ER G.987. Reversal of parkinsonism in theM PT P rhesus monkey model by intraventricular L-Dopa m ethyl ester. Presented a t theAnnual Meeting of the American Association of Neurological Surgeons. May 3-7.Dallas. TX.

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Terry W. Hood, Edward F. Domino and Harry S. Greenberg- Possible Treatment of Parkinson’s Disease with Intrathecal Medication in the MPTP Model