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Chapter 5. Antiparkinsonism Drugs
Chapter 5.
Antiparkinsonism Drugs
Vernon G. V e r n i e r E. I. du Pont de Nemours and Co., Wilmington, Delaware 19898 P h y s i c i a n s now c a n treat p a t i e n t s w i t h parkinsonism more e f f e c t i v e l y and d e f i n i t i v e l y . T h i s improvement of t h e r a p e u t i c o u t l o o k h a s followed a s p u r t of r e c e n t r e s e a r c h a c t i v i t y . T h i s r e s e a r c h and t h e drug developments stemming from i t are summarized h e r e . The medicinal chemist should c o n s u l t t h e r e c e n t review of Engelhardt and S t o n e l . Other reviews of p e r t i n e n t area stress t h e r a p e u t i c s (Klawans, I l a h i and Shenker2 ; Calne3), pharmacolo (Hornykiewicz4), physiology (Shute and Lewis5,6) and anatomy (Carman ).
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Levodopa T h i s n a t u r a l l y - o c c u r r i n g amino a c i d (I, L-3,4-dihydroxyphenyla l a n i n e ) was f i r s t used t o t r e a t p a r k i n s o n i a n p a t i e n t s i n 1961. Morgan H O - @ X ~ - T H -COOH HO
MI2
I
Hd
I1
and Bianchine8 and Barbeau9 have w e l l suuunarized t h e medical use and h i s t o r y of levodopa. A more d e t a i l e d monograph w i t h e x t e n s i v e documentat i o n h a s r e c e n t l y appeared100 The background and t h e o r e t i c a l b a s i s of levodopa t h e r a p y c a n be summar i z e d thus :
1.
P a r k i n s o n i a n p a t i e n t s b r a i n s show c y t o l o g i c a l d e t e r i o r a t i o n , p r i n c i p a l l y b u t n o t e x c l u s i v e l y in midbrain and b a s a l g a n g l i a .
2.
P a r k i n s o n i a n p a t i e n t s ' b r a i n s show a d e f i c i e n c y of dopamine (11) i n t h e s u b s t a n t i a n i g r a of t h e midb r a i n and i n t h e corpus s t r i a t u m ( c a u d a t e n u c l e u s and putamen) i n the b a s a l g a n g l i a of t h e f o r e b r a i n .
3.
The d e p l e t i o n of dopamine i s presumably due t o d e g e n e r a t i o n of f i b e r s of t h e n i g r o s t r i a t a l t r a c t .
4.
Dopamine may a c t as a s p e c i f i c t r a n s m i t t e r a t c e r t a i n "dopaminergic" synapses.
5.
Dopamine cannot c r o s s t h e b l o o d - b r a i n b a r r i e r , b u t i t s immediate biochemical p r e c u r s o r levodopa does s o r e a d i l y and could r e s t o r e f u n c t i o n by r e p l e n i s h i n g dopamine.
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Although the r e s u l t s of e a r l y trials were c o n f l i c t i n g , probabl
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t o the use of low doses and b r i e f treealtment periods, Cotzias e t a l . 111,12 convincingly established the e t r i k l n g e f ficecy, of a degree exceeding t h a t o f a l l previous medications, when high sustained doses oE levodopa were administered. Many others subsequently confinned t h i s finding. I n over 3,000 p a t i e n t s the success rate has been between 70 and 80%.
Levodopa favorably a l t e r e d nearly a l l symptoms of Parkinson's disease, though not equally. R i g i d i t y and hypokinesia have responded w e l l and e a r l y . Tremor responded i r r e g u l a r l y and later. Many o t h e r symptoms were p a r t i a l l y or completely reversed by levodopa, including impaired posture, l o s s of associated movements, increased sebum secretion, impaired speech and sialorrhea. Levodopa induced g r e a t e r o v e r a l l improvement i n modera t e l y t o severely a f f e c t e d p a t i e n t s than d i d a n t i c h o l l n e r g i c drugs. Most observers noted no loss of levodopa e f f i c a c y wlth time i n c o n t r a s t t o previously e f f e c t f v e drugs. Levodopa is superior t o surgery, which is plagued by i r r e g u l a r response, s e r i o u s hazards and recurrence of symptoms. Levodopa works b e s t i n p a t i e n t s with mild disease of s h o r t duration but i t also helps p a t i e n t s with severe longterm disease. While i t helps a l l forms of the disease, postencephalitic cases are very s e n s i t i v e t o both the therapeutic e f f e c t s and the s i d e e f f e c t s . Levodopa treatment must always be s t a r t e d with low doses (300 t o 500 rng per day) and the dose must be slowly and c a r e f u l l y increased up to the point of optimal e f f i c a c y or l i m i t i n g s i d e e f f e c t s (usually 2.5 t o 6 g per day, although a few p a t i e n t s may r e c e i v e t h e maximal recommended dose of 8 g ) . S k i l l and diligence in management of dosage, symptoms and s i d e e f f e c t s is e s s e n t i a l t o e f f e c t i v e therapy with t h i s drug, s i n c e t h e r e are d a i l y and within -day v a r i a t i o n s in e f f e c t , which are r e l a t e d to the s h o r t h a l f - l i f e and t o i n t e r a c t i o n s with d i e t a r y amino a c i d intake (mainly phenylalanine) which cause r e f r a c t o r y periods of rapfd onset and v a r i a b l e length. S i d e e f f e c t s are numerous and troublesome occurring i n nearly 100% of p a t i e n t s , bur a r e not generally serious. They have caused termination of drug i n about 5% of cases. They involve nearly a l l organ systems but the most important are 1) nausea, vomiting and anorexia, 2) cardiac dysrhythmias, 3) hypotension, 4) abnormal involuntary movements, and 5) behavioral and personality changest
Nausea, o f t e n accompanied by vomiting, i s seen a t some stage of therapy i n all patients. Loss o f a p p e t i t e may occur with o r without these signs. G a s r t o - i n t e s t i n a l signa, d e s p i t e t h e i r frequency, a r e r a r e l y doselimiting. Co-administration of food may c o n t r o l nauseal Phenothiazine anti-emetics and pyridoxine may block or reduce levodopa e f f i c a c y and should not be used for c o n t r o l of nausea o r emesis.
The commonest cardiac problems with levodopa therapy a r e sinus tachyc a r d i a and premature v e n t r i c u l a r contractions, with r a r e instances of a t r i a l f i b r i l l a t i o n . Cardiac deaths with v e n t r i c u l a r tachycardia and f i b r i l l a t i o n have been reported but drug causation is unclear. The cardiac s i d e e f f e c t s of levodopa can b e a serious t h r e a t p a r t i c u l a r l y t o p a t i e n t s
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CNSAgents
E n g e l h a r d t , Ed.
w i t h coronary a r t e r y d i s e a s e . Levodopa t h e r a p y i n t h e s e p a t i e n t s should be i n s t i t u t e d c a u t i o u s l y i n t h e h o s p i t a l w i t h access t o monitoring and c o n t r o l equipment. Levodopa c a r d i a c r e s p o n s e s are mediated by conversion t o dopamine, which a c t i v a t e s B-adrenergic r e c e p t o r s . A f3-adrenergic blocking a g e n t such as p r o p r a n o l o l would be l o g i c a l t h e r a p y f o r c a r d i a c problems when they occur. P a t i e n t s w i t h P a r k i n s o n ' s d i s e a s e have a lower blood p r e s s u r e t h a n age- and sex-matched c o n t r o l s and o f t e n show o r t h o s t a t i c hypotension. Contrary t o e x p e c t a t i o n s , levodopa produces i n c r e a s e d o r t h o s t a t i c hypotens i o n which may become c l i n i c a l l y important. The i n c i d e n c e i s probably h i g h e r t h a n t h e 25 t o 35% r e p o r t e d s i n c e one c a r e f u l s t u d y of blood p r e s s u r e showed 75% of p a t i e n t s w i t h a d e c r e a s e of g r e a t e r t h a n 10 nun Hg i n blood p r e s s u r e on s t a n d i n g . D i z z i n e s s , v e r t i g o and syncope are unconnnon. They occur e a r l y , can g e n e r a l l y be c o n t r o l l e d , and d i s a p p e a r l a t e r w i t h the development of t o l e r a n c e . The mechanism of t h e o r t h o s t a t i c hypotens i o n due t o a d m i n i s t r a t i o n of a p r e s s o r m i n e p r e c u r s o r i s n o t c l e a r and i t s occurrence i s s u r p r i s i n g . Abnormal i n v o l u n t a r y movements f r e q u e n t l y accompany o p t i m a l improvement w i t h levodopa. The d u r a t i o n and the dose are r e l a t e d t o t h e occurrence of t h e s e movements s o t h a t up t o 73% of p a t i e n t s have them a f t e r 1 2 months of t r e a t m e n t . A b n o r m a l i t i e s are seen e a r l i e s t i n t h e head and mouth, then later i n t h e limbs and t r u n k , sometimes becoming v i o l e n t and severe. Usually they c a n be r e v e r s e d by lowering t h e levodopa dose o r by adding o t h e r drugs ( p h e n o t h i a z i n e s , h a l o p e r i d o l o r p y r i d o x i n e ) b u t w i t h both approaches some t h e r a p e u t i c b e n e f i t i s o f t e n l o s t . The p a r k i n s o n i a n p o p u l a t i o n , g e n e r a l l y aged, h a s a s i g n i f i c a n t i n c i dence of impairment of mental f u n c t i o n (memory , judgment, dementia and s o c i a l a d a p t a t i o n ) . Levodopa t r e a t m e n t i s accompanied by b e h a v i o r a l and p e r s o n a l i t y changes i n some p a t i e n t s . The c e n t r a l s t i m u l a n t e f f e c t seen e a r l y i n therapy may be r e l a t e d t o a t o x i c d e l i r i u m which levodopa can cause. The more f l o r i d cases show paranoid i d e a s , d e l u s i o n s , h a l l u c i n a t i o n s and l o s s of judgment, b u t f r e q u e n t l y a m i l d e r p i c t u r e i s s e e n w i t h less d i s r u p t i v e s t i m u l a n t e f f e c t and nervousness, a n x i e t y and s l e e p l e s s n e s s (sometimes w i t h v i v i d dreams) p l u s some autonomic s i g n s . R a r e l y s e d a t i o n , m a l a i s e , and emotional d e p r e s s i o n t o t h e p o i n t of s u i c i d a l i d e a s a r e noted, b u t drug c a u s a t i o n i s u n c l e a r . Levodopa h a s been p u b l i c i z e d a s a n a p h r o d i s i a c , b u t t h i s may be mainly t h e t a l k of t o x i c d e l i r i u m p a t i e n t s ; however t h e r e m i t t e d i l l n e s s of a p r e v i o u s l y i n c a p a c i t a t e d v i c t i m may perm i t t h e a p p r o p r i a t e renewal of s e x u a l performance. There i s n o t f i r m evidence t h a t i t h a s f u l f i l l e d t h e a n c i e n t concept of a s p e c i f i c aphrodisiac. Many o t h e r i n f r e q u e n t symptoms and abnormal l a b o r a t o r y f i n d i n g s have been a s s o c i a t e d w i t h levodopa t r e a t m e n t . M e t a b o l i t e s c a u s e the u r i n e t o t u r n r e d d i s h and t h e n black. Many drug i n t e r a c t i o n s a r e p o s s i b l e ; few a r e conf inned, b u t t h i s p o s s i b i l i t y should be watched. Some monoamine oxidase i n h i b i t o r s r e p o r t e d e f f e c t i v e i n P a r k i n s o n ' s disease caused h y p e r t e n s i v e r e a c t i o n s i n combination w i t h levodopa, b u t t r i c y c l i c an t i d e p r e s s a n t s
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(imipramine and a m i t r i p t y l i n e ) also e f f e c t i v e i n parkinsonism, have been used with levodopa without s e r i o u s s i d e e f f e c t s . Levodopa was approved by F M i n June 1970 f o r marketing i n the t r e a t ment of Parkinson's disease. Drug c o s t s were r e l a t i v e l y high but a r e d e c l i n i n g and drug a v a i l a b i l i t y is increasing. It i s not known whether levodopa alters the steady progression of Parkinson's disease, s i n c e few p a t i e n t s have been observed longer than 3 years. Generally i t i s s t a t e d t h a t no f u r t h e r d e t e r i o r a t i o n has been observed i n successfully-treated p a t i e n t s .
Other medical uses f o r levodopa include success i n t r e a t i n g the akinetic-dystonic syndrome of manganese poisoning i n miners. Other neurol o g i c a l and p s y c h i a t r i c i n d i c a t i o n s are not y e t established. Levodopa has yielded c o n f l i c t i n g r e s u l t s i n dystonia musculorum deformans, Wilson's disease, Huntington's chorea, and progressive supranuclear palsy. Reports of l i m i t e d t r i a l s of levadopa f o r the possible treatment of d e p r e s s i o P l 6 have appeared, but they are d i f f i c u l t t o i n t e r p r e t . Studies t o resolve the i s s u e are i n progress.
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Decarboxylase I n h i b i t o r s A t least two agents designed t o decrease the p e r i p h e r a l enzymatic i n a c t i v a t i o n of levodopa have been t r i e d . Both Ro 4-4602 (111) and MK 485 (N)have been reported t o lower the optimal
111 IV levodopa dose t o o n e - f i f t h t o one-eighth. It i s not y e t c l e a r t h a t any therapeutic advantage is achieved i n e f f i c a c y or g r e a t e r s i d e e f f e c t margin beyond the decrease i n the levodopa dose requiredl7-21. Abnormal involuntary movements are s t i l l seen a t the lower dosage. More informat i o n is required t o say whether or not t h i s combination therapy with levodopa w i l l be useful. Apomorphine - This morphine d e r i v a t i v e (V, common s t r u c t u r a l elements with dopamine, 11, indicated) has r e c e n t l y assumed considerable t h e o r e t i c a l and possible p r a c t i c a l importance i n understanding the pharmacological r o l e of levodopa and dopamine i n the therapy of parkinsonism. SchwabZ2 reported t h a t i t r e l i e v e d tremor i n p a t i e n t s but was of too s h o r t duration f o r useful therapy and was only e f f e c t i v e p a r e n t e r a l l y . Then, Vernier23j24 found t h a t apomorphine s t r i k i n g l y reduced the tremor of monkeys with midbrain l e s i o n s made by the technique of Ward25 Pe terson26 and of Carpenter27. P o i r i e r e 8 and - v GoldsteinZg have used these methods t o study b r a i n catecholamine changes and t o study these
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and o t h e r drug e f f e c t s . More r e c e n t l y C o t ~ i a hs a~s ~confirmed Schwab' s f i n d i n g i n man. The work of s e v e r a l groups h a s now converged t o i n d i c a t e t h a t apomorphine a c t s upon many p h y s i o l o g i c a l systems and v a s c u l a r beds t o c a u s e e f f e c t s s i m i l a r t o t h o s e o f levodopa o r d 0 p a m i n e 3 1 , ~ ~ .Thus apomorphine probably d i r e c t l y a c t i v a t e s "dopaminer i c " r e c e p t o r s and i t s mode of a c t i o n i n parkinsonism i s c l e a r e r . Sourkes 33 h a s s u g g e s t e d t h a t levodopa o r dopamine may a c t p a r t i a l l y through m e t a b o l i c c o n v e r s i o n t o aporp h i n e s resembling apomorphine. Amantadine - Amantadine h y d r o c h l o r i d e (VI) was i n t r o d u c e d i n 1967 a s an a n t i v i r a l a g e n t f o r i n f l ~ e n z a ~ ~ I~n ~1968 5 . Schwab e t al.36 noted t h a t amantadine caused r e m i s s i o n of p a r k i n s o n i a n symptoms i n a p a t i e n t t r e a t e d p r o p h y l a c t i c a l l y .Hcl d u r i n g a n i n f l u e n z a epidemic and they subseq u e n t l y s t u d i e d t h e e f f e c t i n 163 p a t i e n t s . S i n c e then more than 80 r e l e v a n t papers have appeared of which more t h a n 30 a r e r e p o r t s of c l i n i c a l s t u d i e s . They i n c l u d e over 1,000 VI p a t i e n t s w i t h over 300 from c o n t r o l l e d t r i a l s (e.ga37,38,39). Most a u t h o r s concluded t h a t arnantadine shows some degree of a n t i p a r k i n s o n i a n a c t i v i t y ( e . g . 4 O ~ 4 ~ , 4 ~ ) . The o n s e t of e f f e c t i s g e n e r a l l y r a p i d , 24 t o 48 h o u r s , compared w i t h w e e k s or months w i t h levodopa. The c l i n i c a l r e p o r t s s u g g e s t t h a t t h e amantadine degree of a c t i v i t y i s a t least as g r e a t and perhaps g r e a t e r t h a n t h a t of t h e s t a n d a r d a n t i p a r k i n s o n i a n d r u g s , p r i n c i p a l l y a n t i c h o l i n e r g i c s , b u t n o t a s g r e a t as t h a t of levodopa. Dose r e s p o n s e r e l a t i o n s h i p s f o r t h e a c t i v i t y of amantadine i n d i c a t e t h a t doses of 200 t o 300 mg d a i l y a r e o p t i m a l f o r most p a t i e n t s 4 3 . Schwab36 n o t e d some d e c r e a s e d e f f e c t a f t e r prolonged t r e a t m e n t .
a
Amantadine has been s u c c e s s f u l l y a d m i n i s t e r e d c o n c u r r e n t l y w i t h o t h e r drugs, i n c l u d i n g levodopa whose e f f i c a c y i t t e n d s t o p r e d i c t 3 6 . Arnantadine i s g e n e r a l l y w e l l t o l e r a t e d i n most p a t i e n t s 4 4 ~ 4 5and c a u s e s fewer s i d e e f f e c t s t h a n levodopa o r a n t i c h o l i n e r g i c s . Some r e p o r t e d s i d e e f f e c t s may be due t o c o n c u r r e n t a n t i c h o l i n e r g i c medication o r t o amantadine i n t e n s i f i c a t i o n of t h e i r e f f e c t s , b u t t h i s i s n o t y e t c l e a r l y e s t a b l i s h e d . Livedo r e t i c u l a r i s h a s been r e p o r t e d 4 6 . V e r n i e r e t a l . 4 7 concluded t h a t amantadine was a d e q u a t e l y t o l e r a t e d on long term c h r o n i c a d m i n i s t r a t i o n t o r a t s , dogs and monkeys a t d o s e s more t h a n 13 t o 33 times t h e u s u a l human d o s e s w i t h no e v i d e n c e of organ pathology. These t o x i c o l o g i c a l s t u d i e s showed some c e n t r a l nervous system s t i m u l a t i o n , a n o r e x i a , r a r e emesis and some c o n v u l s i o n s a t h i g h doses. Amantadine caused s e v e r a l e f f e c t s a t h i g h d o s e s , i n d i c a t i v e of c e n t r a l nervous system s t i m u l a t i o n o r catecholamine i n t e r a c t i o n i n c l u d i n g : i n c r e a s e d spontaneous motor a c t i v i t y , antagonism of t e t r a b e n a z i n e - i n d u c e d s e d a t i o n , a m i l d , t r a n s i e n t v a s o d e p r e s s o r e f f e c t , some c a r d i a c arrhythmias, and some b l o c k of uptake of n o r e p i n e p h r i n e i n t o l a b i l e s t o r e s ( p o t e n t i a t i o n of n o r e p i n e p h r i n e v a s o p r e s s o r e f f e c t , b l o c k of phenethylamine vasop r e s s o r r e s p o n s e , i n c r e a s e of myocardial c o n t r a c t i l e f o r c e , r a d i o a c t i v e
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norepinephrine d i s t r i b u t i o n s t u d i e s , and antagonism of tetrabenazine effects). The possible modes of a c t i o n of amantadine and other drugs i n parkinsonism a r e summarized i n Table 1. Amantadine does not a c t l i k e the c e n t r a l l y - a c t i n g anticholinergics48,49. I n three animal preparations amantadine f a i l e d t o cause a n t i c h o l i n e r g i c e f f e c t s (guinea pig ileum, acetylcholine-induced depressor e f f e c t s i n dogs, oxotremorine tremor i n mice). Amantadine i n t e r a c t s with catecholamines i n the c e n t r a l nervous s y s tem and i n the periphery. This might be predicted from i t s primary amine s t r u c t u r e . How can these i n t e r a c t i o n s c o n t r i b u t e t o i t s e f f e c t i n parkinsonism? Table 1 l i s t s f i v e mechanisms by which amantadine and other drugs could counteract the d e f i c i t of extrapyramidal i n h i b i t i o n which is respons i b l e f o r symptoms of parkinsonism. Recent evidence points t o a l o c a l r e l e a s e of catecholamines as the major mode of a c t i o n of amantadine i n parkinsonism. This i s the most s e n s i t i v e e f f e c t of amantadine reported t o date and occurs a t the lowest dose. Althou h e a r l i e r c l u e s pointed t o t h i s action, the r e s u l t s of Grelak e t a1.88 c l a r i f i e d t h i s point. They reported t h a t a small trans i e n t pressor e f f e c t of amantadine alone, intravenously i n dogs, was markedly i n t e n s i f i e d b dopamine-priming. This suggested t h a t amantadine released dopamine and& other catecholamines from neuronal s t o r e s t o cause the p e r i p h e r a l pressor a c t i o n . The e f f e c t was noted a t very low amantadine doses. There was no evidence f o r block of dopamine uptake. E a r l i e r Vernier47 reported t h a t t r a n s i e n t increases i n myocardial cont r a c t i l e force occurred following moderate intravenous doses of amantadine. These a l s o suggested l o c a l catecholamine r e l e a s e , since they were abolished by r e s e r p i n i z a t i o n and r e s t o r e d by norepinephrine infusion. Recently several l a b o r a t o r i e s have reported evidence f o r amantadineinduced release of r a d i o l a b e l l e d catecholamine (mainly dopamine) from r a t brain50?51,52. This seems t o confirm in the c e n t r a l nefvous system what was seen i n the periphery. Although t h i s may be the most l i k e l y major mode of a c t i o n of amantadine i n parkinsonism, the q u a n t i t a t i v e r e l a t i o n s between t h i s and o t h e r biochemical actions upon catecholamines remain t o be worked out. It i s i n t e r e s t i n g t o note t h a t several authors have shown t h a t levodopa may release amines i n the brain, s p e c i f i c a l l y serotonin, which may imply t h a t i t shares a somewhat similar a c t i o n with a1naneadine5~,54.
Recent biochemical findings suggest t h a t under some conditions amantadine may i n c r e a s e dopamine accumulation in brain. Thus Scatton50 concluded t h a t amantadfne may s t i m u l a t e dopamine s y n t h e s i s and Stromberg5l has reported compatible data. It: i s too early t o assess the relevance of t h i s finding t o the clinical efficacy of amantadine Does amantadine block the reuptake of catecholamines and i s t h i s
48 -
Sect, I
-
CNS Agents
Engelhardt, Ed.
e f f e c t r e l a t e d t o i t s a n t i p a r k i n s o n a c t i o n ? S e v e r a l groups have s t u d i e d the e f f e c t of amantadine upon catecholamine uptake s i n c e Vernier47 r e p o r t e d d a t a compatible w i t h r e u p t a k e blockade. At doses 5-10 t i m e s t h e human t h e r a p e u t i c dose amantadine antagonized t e trabenazine-induced sedat i o n i n mice. It a l s o p o t e n t i a t e d norepinephrine-induced p r e s s o r response i n dogs, blocked pehenethylamine-induced p r e s s o r response i n dogs, and blocked t h e uptake of r a d i o l a b e l l e d n o r e p i n e p h r i n e by mouse h e a r t . I n c o n t r a s t Grelak48 r e p o r t e d no clear i n d i c a t i o n of amantadine p o t e n t i a t i n g dopamine i n t h e i r r e l e a s e experiments. I t i s n o t y e t c l e a r whether amantadine b l o c k s uptake of dopamine ( o r o t h e r catecholamines) i n b r a i n t o prolong t h e u s e f u l presence of t r a n s m i t t e r . While uptake b l o c k of dopamine and n o r e p i n e p h r i n e h a s been r e p o r t e d a t h i g h amantadine d o s e s , i t probably does n o t p l a y a major r o l e and the evidence of several groups i s a g a i n s t i t s o - 5 5 . The q u a n t i t a t i v e and q u a l i t a t i v e r e l a t i o n s must be worked o u t b e f o r e t h e r o l e of reuptake block of catecholamines can be a s s e s s e d . Snyder57 suggested t h a t c a t e cholamine uptake blockade (mainly b l o c k of dopamine u p t a k e by striatum) may c o n t r i b u t e t o t h e mode of a c t i o n of a n t i c h o l i n e r g i c s and a n t i h i s t amines i n a n t i p a r k i n s o n i a n therapy.
Since amantadine g e n e r a l l y l a c k s t h e prominent g a s t r o i n t e s t i n a l symptoms (nausea and emesis) shared by apomorphine and levodopa i t i s n o t l i k e l y t h a t i t stimulates dopamine r e c e p t o r s d i r e c t l y . Z e t l e d g and Simon, Malatray and B o i s s i e r 5 6 have r e p o r t e d amantadine antagonism t o phenothiazine-induced and o t h e r drug-induced c a t a l e p s y . They s u g g e s t t h a t amantadine may be e f f e c t i v e i n drug-induced parkinsonism o r o t h e r e x t r a p y r a m i d a l d i s o r d e r s i n man. References
1.
E . L. Engelhardt and C . A . Stone, i n Medicinal Chemistry, 3rd E d i t i o n , A . Burger, Ed., Chapter 59, John Wiley and Sons, New York (1970). 2. H a Klawans, M. M. I l a h i and D. Shenker, Acta Neurol. Scand., 46, 409441 (1970). 3 . D. Be Calne, C l i n . Pharm. Ther., ll, 789-801 (1970). 4 . 0 Efornyklewicz Pharmacol Rev., l8, 925- 964 (1966) 5 . C - C. D o Shute and P. R. Lewis, Nature, 212, 710-711 (1966). 6. C . C. D o Shute and P. R. Lewis, B r i t . Med. Bull., 22, 212-226 (1966). 7. J. B. Carman, New Eng. J. Med., 279, 919-930 (1968). 8. J * P O Morgan and J. R. Bianchine, R a t i o n a l Drug Therapy (formerly Pharmacology f o r P h y s i c i a n s ) , 5, 1-8 (January 1971). 9 . A . Barbeau, Canad. Med. Assoc. J., 101, 791-800 (1969). 10. A . Barbeau and F. H. McDaJe11, L-Dopa and Parkinsonism, F. A . Davis Company, P h i l a d e l p h i a , Pennsylvania (1970) 11. G. C. C o t z i a s , M. H. Van Woert and L. M. S c h i f f e r , New Eng. J. Med., 276, 374-379 (1967). 12 G. C . C o t z i a s , P. S. P a p a v a s i l i o u and R. G e l l e n e , New Eng. J . Med., 280, 337-345 (1969). 13. 5 7 . S c h i l d k r a u t , G. L. Klerman, D. G. F r i e n d and M. G r e e n b l a t t ,
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Antiparkinsonism D r u g s
Chap. 5
Vernier
49 -
Ann. N.Y. Acad. Sci., 107, 1005 (1963). G. L. Rlerman, J. J. S c h i l d k r a u t and L. L. Hasenbush, J. P s y c h i a t . Res ,.l 289 (1963). 15 D. G. F r i e n d , W. R. B e l l and N. S. Kline, C l i n . Pharm. Ther., 5, 362 (1965) 16 W. E. Bunney, B. S. J a n m s k y , F. K. Goodwin, J. M. Davis, H. K. H. Brodie, D. L. Murphy and T. N. Chase, Lancet, 1, 885 (1969). 1 7 . W. Birkmayer and M. Mentasti, Arch. P s y c h i a t . Nervenkr., 210, 29 (1967). 18 R . T i s s o t , J.-M. G a i l l a r d , M. Guggisberg, G. G a u t h i e r and J. deAjuriaguerra, P r e s s e Med., 77, 619 (1969). 19. J. S i e g f r i e d , F o u r t h I n t e r n . Congress of N e u r o b i o l o g i c a l Surgery, and t h e Ninth I n t e r n . Congress of Neurology, New York, September 1969, Brcerpta-Medica I n t e r n . Congress S e r i e s #193, Amsterdam, 1969, p. 17 1 ( A b s t r a c t ) 20. A. Barbeau and L. G i l l o - J o f f r o y , Fourth I n t e r n . Congress of Neurob i o l o g i c a l Surgery, and t h e Ninth I n t e r n . Congress of Neurology, New York, September 1969, Excerpta-Medica I n t e r n . Congress S e r i e s #193, Amsterdam, 1969, p. 171 ( A b s t r a c t ) . 21. G. C = C o t z i a s and P. S . P a p a v a s i l i o u , Second I n t e r n . Congress of Neuro-Genetics and Neuro-Ophthalmology of t h e World F e d e r a t i o n of Neurology, Montreal, September 1967 Excerpta Medica I n t e r n . Cong r e s s Series #154, Amsterdam, 1967, p. 30 ( A b s t r a c t ) . 22. R e S. Schwab, L- V. Amador and J e Y. L e t t v i n , Trans. Amer. Neurol. ASSOC., 76, 251-253 (1951). 23 V. G. V e r n i e r and K. R. Unna, J. Pharmacol. and Exp. Ther., 103, 365 (195 1) 24 V. G. V e r n i e r and K. R. Unna, Ann. N.Y. Acad. Sci., 64, 690-704 (1956). 25 A - A. Ward, Jr., He W. Magoun and W. S. McCulloch, J. Neurophysiol., 11, 317 (1948) 26 E. W O P e t e r s o n , H. W. Magoun, W e S. McCulloch and D. B. Lindsley, J. Neurophyaiol. l2, 37 (1949) 27 M. B. Carpenter, J. R. Whittier and F. A. Mettler, J. Comp. Neurol., 93, 1 (1950). 28 L T J . P o i r i e r and T. L. Sourkes, Brain, 88, 181 (1965). 29 M. G o l d s t e i n , A. F. Battista, S. Nakatani and B. Anagnoste, i n L-Dopa and Parkinsonism, A. Barbeau and F. H. McDowell, Eds., F. A. Davis Company, P h i l a d e l p h i a , Pennsylvania (1970). 30 G O C . C o t z i a s , P. S. P a p a v a s i l i o u , C. Fehling, B. Kaufman and I. Mena, New Eng. J. Med., 282, 31-33 (1970). 31. A. M e E r n s t , Psychopharmacologia, 391-399 (1965). 32 L. I. Goldberg, P. F. S o n n e v i l l e and J. L. McNay, J. Pharmacol. Exp. Ther., 163, 188-197 (1968). 33. T. L. Sourkes, Nature, 229, 413-414 (1971). 34 W. L a Davies, R. R e Grunert, R. F. Haff, J. W. McGahen, E. M. Neumayer, M. Paulshock, J. C. Watts, T. R. Wood, E. C. Hermann and G . E. Hoffmann, Science, 862-863 (1964). 35. W e L O Wingfield, D = P o l l a c k and R. R. Grunert, New Eng. J. Med., 281, 579-584 (1969) 36 R e S o Schwab, A. C. England, Jr., D. C. Poskanzer and R. R. Young, JAM, 208, 1168-1170 (1969). 14
.,
.
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,
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z,
0
144,
Sect. I
50
_.
37
0
38 39 40 41 42 43 44. 45. 46 47 48 49. 50. 51. 52
53.
54
55. 56. 57 58 59
9
- CNS A g e n t s
E n g e l h a r d t , Ed,
J. D o Parkes, K. L. Z i l k h a , D. M. Calver and R. P. Kni11-Jones,
Lancet, 1,259-262 (1970). B. S. G i l l i g a n , J. Veale and J . Wodak, Med. J. Aust., 2, 634-637 (1970) J . B - Welten, Ned. T. Geront., 1, 23-30 (1970). G. W. V o l l e r , Deut. Med. Wochenachr., 7 l ., 934-937 (1970). R e Getz, South A f r i c a Med. J., 44, 955-956 (1970). V. A. Fasano, R. U r c i u o l i and G . Broggi, Minerva Med., 5 l , 2895-2903 (1970) J. D = Parkes, K. J. Z i l k h a , P. Marsden, R. C . H. Baxter and R. P. h i l l - J o n e s , Lancet,,.I 1130-1133 (1970). R e 0. Peckinpaugh, F. B. Askin, W. E. P i e r c e , E. A . Edwards, D. P. Johnson and G. G. Jackson, Ann. N.Y. Acad. S c i . , 173, 63-73 (1970). H. Seus and R. Seus, Arzneim. Forsch., 20, 274-277-970). C. N o Shealy, J . B. Weeth and D. Mercier,JAMA, 1522-1523 (1970). V. G - V e r n i e r , J. B. Harmon, J. M. Stump, T. E. Lynes, J. P. Marvel and D - H. Smith, T o x i c o l . Appl. Pharmacal., 2,642-665 (1969). R e P O Grelak, R. C l a r k , J. M. Stump and V . G. V e r n i e r , Science, 169, 203-204 (1970). G. Zetler, Naunyn-Schmiedebergs Arch. Pharmakol. Exp. P a t h o l . , 266, 276-278 (1970). B. S c a t t o n , A . Cheramy, M. J. Besson and J. Glowinski, Eur. J. Pharmacol., l3, 131-133 (1970). U. Stromberg, T. H. Svensson and B. Waldeck, J . Pharm. Pharmacol., 22, 959-962 (1970). R. J OB a l d e s s a r i n i , Biochem. Pharmacol. I n P r e s s 1971. G. M - Everett and J. W . Borcherding, S c i e n c e , 168, 849-850 (1970). K. Y e Ng, T - N . Chase, R. W. Colburn and I. J . Kopin, Science, 170, 76-77 (1970) E. A. F l e t c h e r and P. H. Redfern, J. Pharm. Pharmacol., 22, 957-959 (197 0) P. Simon, J. Malatray and J . R. B o i s s i e r , J. P h a r m . Pharmacol., 22, 546-547 (1970) S. H. Snyder, B i o l . P s y c h i a t . , 2, 367-389 (1970). R. C . Duvoisin, Arch. Neurol., 17, 124-136 (1967). V. G. V e r n i e r , Chapter 14, 301-311, i n E v a l u a t i o n of Drug Activities: Pharmacometrics, D. R. Laurence and A. L. Bacharach, Eds., Academic P r e s s , London (1964)
212,
-
.
(3 P P
TABLE 1
-
ACT ION I*
?
MECHANISMS OF ACTION OF ANTIPARKINSONISM DRUGS.
UI
DRUGS
EVIDENCE
INCREASE EXTRAPYRAMIDAL I N H I B I T I O N (Restore Deficient Central Adrenergic T r a n s m i s s i o n - Mainly D o p a m i n e ) A.
SUPPLY PRECURSOR
LEVODOPA
HORNYKIEWICZ' ; BARBEAU' ; COTZIAS
B.
RELEASE LOCAL TRANSMITTER
AMANTADINE
GRELAK48 ; VERNIER47 ; SCATTON50 ; BALDESSARIN152 ; STROMBERG51;
OTHERS
C
INCREASE TRANSMITTER SYNTHESIS
AMANTADINE
SCATTON5
D
PROLONG TRANSMITTER AVAILABILITY BLOCK DOPAMINE UPTAKE
ANTIHISTAMINES ANTICHOLINERGICS
SNYDER57 SNYDER57
APOMORPHINE
SCHWAB22 ; VERNIER2'
SCOPOLAMINE ATROPINE BENZTROPINE TRIHHCYPHENIDYL OTHERS
EXTENSIVE CLINICAL AND PHARMACOLOGICAL EVIDENCE - D W O I S I N 5 8 ; VERNIER59
E - ACTS AS TRANSMITTER I1
l2
F. 3
: E.
; STROMBERG5
DECREASE EXTRAPYRAMIDAL FACILITATION (Block C e n t r a l A c e t y l c h o l i n e Muscarinic Transmission)
2 Y
2. ID Y
Antiparkinsonism Drugs
Vernon G. V e r n i e r E. I. du Pont de Nemours and Co., Wilmington, Delaware 19898 P h y s i c i a n s now c a n treat p a t i e n t s w i t h parkinsonism more e f f e c t i v e l y and d e f i n i t i v e l y . T h i s improvement of t h e r a p e u t i c o u t l o o k h a s followed a s p u r t of r e c e n t r e s e a r c h a c t i v i t y . T h i s r e s e a r c h and t h e drug developments stemming from i t are summarized h e r e . The medicinal chemist should c o n s u l t t h e r e c e n t review of Engelhardt and S t o n e l . Other reviews of p e r t i n e n t area stress t h e r a p e u t i c s (Klawans, I l a h i and Shenker2 ; Calne3), pharmacolo (Hornykiewicz4), physiology (Shute and Lewis5,6) and anatomy (Carman ).
7
-
Levodopa T h i s n a t u r a l l y - o c c u r r i n g amino a c i d (I, L-3,4-dihydroxyphenyla l a n i n e ) was f i r s t used t o t r e a t p a r k i n s o n i a n p a t i e n t s i n 1961. Morgan H O - @ X ~ - T H -COOH HO
MI2
I
Hd
I1
and Bianchine8 and Barbeau9 have w e l l suuunarized t h e medical use and h i s t o r y of levodopa. A more d e t a i l e d monograph w i t h e x t e n s i v e documentat i o n h a s r e c e n t l y appeared100 The background and t h e o r e t i c a l b a s i s of levodopa t h e r a p y c a n be summar i z e d thus :
1.
P a r k i n s o n i a n p a t i e n t s b r a i n s show c y t o l o g i c a l d e t e r i o r a t i o n , p r i n c i p a l l y b u t n o t e x c l u s i v e l y in midbrain and b a s a l g a n g l i a .
2.
P a r k i n s o n i a n p a t i e n t s ' b r a i n s show a d e f i c i e n c y of dopamine (11) i n t h e s u b s t a n t i a n i g r a of t h e midb r a i n and i n t h e corpus s t r i a t u m ( c a u d a t e n u c l e u s and putamen) i n the b a s a l g a n g l i a of t h e f o r e b r a i n .
3.
The d e p l e t i o n of dopamine i s presumably due t o d e g e n e r a t i o n of f i b e r s of t h e n i g r o s t r i a t a l t r a c t .
4.
Dopamine may a c t as a s p e c i f i c t r a n s m i t t e r a t c e r t a i n "dopaminergic" synapses.
5.
Dopamine cannot c r o s s t h e b l o o d - b r a i n b a r r i e r , b u t i t s immediate biochemical p r e c u r s o r levodopa does s o r e a d i l y and could r e s t o r e f u n c t i o n by r e p l e n i s h i n g dopamine.
Chap. 5
Antiparkinsoni s m Drugs
V e rni e r
Although the r e s u l t s of e a r l y trials were c o n f l i c t i n g , probabl
43 -
due
t o the use of low doses and b r i e f treealtment periods, Cotzias e t a l . 111,12 convincingly established the e t r i k l n g e f ficecy, of a degree exceeding t h a t o f a l l previous medications, when high sustained doses oE levodopa were administered. Many others subsequently confinned t h i s finding. I n over 3,000 p a t i e n t s the success rate has been between 70 and 80%.
Levodopa favorably a l t e r e d nearly a l l symptoms of Parkinson's disease, though not equally. R i g i d i t y and hypokinesia have responded w e l l and e a r l y . Tremor responded i r r e g u l a r l y and later. Many o t h e r symptoms were p a r t i a l l y or completely reversed by levodopa, including impaired posture, l o s s of associated movements, increased sebum secretion, impaired speech and sialorrhea. Levodopa induced g r e a t e r o v e r a l l improvement i n modera t e l y t o severely a f f e c t e d p a t i e n t s than d i d a n t i c h o l l n e r g i c drugs. Most observers noted no loss of levodopa e f f i c a c y wlth time i n c o n t r a s t t o previously e f f e c t f v e drugs. Levodopa is superior t o surgery, which is plagued by i r r e g u l a r response, s e r i o u s hazards and recurrence of symptoms. Levodopa works b e s t i n p a t i e n t s with mild disease of s h o r t duration but i t also helps p a t i e n t s with severe longterm disease. While i t helps a l l forms of the disease, postencephalitic cases are very s e n s i t i v e t o both the therapeutic e f f e c t s and the s i d e e f f e c t s . Levodopa treatment must always be s t a r t e d with low doses (300 t o 500 rng per day) and the dose must be slowly and c a r e f u l l y increased up to the point of optimal e f f i c a c y or l i m i t i n g s i d e e f f e c t s (usually 2.5 t o 6 g per day, although a few p a t i e n t s may r e c e i v e t h e maximal recommended dose of 8 g ) . S k i l l and diligence in management of dosage, symptoms and s i d e e f f e c t s is e s s e n t i a l t o e f f e c t i v e therapy with t h i s drug, s i n c e t h e r e are d a i l y and within -day v a r i a t i o n s in e f f e c t , which are r e l a t e d to the s h o r t h a l f - l i f e and t o i n t e r a c t i o n s with d i e t a r y amino a c i d intake (mainly phenylalanine) which cause r e f r a c t o r y periods of rapfd onset and v a r i a b l e length. S i d e e f f e c t s are numerous and troublesome occurring i n nearly 100% of p a t i e n t s , bur a r e not generally serious. They have caused termination of drug i n about 5% of cases. They involve nearly a l l organ systems but the most important are 1) nausea, vomiting and anorexia, 2) cardiac dysrhythmias, 3) hypotension, 4) abnormal involuntary movements, and 5) behavioral and personality changest
Nausea, o f t e n accompanied by vomiting, i s seen a t some stage of therapy i n all patients. Loss o f a p p e t i t e may occur with o r without these signs. G a s r t o - i n t e s t i n a l signa, d e s p i t e t h e i r frequency, a r e r a r e l y doselimiting. Co-administration of food may c o n t r o l nauseal Phenothiazine anti-emetics and pyridoxine may block or reduce levodopa e f f i c a c y and should not be used for c o n t r o l of nausea o r emesis.
The commonest cardiac problems with levodopa therapy a r e sinus tachyc a r d i a and premature v e n t r i c u l a r contractions, with r a r e instances of a t r i a l f i b r i l l a t i o n . Cardiac deaths with v e n t r i c u l a r tachycardia and f i b r i l l a t i o n have been reported but drug causation is unclear. The cardiac s i d e e f f e c t s of levodopa can b e a serious t h r e a t p a r t i c u l a r l y t o p a t i e n t s
44
Sect. I
-
CNSAgents
E n g e l h a r d t , Ed.
w i t h coronary a r t e r y d i s e a s e . Levodopa t h e r a p y i n t h e s e p a t i e n t s should be i n s t i t u t e d c a u t i o u s l y i n t h e h o s p i t a l w i t h access t o monitoring and c o n t r o l equipment. Levodopa c a r d i a c r e s p o n s e s are mediated by conversion t o dopamine, which a c t i v a t e s B-adrenergic r e c e p t o r s . A f3-adrenergic blocking a g e n t such as p r o p r a n o l o l would be l o g i c a l t h e r a p y f o r c a r d i a c problems when they occur. P a t i e n t s w i t h P a r k i n s o n ' s d i s e a s e have a lower blood p r e s s u r e t h a n age- and sex-matched c o n t r o l s and o f t e n show o r t h o s t a t i c hypotension. Contrary t o e x p e c t a t i o n s , levodopa produces i n c r e a s e d o r t h o s t a t i c hypotens i o n which may become c l i n i c a l l y important. The i n c i d e n c e i s probably h i g h e r t h a n t h e 25 t o 35% r e p o r t e d s i n c e one c a r e f u l s t u d y of blood p r e s s u r e showed 75% of p a t i e n t s w i t h a d e c r e a s e of g r e a t e r t h a n 10 nun Hg i n blood p r e s s u r e on s t a n d i n g . D i z z i n e s s , v e r t i g o and syncope are unconnnon. They occur e a r l y , can g e n e r a l l y be c o n t r o l l e d , and d i s a p p e a r l a t e r w i t h the development of t o l e r a n c e . The mechanism of t h e o r t h o s t a t i c hypotens i o n due t o a d m i n i s t r a t i o n of a p r e s s o r m i n e p r e c u r s o r i s n o t c l e a r and i t s occurrence i s s u r p r i s i n g . Abnormal i n v o l u n t a r y movements f r e q u e n t l y accompany o p t i m a l improvement w i t h levodopa. The d u r a t i o n and the dose are r e l a t e d t o t h e occurrence of t h e s e movements s o t h a t up t o 73% of p a t i e n t s have them a f t e r 1 2 months of t r e a t m e n t . A b n o r m a l i t i e s are seen e a r l i e s t i n t h e head and mouth, then later i n t h e limbs and t r u n k , sometimes becoming v i o l e n t and severe. Usually they c a n be r e v e r s e d by lowering t h e levodopa dose o r by adding o t h e r drugs ( p h e n o t h i a z i n e s , h a l o p e r i d o l o r p y r i d o x i n e ) b u t w i t h both approaches some t h e r a p e u t i c b e n e f i t i s o f t e n l o s t . The p a r k i n s o n i a n p o p u l a t i o n , g e n e r a l l y aged, h a s a s i g n i f i c a n t i n c i dence of impairment of mental f u n c t i o n (memory , judgment, dementia and s o c i a l a d a p t a t i o n ) . Levodopa t r e a t m e n t i s accompanied by b e h a v i o r a l and p e r s o n a l i t y changes i n some p a t i e n t s . The c e n t r a l s t i m u l a n t e f f e c t seen e a r l y i n therapy may be r e l a t e d t o a t o x i c d e l i r i u m which levodopa can cause. The more f l o r i d cases show paranoid i d e a s , d e l u s i o n s , h a l l u c i n a t i o n s and l o s s of judgment, b u t f r e q u e n t l y a m i l d e r p i c t u r e i s s e e n w i t h less d i s r u p t i v e s t i m u l a n t e f f e c t and nervousness, a n x i e t y and s l e e p l e s s n e s s (sometimes w i t h v i v i d dreams) p l u s some autonomic s i g n s . R a r e l y s e d a t i o n , m a l a i s e , and emotional d e p r e s s i o n t o t h e p o i n t of s u i c i d a l i d e a s a r e noted, b u t drug c a u s a t i o n i s u n c l e a r . Levodopa h a s been p u b l i c i z e d a s a n a p h r o d i s i a c , b u t t h i s may be mainly t h e t a l k of t o x i c d e l i r i u m p a t i e n t s ; however t h e r e m i t t e d i l l n e s s of a p r e v i o u s l y i n c a p a c i t a t e d v i c t i m may perm i t t h e a p p r o p r i a t e renewal of s e x u a l performance. There i s n o t f i r m evidence t h a t i t h a s f u l f i l l e d t h e a n c i e n t concept of a s p e c i f i c aphrodisiac. Many o t h e r i n f r e q u e n t symptoms and abnormal l a b o r a t o r y f i n d i n g s have been a s s o c i a t e d w i t h levodopa t r e a t m e n t . M e t a b o l i t e s c a u s e the u r i n e t o t u r n r e d d i s h and t h e n black. Many drug i n t e r a c t i o n s a r e p o s s i b l e ; few a r e conf inned, b u t t h i s p o s s i b i l i t y should be watched. Some monoamine oxidase i n h i b i t o r s r e p o r t e d e f f e c t i v e i n P a r k i n s o n ' s disease caused h y p e r t e n s i v e r e a c t i o n s i n combination w i t h levodopa, b u t t r i c y c l i c an t i d e p r e s s a n t s
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(imipramine and a m i t r i p t y l i n e ) also e f f e c t i v e i n parkinsonism, have been used with levodopa without s e r i o u s s i d e e f f e c t s . Levodopa was approved by F M i n June 1970 f o r marketing i n the t r e a t ment of Parkinson's disease. Drug c o s t s were r e l a t i v e l y high but a r e d e c l i n i n g and drug a v a i l a b i l i t y is increasing. It i s not known whether levodopa alters the steady progression of Parkinson's disease, s i n c e few p a t i e n t s have been observed longer than 3 years. Generally i t i s s t a t e d t h a t no f u r t h e r d e t e r i o r a t i o n has been observed i n successfully-treated p a t i e n t s .
Other medical uses f o r levodopa include success i n t r e a t i n g the akinetic-dystonic syndrome of manganese poisoning i n miners. Other neurol o g i c a l and p s y c h i a t r i c i n d i c a t i o n s are not y e t established. Levodopa has yielded c o n f l i c t i n g r e s u l t s i n dystonia musculorum deformans, Wilson's disease, Huntington's chorea, and progressive supranuclear palsy. Reports of l i m i t e d t r i a l s of levadopa f o r the possible treatment of d e p r e s s i o P l 6 have appeared, but they are d i f f i c u l t t o i n t e r p r e t . Studies t o resolve the i s s u e are i n progress.
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Decarboxylase I n h i b i t o r s A t least two agents designed t o decrease the p e r i p h e r a l enzymatic i n a c t i v a t i o n of levodopa have been t r i e d . Both Ro 4-4602 (111) and MK 485 (N)have been reported t o lower the optimal
111 IV levodopa dose t o o n e - f i f t h t o one-eighth. It i s not y e t c l e a r t h a t any therapeutic advantage is achieved i n e f f i c a c y or g r e a t e r s i d e e f f e c t margin beyond the decrease i n the levodopa dose requiredl7-21. Abnormal involuntary movements are s t i l l seen a t the lower dosage. More informat i o n is required t o say whether or not t h i s combination therapy with levodopa w i l l be useful. Apomorphine - This morphine d e r i v a t i v e (V, common s t r u c t u r a l elements with dopamine, 11, indicated) has r e c e n t l y assumed considerable t h e o r e t i c a l and possible p r a c t i c a l importance i n understanding the pharmacological r o l e of levodopa and dopamine i n the therapy of parkinsonism. SchwabZ2 reported t h a t i t r e l i e v e d tremor i n p a t i e n t s but was of too s h o r t duration f o r useful therapy and was only e f f e c t i v e p a r e n t e r a l l y . Then, Vernier23j24 found t h a t apomorphine s t r i k i n g l y reduced the tremor of monkeys with midbrain l e s i o n s made by the technique of Ward25 Pe terson26 and of Carpenter27. P o i r i e r e 8 and - v GoldsteinZg have used these methods t o study b r a i n catecholamine changes and t o study these
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and o t h e r drug e f f e c t s . More r e c e n t l y C o t ~ i a hs a~s ~confirmed Schwab' s f i n d i n g i n man. The work of s e v e r a l groups h a s now converged t o i n d i c a t e t h a t apomorphine a c t s upon many p h y s i o l o g i c a l systems and v a s c u l a r beds t o c a u s e e f f e c t s s i m i l a r t o t h o s e o f levodopa o r d 0 p a m i n e 3 1 , ~ ~ .Thus apomorphine probably d i r e c t l y a c t i v a t e s "dopaminer i c " r e c e p t o r s and i t s mode of a c t i o n i n parkinsonism i s c l e a r e r . Sourkes 33 h a s s u g g e s t e d t h a t levodopa o r dopamine may a c t p a r t i a l l y through m e t a b o l i c c o n v e r s i o n t o aporp h i n e s resembling apomorphine. Amantadine - Amantadine h y d r o c h l o r i d e (VI) was i n t r o d u c e d i n 1967 a s an a n t i v i r a l a g e n t f o r i n f l ~ e n z a ~ ~ I~n ~1968 5 . Schwab e t al.36 noted t h a t amantadine caused r e m i s s i o n of p a r k i n s o n i a n symptoms i n a p a t i e n t t r e a t e d p r o p h y l a c t i c a l l y .Hcl d u r i n g a n i n f l u e n z a epidemic and they subseq u e n t l y s t u d i e d t h e e f f e c t i n 163 p a t i e n t s . S i n c e then more than 80 r e l e v a n t papers have appeared of which more t h a n 30 a r e r e p o r t s of c l i n i c a l s t u d i e s . They i n c l u d e over 1,000 VI p a t i e n t s w i t h over 300 from c o n t r o l l e d t r i a l s (e.ga37,38,39). Most a u t h o r s concluded t h a t arnantadine shows some degree of a n t i p a r k i n s o n i a n a c t i v i t y ( e . g . 4 O ~ 4 ~ , 4 ~ ) . The o n s e t of e f f e c t i s g e n e r a l l y r a p i d , 24 t o 48 h o u r s , compared w i t h w e e k s or months w i t h levodopa. The c l i n i c a l r e p o r t s s u g g e s t t h a t t h e amantadine degree of a c t i v i t y i s a t least as g r e a t and perhaps g r e a t e r t h a n t h a t of t h e s t a n d a r d a n t i p a r k i n s o n i a n d r u g s , p r i n c i p a l l y a n t i c h o l i n e r g i c s , b u t n o t a s g r e a t as t h a t of levodopa. Dose r e s p o n s e r e l a t i o n s h i p s f o r t h e a c t i v i t y of amantadine i n d i c a t e t h a t doses of 200 t o 300 mg d a i l y a r e o p t i m a l f o r most p a t i e n t s 4 3 . Schwab36 n o t e d some d e c r e a s e d e f f e c t a f t e r prolonged t r e a t m e n t .
a
Amantadine has been s u c c e s s f u l l y a d m i n i s t e r e d c o n c u r r e n t l y w i t h o t h e r drugs, i n c l u d i n g levodopa whose e f f i c a c y i t t e n d s t o p r e d i c t 3 6 . Arnantadine i s g e n e r a l l y w e l l t o l e r a t e d i n most p a t i e n t s 4 4 ~ 4 5and c a u s e s fewer s i d e e f f e c t s t h a n levodopa o r a n t i c h o l i n e r g i c s . Some r e p o r t e d s i d e e f f e c t s may be due t o c o n c u r r e n t a n t i c h o l i n e r g i c medication o r t o amantadine i n t e n s i f i c a t i o n of t h e i r e f f e c t s , b u t t h i s i s n o t y e t c l e a r l y e s t a b l i s h e d . Livedo r e t i c u l a r i s h a s been r e p o r t e d 4 6 . V e r n i e r e t a l . 4 7 concluded t h a t amantadine was a d e q u a t e l y t o l e r a t e d on long term c h r o n i c a d m i n i s t r a t i o n t o r a t s , dogs and monkeys a t d o s e s more t h a n 13 t o 33 times t h e u s u a l human d o s e s w i t h no e v i d e n c e of organ pathology. These t o x i c o l o g i c a l s t u d i e s showed some c e n t r a l nervous system s t i m u l a t i o n , a n o r e x i a , r a r e emesis and some c o n v u l s i o n s a t h i g h doses. Amantadine caused s e v e r a l e f f e c t s a t h i g h d o s e s , i n d i c a t i v e of c e n t r a l nervous system s t i m u l a t i o n o r catecholamine i n t e r a c t i o n i n c l u d i n g : i n c r e a s e d spontaneous motor a c t i v i t y , antagonism of t e t r a b e n a z i n e - i n d u c e d s e d a t i o n , a m i l d , t r a n s i e n t v a s o d e p r e s s o r e f f e c t , some c a r d i a c arrhythmias, and some b l o c k of uptake of n o r e p i n e p h r i n e i n t o l a b i l e s t o r e s ( p o t e n t i a t i o n of n o r e p i n e p h r i n e v a s o p r e s s o r e f f e c t , b l o c k of phenethylamine vasop r e s s o r r e s p o n s e , i n c r e a s e of myocardial c o n t r a c t i l e f o r c e , r a d i o a c t i v e
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norepinephrine d i s t r i b u t i o n s t u d i e s , and antagonism of tetrabenazine effects). The possible modes of a c t i o n of amantadine and other drugs i n parkinsonism a r e summarized i n Table 1. Amantadine does not a c t l i k e the c e n t r a l l y - a c t i n g anticholinergics48,49. I n three animal preparations amantadine f a i l e d t o cause a n t i c h o l i n e r g i c e f f e c t s (guinea pig ileum, acetylcholine-induced depressor e f f e c t s i n dogs, oxotremorine tremor i n mice). Amantadine i n t e r a c t s with catecholamines i n the c e n t r a l nervous s y s tem and i n the periphery. This might be predicted from i t s primary amine s t r u c t u r e . How can these i n t e r a c t i o n s c o n t r i b u t e t o i t s e f f e c t i n parkinsonism? Table 1 l i s t s f i v e mechanisms by which amantadine and other drugs could counteract the d e f i c i t of extrapyramidal i n h i b i t i o n which is respons i b l e f o r symptoms of parkinsonism. Recent evidence points t o a l o c a l r e l e a s e of catecholamines as the major mode of a c t i o n of amantadine i n parkinsonism. This i s the most s e n s i t i v e e f f e c t of amantadine reported t o date and occurs a t the lowest dose. Althou h e a r l i e r c l u e s pointed t o t h i s action, the r e s u l t s of Grelak e t a1.88 c l a r i f i e d t h i s point. They reported t h a t a small trans i e n t pressor e f f e c t of amantadine alone, intravenously i n dogs, was markedly i n t e n s i f i e d b dopamine-priming. This suggested t h a t amantadine released dopamine and& other catecholamines from neuronal s t o r e s t o cause the p e r i p h e r a l pressor a c t i o n . The e f f e c t was noted a t very low amantadine doses. There was no evidence f o r block of dopamine uptake. E a r l i e r Vernier47 reported t h a t t r a n s i e n t increases i n myocardial cont r a c t i l e force occurred following moderate intravenous doses of amantadine. These a l s o suggested l o c a l catecholamine r e l e a s e , since they were abolished by r e s e r p i n i z a t i o n and r e s t o r e d by norepinephrine infusion. Recently several l a b o r a t o r i e s have reported evidence f o r amantadineinduced release of r a d i o l a b e l l e d catecholamine (mainly dopamine) from r a t brain50?51,52. This seems t o confirm in the c e n t r a l nefvous system what was seen i n the periphery. Although t h i s may be the most l i k e l y major mode of a c t i o n of amantadine i n parkinsonism, the q u a n t i t a t i v e r e l a t i o n s between t h i s and o t h e r biochemical actions upon catecholamines remain t o be worked out. It i s i n t e r e s t i n g t o note t h a t several authors have shown t h a t levodopa may release amines i n the brain, s p e c i f i c a l l y serotonin, which may imply t h a t i t shares a somewhat similar a c t i o n with a1naneadine5~,54.
Recent biochemical findings suggest t h a t under some conditions amantadine may i n c r e a s e dopamine accumulation in brain. Thus Scatton50 concluded t h a t amantadfne may s t i m u l a t e dopamine s y n t h e s i s and Stromberg5l has reported compatible data. It: i s too early t o assess the relevance of t h i s finding t o the clinical efficacy of amantadine Does amantadine block the reuptake of catecholamines and i s t h i s
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e f f e c t r e l a t e d t o i t s a n t i p a r k i n s o n a c t i o n ? S e v e r a l groups have s t u d i e d the e f f e c t of amantadine upon catecholamine uptake s i n c e Vernier47 r e p o r t e d d a t a compatible w i t h r e u p t a k e blockade. At doses 5-10 t i m e s t h e human t h e r a p e u t i c dose amantadine antagonized t e trabenazine-induced sedat i o n i n mice. It a l s o p o t e n t i a t e d norepinephrine-induced p r e s s o r response i n dogs, blocked pehenethylamine-induced p r e s s o r response i n dogs, and blocked t h e uptake of r a d i o l a b e l l e d n o r e p i n e p h r i n e by mouse h e a r t . I n c o n t r a s t Grelak48 r e p o r t e d no clear i n d i c a t i o n of amantadine p o t e n t i a t i n g dopamine i n t h e i r r e l e a s e experiments. I t i s n o t y e t c l e a r whether amantadine b l o c k s uptake of dopamine ( o r o t h e r catecholamines) i n b r a i n t o prolong t h e u s e f u l presence of t r a n s m i t t e r . While uptake b l o c k of dopamine and n o r e p i n e p h r i n e h a s been r e p o r t e d a t h i g h amantadine d o s e s , i t probably does n o t p l a y a major r o l e and the evidence of several groups i s a g a i n s t i t s o - 5 5 . The q u a n t i t a t i v e and q u a l i t a t i v e r e l a t i o n s must be worked o u t b e f o r e t h e r o l e of reuptake block of catecholamines can be a s s e s s e d . Snyder57 suggested t h a t c a t e cholamine uptake blockade (mainly b l o c k of dopamine u p t a k e by striatum) may c o n t r i b u t e t o t h e mode of a c t i o n of a n t i c h o l i n e r g i c s and a n t i h i s t amines i n a n t i p a r k i n s o n i a n therapy.
Since amantadine g e n e r a l l y l a c k s t h e prominent g a s t r o i n t e s t i n a l symptoms (nausea and emesis) shared by apomorphine and levodopa i t i s n o t l i k e l y t h a t i t stimulates dopamine r e c e p t o r s d i r e c t l y . Z e t l e d g and Simon, Malatray and B o i s s i e r 5 6 have r e p o r t e d amantadine antagonism t o phenothiazine-induced and o t h e r drug-induced c a t a l e p s y . They s u g g e s t t h a t amantadine may be e f f e c t i v e i n drug-induced parkinsonism o r o t h e r e x t r a p y r a m i d a l d i s o r d e r s i n man. References
1.
E . L. Engelhardt and C . A . Stone, i n Medicinal Chemistry, 3rd E d i t i o n , A . Burger, Ed., Chapter 59, John Wiley and Sons, New York (1970). 2. H a Klawans, M. M. I l a h i and D. Shenker, Acta Neurol. Scand., 46, 409441 (1970). 3 . D. Be Calne, C l i n . Pharm. Ther., ll, 789-801 (1970). 4 . 0 Efornyklewicz Pharmacol Rev., l8, 925- 964 (1966) 5 . C - C. D o Shute and P. R. Lewis, Nature, 212, 710-711 (1966). 6. C . C. D o Shute and P. R. Lewis, B r i t . Med. Bull., 22, 212-226 (1966). 7. J. B. Carman, New Eng. J. Med., 279, 919-930 (1968). 8. J * P O Morgan and J. R. Bianchine, R a t i o n a l Drug Therapy (formerly Pharmacology f o r P h y s i c i a n s ) , 5, 1-8 (January 1971). 9 . A . Barbeau, Canad. Med. Assoc. J., 101, 791-800 (1969). 10. A . Barbeau and F. H. McDaJe11, L-Dopa and Parkinsonism, F. A . Davis Company, P h i l a d e l p h i a , Pennsylvania (1970) 11. G. C. C o t z i a s , M. H. Van Woert and L. M. S c h i f f e r , New Eng. J. Med., 276, 374-379 (1967). 12 G. C . C o t z i a s , P. S. P a p a v a s i l i o u and R. G e l l e n e , New Eng. J . Med., 280, 337-345 (1969). 13. 5 7 . S c h i l d k r a u t , G. L. Klerman, D. G. F r i e n d and M. G r e e n b l a t t ,
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Vernier
49 -
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0
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_.
37
0
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53.
54
55. 56. 57 58 59
9
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212,
-
.
(3 P P
TABLE 1
-
ACT ION I*
?
MECHANISMS OF ACTION OF ANTIPARKINSONISM DRUGS.
UI
DRUGS
EVIDENCE
INCREASE EXTRAPYRAMIDAL I N H I B I T I O N (Restore Deficient Central Adrenergic T r a n s m i s s i o n - Mainly D o p a m i n e ) A.
SUPPLY PRECURSOR
LEVODOPA
HORNYKIEWICZ' ; BARBEAU' ; COTZIAS
B.
RELEASE LOCAL TRANSMITTER
AMANTADINE
GRELAK48 ; VERNIER47 ; SCATTON50 ; BALDESSARIN152 ; STROMBERG51;
OTHERS
C
INCREASE TRANSMITTER SYNTHESIS
AMANTADINE
SCATTON5
D
PROLONG TRANSMITTER AVAILABILITY BLOCK DOPAMINE UPTAKE
ANTIHISTAMINES ANTICHOLINERGICS
SNYDER57 SNYDER57
APOMORPHINE
SCHWAB22 ; VERNIER2'
SCOPOLAMINE ATROPINE BENZTROPINE TRIHHCYPHENIDYL OTHERS
EXTENSIVE CLINICAL AND PHARMACOLOGICAL EVIDENCE - D W O I S I N 5 8 ; VERNIER59
E - ACTS AS TRANSMITTER I1
l2
F. 3
: E.
; STROMBERG5
DECREASE EXTRAPYRAMIDAL FACILITATION (Block C e n t r a l A c e t y l c h o l i n e Muscarinic Transmission)
2 Y
2. ID Y