You are on page 1of 7

Br. J. clin. Pharmac.

, (1976), 3, 883-889

EFFECT OF AMANTADINE
ON DRUG-INDUCED
PARKISONISM: RELATIONSHIP
BETWEEN PLASMA LEVELS AND EFFECT

G.M. PACIFICI1, M. NARDINI2, P. FERRARI3, R. LATINI1, C. FIESCHI2 & P.L.
MORSELLI1 *
Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy,
2 Department of Nervous and Mental Diseases, University of Siena, Italy and

3 Istituto De Angeli, Milano, Italy

1 Amantadine, administered at a dose of 200 mg/day, antagonized the extapyramidal
symptomatology induced by neuroleptic drugs in fifteen psychiatric patients.
2 Steady-state levels were reached within 4-7 days of treatment. Individual plasma levels
ranged from 200-900 ng/ml.
3 Apparent plasma half-lives varied from 10-28.5 h with an apparent VD of 200-400 litres.
4 A significant relationship was found between the plasma levels of amantadine and the
effects on the extrapyramidal symptomatology.
5 The data suggest a direct effect of amantadine on dopaminergic receptors.

Introduction
The antiparkinson activity of amantadine, firstly not satisfactory prompted us to evaluate the
described by Schwab, England, Poskanzer & possible relationships between amantadine plasma
Young (1969) has been subsequently confirmed levels and effects. No data are in fact available on
by several authors in controlled trials where the amantadine pharmacokinetics in the course of
drug was administered either alone (Fieschi, chronic treatment.
Nardini, Casacchia, Tedone & Robotti, 1970a;
Parkes, Zilkha, Marsden, Baxter & Knill-Jones,
1970; Hunter Stern, Laurence & Armitage, 1970a; Methods
Bauer & McHenry, 1974; Mann, Pearce &
Waterbury, 1971) or in association with levodopa Observations were carried out on fifteen female
(Fieschi, Nardini, Casacchia, Tedone, Reitano & patients admitted to the psychiatric unit with
Robotti, 1970b; Hunter, Stern, Laurence & various psychiatric syndromes and behavioural
Armitage, 1970b; Mawdsley, Williams, Pullar, changes. Their ages ranged from 31-62 years and
Davidson & Kinloch, 1972; Fiunfgeld, 1972; all were on constant treatment with neuroleptics
Schwab, Poskanzer, England & Young, 1972). and anticholinergic drugs. The motivation for their
Amantadine has also been found to be variably inclusion in the study was the poor control of the
active in the extrapyramidal syndrome induced by extrapyramidal syndrome by classical anticholin-
chronic administration of neuroleptic drugs ergic drugs.
(Fanali, Nardini & Sorgona, 1970; Nardini, Fanali, Observations were carried out according to a
Sorgona, Vergnano & Fieschi, 1971; Kelly & double-blind crossover design; the neurologists
Abuzzahab, 1971). The considerable intersubject who performed the clinical evaluations were not
variability in the amantadine effects in these aware of the experimental design. Upon admission
patients and on the other hand, its utility in those to the observation period, the anticholinergic
cases in which a classic anticholinergic therapy is medication was substituted by a placebo, while
neuroleptics (butyrophenones and/or phenothia-
zines) were continued at the usual dose. After 7
* Present address:
Synthelabo, Rue de la glaciere, 58, days, amantadine was administered for 15 days at
Paris-Cedex 13, France. a dose of 200 mg, and then the amantadine

The severity of the extrapyramidal performance tests was carried out by trend syndrome was assessed according to Fieschi et al. The latter can be considered as 'during the method of least-squares to yield the apparent course of absorptive phase' since in volunteers we elimination rate constant (Kel) and the apparent observed that the absorption peak of amantadine plasma half-life may occur between 2 and 8 h. amantadine dose. Pacifici. putting finger to nose ten times with each arm. 4. Ferrari & Robotti (1970c) by a means of univariate and multivariate regression 22 items rating scale evaluating akinesia. No variations in the neuroleptic dose distribution was calculated according to the were introduced. Tognoni. 14. . Rizzo & extrapyramidal symptoms was observed within Morselli. Kel Latini. P. 21 and 22. 1974).c. R. Serial blood well as hypokinesia and vegetative disturbances. 14. 11. while eventual relationships between (1 970a) and to Fieschi. The amantadine administration led in most of the Occurrence of possible side effects was also patients to a rapid and marked improvement of evaluated by means of routine physical and the extrapyramidal symptomatology with a laboratory controls. and correlataion analysis. after the daily intake of amantadine or placebo on Rigidity and tremor were favorably affected as days 8. LATINI. 48-72 h. V= D AUC X Kel Clinical assessment (where D is the dose and F is the fraction Clinical evaluations were performed before absorbed) assuming complete (F = 100) bioavail- initiating amantadine treatment on days 1. MORSELLI treatment was again switched to placebo for 4 extrapolation to infinity after correction for the days. FERRARI. noticeable decrease in rating within 4-6 days for all the items considered.21.l. 7 at ability. NARDINI. and the apparent volume of were used. With the discontinuation of derivatization with trichloracetylchloride (Bian. 09. by the oral route The area under the curve (AUC) following the last at 08.20. however. Plasma levels of amantadine were measured before ated by plotting log-concentration versus time the morning dose and 6 h after drug adminis- curves and the terminal slope calculated by the tration. samples were also collected after the last but to a lesser extent. Nardini. plasma levels and clinical data were evaluated by Reitano. C. M.L. postural impairment. In addition.22. 1972). Sorgona. 17. with a mean value 0.00h and on days 8.00 h. etc. Statistical analysis of the Blood sampling and chemical analysis data showed highly significant (P < 0. rigidity.23. procedure involving extraction in toluene and effects were present. Amanta. Belvedere. The blood collected from the As shown in Figure 1. No evident or noticeable side g. remarkable antecubital vein into heparinized test tubes was differences were present within individual patients immediately centrifuged and the plasma so and the positive effect did not appear to be related obtained kept at -20 C until analysis. and 25. Amandatine and placebo matching capsules initial amount. Ferrari & Fieschi. analysis. and no other drugs were equation administered concomitantly throughout the entire DxF observation period. vegetative symp- toms. FIESCHI & P. a clear reemergence of drate. 17. amantadine administration. 20. Calculations Amantadine plasma levels Amantadine plasma elimination rates were evalu. Daily adminis- tration of amantadine (200 mg).884 G. three timed Results performance tests (walking 2 x 3 m. Casacchia.001) differ- ences in the scores on day 7 (end of placebo Blood sampling was performed before and 6 h period) and day 22 (end of amantadine period). in any way to the severity of the extrapyramidal dine plasma levels were measured by means of a symptomatology. Frigerio. and opening and Clinical effects closing each hand ten times) were carried out on each occasion. 11. Nardini. PACIFICI. leads within 4-7 days to plasma levels dose was calculated by the trapezoidal rule with fluctuating between 400 and 900 ng/ml (Table 1). tremor. Tedone.M.693 of 6 ± 2 h (Morselli. Statistical analysis of the clinical data and 24. Each item was scored from absent (score 0) to very marked (score 3).

Analysis of the 14.. [I i] .00 743 + 72 Drug was started on day 7 and discontinued on day 22. .00 h and according to a first order kinetics.. while in more irregular with day to day fluctuation of seven significant amounts were still measurable + 30%. 1 nn] n O la It II 2 3 4 5 6 7 8 Total score . . = not determined .. mean) plasma levels (.. . while absorptive phase values were drug within 72 h in five of the subjects.00 h values as shown in Figure 2 where the apparent plasma decay curves after amantadine individual plasma concentrations relative to day 17 discontinuation led to the values reported in are reported.00 0 331 404 429 450 461 453 222 118 61 +38 +47 ±59 ±65 ±60 ±57 ±42 ±24 ± 17 14. The drug plasma A remarkable interindividual variability was levels appeared to decay monoexponentially however present considering both the 08.d. AMANTADINE AND DRUG-INDUCED PARKINSONISM 885 Rigidity Tremor 12 8 a) o CO 0) 9 6 c_ 12 1 2 3 Hypokinesia 4 5 6 7 8 9 10 11 12 13 14 15 6 4 2 24- -D . (Last administration at 08.d.ug/ml) of amantadine during the course of administration of amantadine (200 mg/day) orally at 08. .d. 9 10 11 12 13 14 15 . n. I 0 9 18- 6 12- 3 6- 1~~~.00 h on day 21) n. n.00 h) administration resulted in all cases in a fall of appeared to be relatively constant after 7 days of plasma levels and in complete disappearance of the treatment. 96 h after drug discontinuation.e.00 278 745 841 891 729 974 n.I 1 2 3 4 III11 li 5 6 7 8 9 10 11 12 13 14 15 L1 2 1 '2 4 6 8 9 1 1213 41 15 3 4 5 6 7 8 9 10 11 12 13 14 15 Patient number Figure 1 Effect of amantadine (200 mg/day) on clinical rating score before (open columns) and after (closed columns) 15 days of treatment. It can be seen that a noticeable Table 1 Mean (+ s. The mean basal morning values (08. . ±18 ± 43 ± 55 ±64 ± 69 ± 64 18.d.00 h to fifteen psychiatric patients Sampling Study days time (h) 7 11 14 17 20 21 22 23 24 25 08. Discontinuation of amantadine Table 2. .

Correlation coefficient subjects was present but did not reach significance. R.L.9 288 257 2 42 13656 0. o 14. mean) plasma levels on days 10-28.mean 18070 0.0350 19. VD = Apparent volume of distribution .0 407 203 14 59 26841 0. while no relationships apparent plasma clearance ranged from were evident between absorptive values (14. no dose dependent kinetics.0418 16.0535 12.0035 ±1. NARDINI.4 304 209 ±1598 ±0. Apparent plasma TjH (h) interindividual variability was present also for Figure 3 Relationships between apparent plasma plasma half-lives values which ranged from half-lives and mean (± s. MORSELLI cu C 1500 1 Eco 0 en ' co 1200 1000 C D CD 800 a :600 cu -Z 400 C 200 E5-> Q E 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 coC Patient number a)V' Figure 2 Individual plasma levels of amantadine on day 17.0675 10.00 h values.4 255 116 6 49 18710 0.4 358 363 8 62 17403 0.790 (P < 0.0408 17.0413 18. M.4 258 260 5 44 28750 0.8 328 191 9 51 13972 0. suggesting an clinical rating scores and amantadine plasma levels extensive tissue distribution of the drug.0 356 180 7 45 09174 0.0300 23.4 ±20 ±19 Evaluation of kinetic parameters was performed on decay plasma curve after discontinuation of 15 days treatment with amantadine (200 mg/day). * 08.e.1 309 161 4 44 12779 0.0609 11. FERRARI. C. P.5 402 238 10 40 20327 0. The considering the subjects individually.0272 25.886 G.0344 20.0303 23.00h.M.e. Means are calculated on 08. suggesting clearance values observed in volunteers.0 453 308 12 30 20539 0.3 217 244 3 47 20667 0. The mean plasma levels on day 14 and 17 correlated nicely (P < 0.0243 28.6 232 162 13 51 16345 0.5 285 115 15 33 28118 0. 14 and 17. VD Plasma clearance number (years) (ng mr' h) (If1') (h) (I) (ml/mini 1 38 12953 0. PACIFICI. However an Table 2 Pharmacokinetic parameters of amantadine in psychiatric patients Patient Age AUC Kel Plasma Ty.01). LATINI.5 hours.00 h plasma values. FIESCHI & P. (r) = 0.1 214 164 11 41 10810 0. Plasma Ty2 = Apparent plasma half-life.0355 19.00 h 115-363 ml/min.00 h and A trend towards a longer half-life in older 14.0460 15. and is of the same order of on day 17 and 21 ) and plasma half-lives.1 206 118 Mean ± s. The apparent VD calculated assuming complete bioavailability Relationships between plasma levels and effects (F = 100) was of the same order as that observed in volunteers and ranged between 206-453 litres No direct relationships could be observed between (mean value 304 ± 20 litres). AUC = area under the plasma concentration-time curve extrapolated to infinity Kel= Rate constant of elimination.0313 22.0605 11.01) with the apparent half-life values (Figure 3).

in observations. amantadine discontinuation. where the disappearance rate of in plasma levels is probably due to differences in amantadine was faster. intracellular fluids. showing an apparent plasma half-life of 13-19 h.686 evident relationship could be observed by plotting (P<0. a remarkable control and reduction of important variable could not be adequately the symptomatology.00 h plasma levels over the observation time (Figure 4). Unfortunately. the out-flow from tissues could . :5a Time (days) 10 Figure 4 Relationship between the mean (+ s. 0 a A . 98-99% of the dose can be recovered in urine within 80-120 h (Morselli et al. A significant relationship was present between cant relationship (P < 0. Tognoni & Morselli. and that the inverse holds true after first order kinetics. the mean of the rating scores and the mean of 08. Correlation coefficient (r) = 0. in good agreement with single dose (200-400 litres or 4-6 1/kg) (Morselli et preliminary observations run on four depressed al. tology in each individual patient (Figure 5). Amanta- and severe reappearance of extrapyramidal dine is virtually entirely excreted as such. and in symptomatology.= rating score. 1974). plasma levels... atric patients suffering from extrapyramidal unpublished results). over the observation % worsening of clinical rating score period. co 0 . there was a more evident absorption (Figure 2) and excretion rate. dependent kinetics. The large apparent Vd suggests that patients (Rizzo. . a signifi. Due indicating an apparent plasma half-life of to pH differences between plasma and extra and 10-28 hours. Biandrate. due to poor patient cooperation. c0 I. 0 a c -E CO) 0 Er E > I0 0) -C 0 co a) 0) -a 3 E) 0 -a co E E:cO . amantadine distributes not only to all the body 1973) and with the kinetic profile of the drug fluids but also accumulates in certain tissues. The computed apparent volume of with plasma levels ranging from 200-900 ng/ml.02). this most cases.e. AMANTADINE AND DRUG-INDUCED PARKINSONISM 887 U) . Figure 5 Relationship between the percentage worsening of clinical rating scores 48 h after the last administration of amantadine and log plasma levels at the same time. and there was no evidence of dose and the percentage worsening of the symptoma. __j mean) total clinical rating score and the mean (+ s.e. In The observed interindividual four-fold variation other words. 1974). distribution during chronic treatment was of the Steady state plasma levels were achieved within same order of that observed in volunteers after a 4-7 days of treatment. This effect was observed controlled.02) was observed between apparent plasma half-life and mean steady-state the plasma levels 48 h after drug discontinuation plasma levels. volunteers. Moreover. 250 500 mean) amantadine plasma levels. impact on amantadine plasma half-life (Latini. It can in fact be seen that a gradual increase of amantadine plasma levels mirrors After drug discontinuation plasma concen- the concomitant decrease in the mean trations decayed monoexponentially according to rating score. in the present symptoms due to neuroleptic drugs induced. In Discussion studies on volunteers we demonstrated that even small variations in urinary pH may have a definite Administration of amantadine to fifteen psychi.

K. NARDINI. 154-155.. (1970a). E. Dopamine and noradrenaline releasing action of aman. C.. 13. tend to suggest individual differences in the drug decay. Hamberger & the fact that a significant relationship was Ungerstedt. Comparison of HUNTER. M... ARMITAGE. The anti- (1972). & amantadine placebo. P. (1973) in depressed patients. nel volontario e nelle sindromi extrapiramidali da M. L. FIESCHI. FIESCHI. D. G. observed between the worsening of the clinical Papeschi. in analogy with the data obtained by after discontinuation of amantadine appears to us Maj et al.M. HK BARAN. Res. Brown & Redfern. TEDONE. 22.. Kelly & Abuzzahab (1971). A. NARDINI. & ABUZZAHAB.T. 552-558.M. M. Azione della amantadina nelle sindromi extrapira. parkinson properties of amantadine in drug-indiced mination of amantadine in human plasma. p.. (1974). FERRARI.L. HUNTER. P.R. P. 273-285. STERN. P.. F. E. A. ahromatogr.M. (1972). PEARCE. R. mine and noradrenaline receptors. & WATERBURY. FERRARI. NARDINI.L. chloride (Symmetrel). and Merrick & been recently given by Stone & Bailey (1975).-O. Neurology. neurolettici. LAURENCE. 211-214. tadine in the central and peripheral nervous system: a MERRICK. Neurology.D. & FIESCHI. 16. Ther. Amantadine may stimulate dopa- woche. amantadine antagonized lack of correlation between plasma levels and efficiently the extrapyramidal syndrome induced effects in a steady condition is not surprising since by neuroleptic medication. In Atti 1' Riunione Stato Attuale dell Lancet. different concentrations of neuroleptics. RIZZO. R. C. 27-38. M. M. Studio SistemaNervoso. (1974). Amantadine for Parkinson's disease. KNILL-JONES. U. FANALI. 15..D. Amantadine for SORGONA.R. Goldstein. P.E. 566. Sistema Nervoso.. picture and the actual plasma levels present 48 h However. (1970c). (1970). B. PAPESCHI. A controlled possible mode of action in Parkinson's disease. 24. (1974).. The Schmitt (1973).. C. Supportive evidence for such a mechanism has also (1971). A. BIANDRATE.Lancet.. M.. (1972).B..J. & UNGERSTEDT. midali da neurolettici. 22. (1970). ROBOTTI. (1970a). PACIFICI. R. K.C. 62. J. P. M. FIESCHI & P. & 77-83. & Bertolani. Parkinsonism. & REDFERN. & ROBOTTI. D. G. R. TOGNONI. 1974. M. P... unfortunately we could not determine. 40204023. sonism. D. 3282-3299. ZILKHA. NARDINI.P.H.R. M. Amantadine in Parkin..888 G. (1971). KELLY. i. 715-720.. Clin. study of the clinical effects of amantadine hydro- Pharnac. & Parkinson's disease. STERN.S. Besson & Glowinsky. FUXE. P. Scatton.. Lancet. MORSELLI. E. Parkinsonism with L-Dopa and amantadine. agreement with previous reports of Nardini et al. 21.E.E. Farmacocinetica deli'amantadina FIESCHI. M. J. P. (1972)... ii. 26. D. Combined treatment of disease. (1970b). FANALI. ii. Cheramy. & SCHMITT. J. PACIFICI.R. i. 13. Fuxe.. P. SOWINSKA. MANN. der Amantadintherapie bei Parkinsonismus. The exact chemical either suprathreshold concentrations could have nature of the mechanism by which amantadine been present.. (1973). F. (Berl. 296-307. M.. which 1970..E. M. 1970. rat brain. Amantadine . 31-34. G. WILLIAMS. The effect of of amantadine on motor activity and catalepsy in rats. N. GOLDSTEIN. PULLAR. Sowinska & Baran. In a direct activation of dopaminergic receptors. J.... and levodopa in Parkinson's ARMITAGE. LATINI. M. FRIGERIO. 1127-1129. E. (1970b). CASACCHIA. FERRARI.C. MAWDSLEY. NARDINI. Zweijahrige Erfahrungen mit da neurolettici.. M. E. F. Ther. eds Agnoli. CASACCHIA.R. & ROBOTTI. M. & SORGONA.. L.H. 11. 1971. FARNEBO. VERGNANO. Treat- HAMBERGER. K. G.L. 945-946. Terapia farmacologica della NARDINI. malattia di Parkinson con amantadina e levodopa. G.M. Svensson & Waldeck. M. 74.A. P... Cirr. L. accepting the hypothesis of a counteracts the extrapyramidal syndrome is still direct effect on dopaminergic receptors.T. & contro il morbo di Parkinson.P... REITANO. 958-962. BAXTER. Roma: Lega Italiana Lotta REITANO. CASACCHIA. C. Minerva Med. G. K. TEDONE. this effect unclear and various hypotheses have been could well have been differently antagonized by advanced so far (Str6mberg. 126-143. Pharmac. I. LATINI. MORSELLI also be another important variable determining et al.W.M. 24. SORGONA.. MAJ.. R. & KINLOCH. Eur.).. Neuropharmac. M. Pharm. 575-583. 1972.. 81P-82P. J. TEDONE. J. FIESCHI. Lancet. References BAUER. MARSDEN. 22. J. 1974). Therapie. (1971).. C. I. (1971). (1971). F. The effect BROWN. Farnebo... A. R. BELVEDERE. M. J. LAURENCE. clinico delramantadina nella sindrome extrapiramidale FUNFGELD. effetti. amantadine on the turnover of catecholamines in the Psychopharnacologia. C. L. conoscenze sulle Malattie Extrapiramidali. Correlazioni tra livelli plasmatici ed tadine versus L-Dopa and amantadine plus L-Dopa. Pharmac..L... C.. Pharmac. clin. Aman. However. ment of Parkinsonism by amantadine and levodopa. PARKES. & McHENRY.. NARDINI. Maj.A. A gas chromatographic method for the deter. (1974). F. 186. & MORSELLI.. (1972) the observations of Papeschi to be a further suggestion for a competitive (1974) in the experimental animals and of Rizzo antagonism at the receptor level.. DAVIDSON. or..

J. Increased synthesis and STROMBERG. B. (Received August 3. POSKANZER. Ass. R. 1130-1 133. (1970). (1975). release of dopamine in the striatum of the rat after (1970). Am. (1973). Ass. Pharmac. 959-961. Pharm. ENGLAND.126-129. Amantadine in the treatment of Parkinson's disease. Amantadine in depression: Am med.R.. AMANTADINE AND DRUG-INDUCED PARKINSONISM 889 dosage in treatment of Parkinson's disease. Amantadine in Oarkinson's RIZZO.S. SCHWAB.Jr. J. SVENSSON. CHERAMY. clin.. J.. M. GLOWINSKI. U. M. 85.W.C.. 1975) .. G. P. & WALDECK. Responses of levels. 222. J. E. 792-795. amantadine treatment. Lancet. (1972). P. Pharmac.V.C. J. BESSON. Eur. A. A. R.. 208. POSKANZER..R. & disease. On the mode of action of amantadine. R. & YOUNG. BIANDRATE. SCHWAB. J... R. MORSELLI. Brain Res. 22. D. Eur. 131-133. & YOUNG.C. TOGNONI. Pharmac.L. relationship between behavioural effects and plasma STONE.. B.. i. 226-228. 13. D. A. T.C. ENGLAND.S.H. J. & BAILEY. (1969).Jr.. med. & dopamine and amphetamine. 5. central neurones to amantadine: comparison with SCATTON. T. 1168-1170.. Review of more than two years' experience.