LEVODOPA AND RELIEF OF PARKINSONIAN SYMPTOMS
RICHARD P . S C H M I D T , M . D . M E L V I N GREER, M . D .
I t is n o t surprising that the discovery of L - D O P A (levodopa, L-3,4,
dihydroxyphenylalanine) as an effective a g e n t against the s y m p t o m s of
par-kinsonism has evoked such interest. A l t h o u g h t h e full range of its side effects
and t o x i c reactions will become k n o w n only after wider use, t h e r e is no
longer a n y serious doubt a s to its efficacy w h e n carefully and properly used.
M a n y patients w h o have been severely incapacitated in spite of surgical
pro-cedures and extensive medication have been able to return to meaningful
mobility, occupation and activities of living. I t is not, however, t h e final
a n s w e r or the cure. S o m e patients m a y be helped little, if a t all, and
others cannot tolerate the drug b e c a u s e of adverse reactions. E v e n in those
patients w h o are markedly or significantly helped, dosage regulation is a
con-tinued long t e r m problem requiring a close partnership w i t h a skilled and
knowledgeable physician.
I n this paper, some of the background and rationale of this n e w therapy
will be reviewed briefly and the results obtained thus far in the United
S t a t e s will be summarized from the reported series and from the patients
treated at the University of Florida under the supervision of one of us
(M.
G . ) .I n the central nervous s y s t e m m a n y substances are found w h i c h are
a s s u m e d to have roles in transmission or regulation of the nerve impulse.
F o r t h e most, the precise action of e a c h of these is unknown. T h e best
k n o w n a m o n g these is acetylcholine w h i c h s o m e consider to be uniquely
involved with transmission a t excitatory synapses. Others include g a m m a
amino butyric acid, histamine, serotonin, norepinephrine and dopamine.
Con-centration of these substances varies in different parts of the nervous s y s t e m .
Thus, norepinephrine is present in high concentration in those anatomic
structures related to autonomic function. T h e concentration of this c a t e
-cholamine in the hypothalamus is a t least ten times t h a t found in the
ce-rebral c o r t e x
1 5. A n o t h e r major catecholamine fraction is dopamine w h i c h is
found in high concentration in the corpus striatum. Concentration in the
c a u d a t e nucleus is more than 50 t i m e s t h a t of the cerebral c o r t e x
1 5. Although
its precise role as a neurotransmitter is unknown, it is logical to hypothesize
an important role in neuronal control of extrapyramidal m o t o r activity.
Deficiencies of dopamine in the corpus s t r i a t u m of patients w i t h
par-kinsonism w a s first noted in 1960
7>
1 2and subsequently a dopamine p a t h w a y
w a s demonstrated b e t w e e n the s u b s t a n t i a nigra and the corpus s t r i a t u m
by special histochemical technics
8. A l t h o u g h the basic pathodynamic process
remained unknown, this provided a potential link b e t w e e n t h e w e l l - k n o w n
degenerative c h a n g e s and depigmentation of the substantia nigra and the
altered physiology of t h e basal nuclei in parkinsonism.
Indirect studies of dopamine m e t a b o l i s m in parkinsonism gave conflicting
results. B a r b e a u and colleagues found reduction of dopamine excretion in
the urine of patients w i t h p a r k i n s o n i s m
2, w h e r e a s one of the authors (M. G.)
with Williams found no difference b e t w e e n patients w i t h parkinsonism and
control groups
1 X.
Early clinical trials of t r e a t m e n t w i t h dopamine or its precursors w e r e
largely disappointing and gave f e w indications of the beneficial effects later
n o t e d
9.
1 3. D o p a m i n e itself does not cross the blood-brain barrier b u t its
precursor, D O P A (3,4, dihydroxyphenylalanine) does. Cotzias and co-workers
6w e r e apparently t h e first to use the precursors of dopamine in sufficient
doses orally over a long enough t i m e to d e m o n s t r a t e the possible
practi-cality of clinical t r e a t m e n t . In the initial s t u d y
6t h e racemic form of D O P A
w a s associated with granulocytopenia in a disturbing proportion of patients.
Subsequently Cotzias et al. and others have used the levorotary isomer w h i c h
h a s not been associated with significant hematologic changes. L-3,4,
dihy-droxyphenylalanine (L-DOPA, levodopa) does cross the blood-brain barrier
and is decarboxlylated to dopamine by the e n z y m e dopa decarboxylase.
CLINICAL T R E A T M E N T W I T H L-DOPA
A t t h e t i m e of final r e v i e w of t h i s m a n u s c r i p t t h e a n n o u n c e m e n t w a s m a d e by t h e Food a n d D r u g A d m i n i s t r a t i o n of t h e U n i t e d S t a t e s of t h e a p p r o v a l of l e v o d o p a for m o r e g e n e r a l use. Prior to t h i s t i m e d i s t r i b u t i o n h a d b e e n limited in t h e U n i t e d S t a t e s to p h y s i c i a n s w i t h a p p r o v e d i n v e s t i g a t i o n a l protocols. E x p e -r i e n c e h a s t h u s been g a i n e d w i t h a l a -r g e n u m b e -r of p a t i e n t s a l t h o u g h m a n y of t h e series are y e t to be reported in t h e m e d i c a l l i t e r a t u r e . Cotzias and c o - w o r k e r s h a v e , perhaps, had t h e l o n g e s t e x p e r i e n c e b u t n o t t h e l a r g e s t n u m b e r of p a t i e n t s5
,6 . I n h i s W a r t e n b e r g l e c t u r e delivered before t h e A m e r i c a n A c a d e m y of N e u r o l o g y in May 1 9 7 04
, Cotzias reported u p o n 48 p a t i e n t s w i t h parkinsonism, 14 w i t h chronic m a n g a n e s e p o i s o n i n g and u p o n s e v e r a l dystonics. S u s t a i n e d t h e r a p e u t i c r e s u l t s w e r e e s s e n t i a l l y confined to t h o s e w i t h p a r k i n s o n i s m and t h o s e w i t h m a n g a n e s e poisoning. H e and h i s c o - w o r k e r s report f e w e r l i m i t i n g side e f f e c t s t h a n do others, p e r h a p s b e c a u s e of more g r a d u a l i n c r e a s e in d o s a g e . A m o n g t h e reports are t h o s e of Y a h r e t a l .J e
, Calne et a l .3
, G o d w i n - A u s t e n e t a l .1 0
and M c D o w e l l e t al. 1 4
. In o u r o w n i n s t i t u t i o n , e x p e r i e n c e w i t h l e v o d o p a b e g a n in J a n u a r y 1969 under t h e s u p e r v i s i o n of o n e of u s ( M . G . ) and t h u s f a r a p p r o x i m a t e l y 120 p a t i e n t s h a v e b e e n s t a r t e d on t r e a t m e n t . E x p e r i e n c e h a s been s i m i l a r to t h a t reported by others, b o t h a s to e f f i c a c y nd side e f f e c t s but is too e a r l y to r e a c h a d e f i n i t i v e s t a t e m e n t . A p p r o x i m a t e l y 40% of t h e p a t i e n t s h a v e had m o d e r a t e or m a r k e d i m p r o v e m e n t and 40% definite t h o u g h l i m i t e d a m e l i o r a t i o n of s y m p t o m s . I n t h e r e m a i n d e r , m i n i m a l or no i m p r o v e m e n t h a s b e e n n o t e d . Y a h r e t al. 1 6
Only 15 i m p r o v e d l e s s t h a n 25% and t h e r e w e r e b u t three w h o w o r s e n e d . For s c o r i n g a w e i g h t e d s c a l e w a s u s e d w h i c h included signs, s y m p t o m s and f u n c t i o n a l a c t i -v i t i e s .
Methods of administration — Our s c h e d u l e h a s c a l l e d for a n i n i t i a l dose of
l e v o d o p a of 250 m g . four t i m e s a day, i n c r e a s i n g in i n c r e m e n t s of 500 m g . e v e r y t w o or t h r e e d a y s to a m a x i m u m of e i g h t g r a m s daily. In m a n y , e a r l y side e f f e c t s l i m i t this to s m a l l e r a m o u n t s a n d s m a l l e r i n c r e m e n t s spread o v e r a l o n g e r period of t i m e . S y m p t o m s s u c h a s n a u s e a and v o m i t i n g , a g i t a t i o n , i n s o m n i a or c o n f u s i o n are f r e q u e n t l y l i m i t i n g in t e r m s of i n i t i a l d o s a g e s and of rapidity of i n c r e a s e . I n s u c h p a t i e n t s one m a y o b v i a t e or m i n i m i z e t h e difficulty by d e c r e a s i n g initial doses a s l o w as 50 to 100 m g . t h r e e t i m e s a d a y and s i m i l a r l y r e d u c e i n c r e m e n t s of increase. Cotzias and c o - w o r k e r s 4
,5
s t a r t w i t h m u c h l o w e r doses, i n c r e a s e m o r e g r a d u a l l y . It is, perhaps, for t h i s reason t h a t t h e y a p p e a r to h a v e less difficulty w i t h d o s e l i m i t i n g side e f f e c t s t h a n h a v e o t h e r s and h a v e been able to t r e a t s u c c e s s -fully s o m e p a t i e n t s w h o h a d u n s u c c e s s f u l l y used t h e d r u g before.
The t o t a l dose required or t o l e r a t e d v a r i e s from p a t i e n t to p a t i e n t a n d c a n n o t be predicted w i t h c e r t a i n t y . F u r t h e r m o r e d o s a g e is s u b j e c t to r e d u c t i o n or c h a n g e w i t h t h e p a s s a g e of t i m e b e c a u s e of induced t r a n s i t o r y d y s k i n e s i a s or o t h e r side effects. A r e d u c t i o n in dose r e q u i r e m e n t for s u s t a i n e d i m p r o v e m e n t h a s a l s o been noted. Thus, a p a t i e n t m a y r e a c h a t o t a l d o s a g e of s i x g r a m s a d a y for m a x i m u m relief w i t h i n t o l e r a n c e . A f t e r s e v e r a l m o n t h s b e c a u s e of l i m i t i n g s i d e - e f f e c t s s u c h a s d y s k i n e s i a t h i s m i g h t be reduced to t h r e e t o four g r a m s a d a y w i t h c o n t i n u e d relief to e x t e n t g r e a t e r t h a n t h a t n o t e d p r e v i o u s l y on t h e s a m e a m o u n t of drug. I n t h e U n i v e r s i t y of Florida series t h e r e h a s been a d i s a p p o i n t i n g r e g r e s s i o n in a p p r o x i m a t e l y h a l f of t h e p a t i e n t s w h o w e r e o v e r 70 y e a r s of a g e or w h o h a d v e r y s e v e r e disability. I n c r e a s i n g or r e d u c i n g d o s a g e h a s not been a s s o c i a t e d w i t h s i g n i -f i c a n t c h a n g e in t h e s e p a t i e n t s .
L e v o d o p a m a y be a s s o c i a t e d w i t h i m p r o v e m e n t of all of t h e m a n i f e s t a t i o n s of p a r k i n s o n i s m . I n i t i a l e f f e c t s appear to be principally a l e s s e n i n g of rigidity a n d a m e l i o r a t i o n of bradykinesia. P a t i e n t s a n d f a m l i e s report a n i n c r e a s e d mobility, c l e a r e r s p e e c h and a q u i c k e n i n g of m e n t a l processes. D e p r e s s i v e s y m p t o m s m a y be m a r k e d l y reduced. T r e a t m e n t h a s a p p e a r e d t o be m o r e e f f e c t i v e a g a i n s t bradyki-nesia a n d rigidity t h a n a g a i n s t tremor, per se.
Side effects — S i d e e f f e c t s m a y be dose l i m i t i n g and t h u s i n t e r f e r e w i t h e f f e c
-t i v e -therapy. U s i n g s m a l l e r ini-tial d o s e s and s m a l l e r i n c r e m e n -t s of i n c r e a s e m a y reduce t h e s e v e r i t y of t h o s e w h i c h l i m i t t r e a t m e n t . A m o n g t h e side e f f e c t s freq u e n t l y observed are n a u s e a or v o m i t i n g , a n o r e x i a , m e n t a l c h a n g e s i n c l u d i n g c o n -fusion and a g i t a t i o n , postural h y p o t e n s i o n , episodic h y p e r t e n s i o n , flushing, d y s k i n e s i a and cardiac a r r h y t h m i a s . Cotzias and c o l l e a g u e s1 6
h a v e n o t e d e p i s o d e s of i m m o -bility w h i c h m a y be corrected, in part, by r e d i s t r i b u t i o n of t i m e of a d m i n i s t r a t i o n . Such s y m p t o m s m a y be a s s o c i a t e d w i t h e a t i n g a h e a v y m e a l .
I n v o l u n t a r y m o v e m e n t s m a y a p p e a r a f t e r t h e p a t i e n t h a s b e e n u n d e r a s t a b l e d o s a g e for s e v e r a l m o n t h s . Most c o m m o n l y t h e s e a r e dyskinetic m o v e m e n t s a b o u t t h e m o u t h and are a n a l o g o u s to t h o s e o b s e r v e d w i t h p h e n o t h i a z i n e drugs. On only rare o c c a s i o n s are s e v e r e d y s k i n e s i a s s u c h a s o p i s t h o t o n i c s p a s m s or m y o c l o n i c j e r k s observed. T h e s e d y s k i n e s i a s are r e v e r s i b l e and m a y require r e d u c t i o n in d o s a g e . A t t i m e s , there m a y be a b a l a n c e b e t w e e n t h e s y m p t o m s of p a r k i n s o n i s m and d r u g - i n d u c e d i n v o l u n t a r y m o v e m e n t s , w i t h t h e f o r m e r b e i n g m o r e d i s a b l i n g t h a n t h e l a t t e r . T h e p a t i e n t m a y be u n a w a r e of t h e s e i n v o l u n t a r y m o v e m e n t s in spite of t h e f a c t t h a t t h e y are readily observed by o t h e r s .
P o s t u r a l h y p o t e n s i o n is u s u a l l y a s y m p t o m a t i c b u t o c c a s i o n a l l y l e a d s to f a i n t i n g or l i g h t - h e a d e d n e s s in t h e erect posture. Cardiac d i s t u r b a n c e s are u s u a l l y limited to v e n t r i c u l a r p r e m a t u r e c o n t r a c t i o n s but o n e p a t i e n t of M c D o w e l l et a l .1 4
e l e c t r o c a r d i o g r a p h i c e v i d e n c e of t r a n s i e n t s u b e n d o c a r d i a l i s c h e m i a w i t h p r e m a t u r e c o n t r a c t i o n s w h i l e r e c e i v i n g 2 . 0 g p e r d a y of l e v o d o p a . T h e r e w e r e n o o t h e r epi-sodes in spite of c o n t i n u e d t r e a t m e n t .
Serious t o x i c r e a c t i o n s h a v e b e e n f e w . I n t h e M c D o w e l l series t e n p a t i e n t s h a d e l e v a t i o n s of s e r u m g l u t a m i c - o x a l a c e t i c a n d g l u t a m i c - p y r u v i c t r a n s a m i n a s e l e v e l s . T h e s e r e t u r n e d to n o r m a l in spite of c o n t i n u e d t r e a t m e n t . Serious h e m a -t o l o g i c or r e n a l -t o x i c i -t y h a s no-t b e e n a problem.
D I S C U S S I O N
Experience thus far h a s largely confirmed the beneficial effects of t r e a t
-m e n t of parkinsonis-m w i t h dopa-mine precursors but the basic proble-m of
pathogenesis of the disease remains unsolved. Furthermore, evidence has
not y e t been forthcoming to indicate that the progressive course of t h e
disease process has been altered. T r e a t m e n t w i t h levodopa does offer
sustained and significant relief of s y m p t o m s for m a n y patients but often a t the
expense of a n n o y i n g side effects produced by the drug w h i c h may, a t times,
seriously limit effective therapy. I t is only in the exceptional patient, usually
w i t h relatively mild symptoms, t h a t amelioration is complete. I t is a s y e t too
early to assess l o n g - t e r m effects. W h a t w i l l be the f a t e of t h e s e patients
five or ten ears from n o w is not known. Also, w i t h expanded clinical
expe-rience obtained w i t h large numbers of patients throughout the world, other
t o x i c reactions m a y be observed. S u c h h a s been the case w i t h other drugs
w h i c h appeared "safe" on initial clinical trials.
On the m o r e encouraging side, t h e discovery of the beneficial effect of
levodopa m a y be looked upon as a first s t e p toward a more effective
treat-ment. A s an example, Cotzias and co-workers
4>
5have been investigating
the effects of a dopa decarboxylase inhibitor D - L alpha-me thy ldopa
hydra-zine (MK-485) w h i c h blocks the formation of dopamine from dopa. This
does not act w i t h i n the nervous s y s t e m because it does not cross t h e
blood-brain barrier. Therapeutic doses of levodopa thus m a y be greatly decreased
by effectively limiting the necessity of flooding all body tissue to obtain a
concentration in the nervous s y s t e m .
It should further be observed t h a t the use of dopa in therapy w a s not a
chance discovery but resulted u l t i m a t e l y from intelligent application of basic
scientific research on the nervous s y s t e m . Continuation of basic scientific
investigation of nervous s y s t e m function m a y lead to further information
w h i c h can be translated u l t i m a t e l y into practical clinical terms.
S U M M A R Y
R E F E R E N C E S
1 . A N D E N , N . E.; C A R L S S O N , A.; D A H L S T R O M , A.; F A X E , K.; H I L L A R P , N . A. & L A R S S O N , K. — D e m o n s t r a t i o n a n d m a p p i n g o u t of n i g r o n e o s t r i a t a l d o p a -m i n e n e u r o n s . L i f e Sci. 3 : 5 2 3 , 1964.
2 . B A R B E A U , A.; M U R P H Y , G. F . & S O U R K E S , T. L. — E x c r e t i o n of d o p a m i n e in d i s e a s e s of b a s a l g a n g l i a . S c i e n c e 133:1706, 1961.
3 . C A L N E , D . B.; S T E R N , G. M.; L A U R E N C E , D . R.; S H A R K E Y , J . & A R M I T A G E , P . — L - d o p a in p o s t e n c e p h a l i t i c p a r k i n s o n i s m . L a n c e t 1:744, 1969.
4 . C O T Z I A S , G. C. — W a r t e n b e r g L e c t u r e d e l i v e r e d a t 1970 a a n u a l m e e t i n g , A m e -r i c a n A c a d e m y of N e u -r o l o g y , M a y 1970.
5 . C O T Z I A S , G. C.; P A P A V A S I L I O U , P . S. & G E L L E N , R. — M o d i f i c a t i o n of p a r k i n s o n i s m - c h r o n i c t r e a t m e n t w i t h L - d o p a . N e w E n g . J . M e d . 280:237, 1969. 6 . C O T Z I A S , G. C.; V A N W O E R T , M. H . & S C H I F F E R , L. M. — A r o m a t i c a m i n o
a c i d s a n d m o d i f i c a t i o n of p a r k i n s o n i s m . N e w E n g . J. Med. 276:374, 1967. 7 . E H R I N G E R , H . & H O R N Y K I E W I C Z , O. — V e r t e i l u n g v o n N o r a d r e n a l i n u n d
D o p a m i n e ( 3 - H y d r o x y t y r a m i n e ) i m G e h i r n d e s M e n s c h e n u n d i h r V e r h a l t e n bei E r k r a n k u n g e n d e s E x t r a p y r i m i v a l i e n S y s t e m s . K l i n W s c h r 38:1236, 1960. 8 . F A L C K , B . — O b s e r v a t i o n s o n t h e p o s s i b i l i t i e s of t h e c e l l u l a r l o c a l i z a t i o n of m o n o a m i n e s by a f l u o r e s c e n c e m e t h o d . A c t a P h y s i o l . S c a n d . 56, S u p p l . 1 9 7 : 1 - 2 6 , 1962.
9 . F E H L I N G , C. — T r e a t m e n t of P a r k i n s o n ' s d i s e a s e w i t h L - d o p a . A d o u b l e b l i n d s t u d y . A c t a N e u r o l . S c a n d . 42:367, 1966.
1 0 . G O D W I N - A U S T E N , R. B.; T O M L I N S O N , E. B . ; F R E A R S , C. C. & K O K , H . W . — E f f e c t s of L - d o p a in P a r k i n s o n ' s d i s e a s e . L a n c e t 2 : 1 6 5 , 1969.
1 1 . G R E E R , M. & W I L L I A M S , C. M. — D o p a m i n e m e t a b o l i s m in P a r k i n s o n ' s d i s e a s e . N e u r o l o g y ( M i n n e a p o l i s ) 1 3 : 7 3 , 1963.
1 2 . H O R N Y K I E W I C Z , O. — D e r T o p i s c h e L o k a l i s a t i o n u n d d a s V e r h a l t e n v o n N o r a d r e n a l i n u n d D o p a m i n e ( 3 h y d r o x y t y r a m i n e ) in d e r s u b s t a n c i a n i g r o d e s n o r -m a l i n u n d P a r k i n s o n k r a n k e n M e n s c h e n . W i e n k l i n W s c h r . 7 5 : 3 0 9 , 1963. 1 3 . M c G E E R , P . L. & Z E L D O W I C Z , L . R. — A d m i n i s t r a t i o n of d i h y d r o x y p h e n y l a l a ¬
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