reljanovic et al. - 1999 - treatment of diabetic polyneuropathy with the antioxidant thioctic acid...

8/2/2019 Reljanovic Et Al. - 1999 - Treatment of Diabetic Polyneuropathy With the Antioxidant Thioctic Acid (Alpha-lipoic Acid) a Two Year Multi Center Randomized Double

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Free Rad. Res., Vol. 31, pp. 171-179Reprints av ailable direct ly from the pub lisherPho toc opy ing pe rmi t t e d by l ic e ns e on ly

1999 OPA (Overseas Publishers As so~ tio n) N.V.Published b y l icense un derth e H a rw ood A c a de m ic Pub l is he rs impr in t ,

p a r t o f Th e Gordon and Breach Publishing Group.Printed in Malays ia .

T r e a t m e n t o f D i a b e t i c P o l y n e u r o p a t h y w i t h t h eA n t i o x i d a n t Th i o c t i c A c i d ( c - L i p o i c A c i d ) :A T w o Y e a r M u l t i c e n t e r R a n d o m i z e d D o u b l e - b l i n dP l a c e b o - c o n t r o ll e d T r i a l ( A L A D I N II)M . R E L J A N O V I C a , G . R E I C H E L b , K . R E T r c, M . L O B I S C H d , K . S C H U E T r E a ,W. MO L L E R d, H . - J. T R IT S C H L E R d , H . M E H N E R T e '* a n d T H E A L A D I N 1 I S T U D Y G R O U PaUniversity Clinic for Diabetes, Endocrino logy and M etabolic Diseases q, uk Vrhovac', Medical faculty, University of Zagreb,Dugi dol 4a, 1 0000 Zagreb , Croatia; bParacelsus Clinic, W erdauer Str. 68, 0 8060 Zwickau, Germa ny; CEberhard-Karls UniversityClinic, Geissweg 3, 72076 ~ubingen, Germany; dAS TA Medica AG , Weismfi llerstr . 45, 60314 Frankfur t am Main, Germany;eIns ti tute for Diabetes Research, City Hospital Munich, KOlner Platz 1, 80 804 M finchen, GermanyA c c e p te d b y P ro f . B . H a U iw e U(Received 10 February 1999; In rev ised o rm 17 March 1999)S h o r t - t e rm t r i a ls w i th th e a n t io x id a n t t h io c t ic a c id (TA )a p p e a r t o i m p r o v e n e u r o p a t h i c s y m p t o m s i n d i a be t i cp a t i e n t s , b u t t h e l o n g - t e r m r e s p o n s e r e m a i n s t o b ee s t a b l i sh e d . T h e re fo re , T y p e 1 a n d T y p e 2 d i a b e t i cp a t i e n t s w i t h s y m p t o m a t i c p o l y n e u r o p a t h y w e r er a n d o m l y a s s i g n e d t o t h r e e t r e a t m e n t r e g i m e n s :(1) 2 x 6 0 0 m g o f T A (T A 1 2 0 0) , (2 ) 6 0 0 m g o f T A p lu sp la c e b o (P L A ) (T A 6 0 0 ) o r (3 ) p l a c e b o a n d p l a c e b o(PL A ) . A t r o m e ta m o l s a l t s o lu t io n o f T A o f 1 2 0 0 o r6 00 m g o r P L A w a s i n t r a v e n o u s l y a d m i n i s t e r e d o n c ed a i ly fo r f iv e c o n s e c u t iv e d a y s b e fo re e n ro l l i n g th ep a t i e n t s i n t h e o r a l t r e a t m e n t p h a s e . T h e s t u d y w a sp r o s p e c t i v e , P L A - c o n t r o l l e d , r a n d o m i z e d , d o u b l e -b l i n d a n d c o n d u c t e d f o r t w o y e a r s. S e v e r i ty o f d i ab e t i cn e u r o p a t h y w a s a s s e s se d b y t h e N e u r o p a t h y D i s a b il i tyS c o re (N D S ) a n d e l e c t ro p h y s io lo g ic a l a t t r i b u te s o f t h es u ra l ( s e n s o ry n e rv e c o n d u c t io n v e lo c i ty (S N C V ) ,s e n s o ry n e r v e a c t io n p o te n t i a l (S N A P )) a n d th e t i b ia ]( m o t o r n e r v e c o n d u c t i o n v e l o c i t y ( M N C V ) , m o t o rn e rv e d i s t a l l a t e n c y (MN D L )) n e rv e . S t a t i st i c a l a n a ly s i sw a s p e r f o r m e d a f t e r i n d e p e n d e n t r e v i e w e r s e x c l u d e d

a l l p a t i e n t s w i th h ig h ly v a r i a b le d a t a a l lo w in g a f in a lana ly s is o f 65 pa t ie n ts (TA 1200: n = 18 , TA 600: n =27 ;P L A : n = 2 0 ). A t b a s e l in e n o s ig n i f i c a n t d i f f e re n c e s w e ren o t e d b e t w e e n t h e g r o u p s r e g a r d i n g t h e d e m o g r a p h i cv a r i a b l e s a n d p e r i p h e r a l n e r v e f u n c t i o n p a r a m e t e r sfo r these 65 pa t ien ts . S ta t is t ica l ly s ign if ican t changesa f t e r 2 4 m o n t h s b e t w e e n T A a n d P L A w e r e o b s e r v e d(m ean SD) fo r su ra l SNCV: + 3 .8 + 4 .2 m /s in TA 1200 ,+ 3 . 0 + 3 . 0 m / s i n T A 6 00 , , - 0 . 1 + 4 .8 m / s i n P L A(p < 0 .0 5 fo r T A 1 2 0 0 a n d T A 6 00 v s . P L A ) ; s u ra l S N A P :+ 0.6 + 2.5 ~V in TA 1200, + 0.3 + 1.4 ~V in TA 600,- 0 .7 4 -1.5 pV in PL A (p = 0 .076 fo r TA 1200 vs . PLA andp < 0 .05 fo r T A 600 vs . PLA ), and in t ib ia l M NCV :+ 1 . 2 4 - 3 .8 m /s in T A 1 20 0 , - 0 .3 4- 5 .2 m /s in TA 600 ,- 1 .5 2 .9 m /s in PLA (p < 0 .05 fo r TA 1200 vs . PLA).N o s ig n i f i c a n t d i f f e re n c e s b e tw e e n th e g ro u p s a f t e r 2 4m o n t h s w e r e n o t e d r e g a r d i n g t h e t ib i a l M N D L a n d t h eN D S . W e c o n c l u d e t h a t i n a s u b g r o u p o f p a t i e n t s a f t e re x c lu s io n o f p a t i e n t s w i th e x c e s s iv e t e s t v a r i a b i l i t yth ro u g h o u t t h e t r i a l , T A a p p e a re d to h a v e a b e n e f i c i a le f f e c t o n s e v e ra l a t t r i b u te s o f n e rv e c o n d u c t io n .

*Cor respond ing author . T el.: 089-3079310. Fax: 089-3081733.t Lis t of partic ipants in the A ladin II Study gro up ap pears at the e nd of this artic le .171


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172 M. RELJANOVICet al .Keywords: Diabeticpolyneuropathy, reatment,thioctic ac id, c~-lipoicacid, antioxidants

I N T R O D U C T I O N

p o l y n e u r o p a t h y . E3'4"25] In th e pr es en t tria l w ee va lu a t e d the e f fi c a c y a nd sa f e ty o f 2 -ye a r t r e a t-m e n t w i t h T A o n p e r i p h e r a l n e r v e f u n c ti o n i np a t i e n t s w i t h d i a b e t i c p o l y n e u r o p a t h y .

T h e D i a b et e s C o n t r o l a n d C o m p l i c a ti o n s Tr ia l( D C C T ) a n d t h e U n i t e d K i n g d o m P r o s p e c t i v eD i a b e t e s S t u d y ( U K P D S ) s h o w e d t h a t n e a r -n o r m o g l y c e m i a p r e v e n ts t h e d e v e l o p m e n t o fd i a b e ti c c o m p l i c a t io n s i n c l u d i n g d i a b e t i c p o l y -ne u r op a thy , 1 '2 ] S inc e on ly a l im i t e d nu m be r o fd i a be t i c pa t i e n t s a r e a b l e t o r e a c h ne a r no r m a lb lood g luc ose c on t r o l , a l t e r na t ive t he r a pe u t i ca p p r o a c h e s a r e b e i n g e v a l u a t e d t o p r e v e n t o rt r ea t d i a b e t i c p o l y n e u r o p a t h y . V a ri o u s p h a r m a -c e u t i c a l c o m p o u n d s a r e b e i n g t e s t e d r e g a r d i n gthe i r a b i li t y to f a vo r a b ly i n f lue n c e ne r v e dys f un c -t i o n i n e x p e r i m e n t a l d i a b e t e s a n d d i a b e t i cpa t ients . [3-121 Th ese inc lud e th e a ldo se red uc ta seinhib i to r s , myo - ino s i to l , ~/ -l inolenic ac id , a m ino -g u a n i d i n e , n e r v e g r o w t h f a c t o r a n d v a s o d i l a -to rs . [5-12] T h e s e t h e r a p e u t i c i n t e r v e n t i o n s h a v es h o w n v a r i a b l e e ff ec t s o n p e r i p h e r a l n e r v e d y s -f u n c t i o n b u t i n g e n e r a l h a v e n o t y e t b e e n a c c e p t eda s s t a n d a r d t r e a t m e n t .

R e c e n t e x p e r i m e n t a l s t u d i e s s u g g e s t t h a t t h ei m b a l a n c e o f o x i d a t i v e s t r e s s a n d a n t i o x i d a n td e f e n s e m a y p l a y a r o l e i n t h e p a t h o g e n e s i s o fd iabe t ic pol yn eur op a th y . la-15] Thioc t ic ac id (TA)h a s b e e n s h o w n t o e x e r t e x c e l l e n t a n t i o x i d a n tp r ope r t i e s e .g . to r e c yc l e g lu t a th ione a nd in t u r nenh anc e Vi ta min E an d Vi ta mi n C . [16"181 n exper i -m e n t a l d i a b e t i c n e u r o p a t h y T A i n c r e a se s e n d o -n e u r i a l b l o o d f lo w , r e d u c e s f r e e r ad i c a l m e d i a t e do x i d a t i v e s t r e s s a n d r a i s e s t h e r e d u c e d g l u -t a t h i o n e c o n t e n t o f t h e p e r i p h e r a l n e r v e i n ad o s e - d e p e n d e n t fa s h i o n , t h u s l e a d i n g to a n i m -p r o v e m e n t i n p e r i p h e r a l ne rv e fun cti on. [19-2I]N e ur o r e ge ne r a t ive e f f e c t s o f TA ha ve a l so be e no b s e r v e d i n b o t h n e u r a l c e l l c u l t u r e a n d e x p e ri -m e n t a l d i a b e t i c p o l y n e u r o p a t h y .L22-24] There isi n c r e as i n g e v i d e n c e f r o m r e c e n t s h o r t - t e rm c l in -i c a l s t u d i e s t h a t T A i m p r o v e s p e r i p h e r a l a n da u t o n o m i c n e r v e f u n c t i o n i n h u m a n d i a b e t i c

M E T H O D SS tu d y Des i g n a n d Po p u l a t io nI n t h i s s t u d y ( A l p h a L i p o i c A c i d i n D i a b e t i cN e u r o p a t h y : A L A D I N I I ) T y p e 1 a n d T y p e 2d i a b e t ic p a t i e n t s w i t h s y m p t o m a t i c d ia b e t i c p o l y -n e u r o p a t h y w e r e r a n d o m l y a s s ig n e d t o t h r eet r e a t m e n t g r o u p s r e c e i v in g s i x t ab l e ts p e r d a y .T h e s t u d y w a s p r o s p e c t i v e , d o u b l e - b l i n d a n dr a n d o m i z e d . P a t i e n t s i n t h e f i r s t g r o u p ( T A1200) r e c e ive d s ix t a b l e t s c on ta in ing 200m g o fTA ( Th ioc t a c id, A S T A M e d i c a A G F r a n k f u r t a mM a in , G e r m a n y) , t he s e c on d ( TA 600 ) t h r e e t a b l e t sc o n t a i n i n g 2 00 m g o f T A a n d t h r e e t a b le t s p l a c e b o( P LA ) a nd the t h i r d ( P LA ) s ix t a b le t s o f P LA . At r o m e t a m o l s a l t s o l u t i o n o f T A ( T h io c t ac i d T) o f1200 o r 600 m g o r P L A w a s in t r a v e no us ly ( i.v .)a d m i n i s t e r e d o n c e d a i l y f o r f iv e c o n s e c u t i v e d a y sb e f o re e n r o l l i n g t h e p a t i e n t s i n t h e l o n g - t e r m o r a lt r e a t m e n t p h a s e . B o t h P L A t a b l et s a n d s o l u t i o n sc o n t a i n e d i n g r e d i e n t s i d e n t i ca l w i t h t h o s e c o n -t a in ing TA e xc e p t f o r t he l at t er . I n o r de r t o a c h i e vea c o lo r s i m i l a r t o t he a c t ive d r u g f e r r oox ide ( E 172 )w a s a d d e d t o t h e t a b le t s a n d 0 .0 3 m g o f r i b o f la v i nt o t h e a m p o u l e s .

T h e s t u d y w a s p e r f o r m e d b y g e n e r a l p r a c t i -t i o n e r s i n G e r m a n y . E t h i c a l a p p r o v a l w a s o b -t a ine d f r om a l l r e g iona l e th i c s c om m i t t e e s . Thee l e c t r o p h y s i o l o g i c a l m e a s u r e m e n t s w e r e p e r -f o r m e d by r e g iona l ne u r o log i s t s . To be e l i g ib l e ,t h e p a t i e n t s a g e d b e t w e e n 1 8 - 6 0 y e a r s h a d t o b es y m p t o m a t i c a n d h a v e e v i d e n ce o f p o ly n e u r o -p a t h y b a s e d o n a b n o r m a l p e r ip h e r a l n e r v e fu n c -t i on a c c o r d ing to c li n i ca l a nd e l e c t r ophys io log ic a le x a m i n a t i o n s .

P a t i e n t s w i t h s e v e r e n e u r o p a t h y i n c l u d i n gp a r e s i s , m u s c l e a t r o p h y , s e v e r e s y m p t o m a t i cd i a b e t ic n e u r o p a t h y , c a u s e s o f n e u r o p a t h i e s o t h e r


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LIPOIC ACID AND NEUROPATHY 173t h a n d i a b e t e s a n d o t h e r s i g n i f ic a n t n e u r o l o g i c a ld i s e a s e s w e r e e x c l u d e d f r o m t h e s t u d y . T h e u s eo f m e d i c a t i o n s l i k e l y t o i n t e r f e r e w i t h t h e i n t e r -pre ta t ion of the resu l t s (e .g . q , - l ino lenic ac id ,a n t i o x i d a n t s , a n t i d e p r e s s a n t s , a n t i c o n v u l s a n t s ,m e x i l e t i n e , n e u r o l e p t i c s , V i t a m i n B ) p r e v e n t e di n c l u s i o n .

Per ipheral Nerve Funct ionN e u r o p a t h i c d e f i c it s w e r e a s s e s s e d u s i n g t h eN e u r o p a t h y D i s a b i li ty S c o r e (N D S ) d e s c r i b e d b yY o u n g eta/. I27] S u r a l s e n s o r y n e r v e c o n d u c t i o nv e l o c i t y ( S N C V ) a n d s e n s o r y n e r v e a c t i o n p o t e n -t ia l ( S N A P ) a s w e l l a s t ib i a l m o t o r n e r v e c o n d u c -t i o n v e l o c i t y ( M N C V ) a n d m o t o r n e r v e d i s t a ll a te n c y ( M N D L ) w e r e m e a s u r e d a t b a s e li n e a n da f t e r 12 a n d 2 4 m o n t h s . T h e s e e l e c t r o p h y s i o lo g -i ca l m e a s u r e m e n t s w e r e p e r f o r m e d w i t h s u r f a c ee l e c t r o d e s a t a l i m b t e m p e r a t u r e o f 3 3 -3 4 Ca c c o r d i n g t o t h e p r o t o c o l o f S t o r r a n dBlu tha rdt . [261

Laboratory MeasurementsG l y c o s y l a te d h e m o g l o b i n ( H b A l c ) w a s d e t e r -m i n e d a t b a s e li n e a n d a f t e r 6 ,1 2 , 1 8 a n d 2 4 m o n t h sw i t h t h e H P L C t e c h n i q u e u s i n g a d i a m a t a n a l y z -i n g s y s t e m ( B io - R a d , M u n i c h , G e r m a n y ) . L a b o r a -t o r y t e s t s i n c l u d i n g c r e a t i n i n e , h e m o g l o b i n ,S G O T , S G P T , g a m m a G T , a l k a l i n e p h o s p h a t a s e ,e r y t h r o c y t e s e d i m e n t a t i o n r a t e , l e u c o c y t e s , p l a t e-l e t s , t o t a l b i l i r u b i n , u r i c a c i d , c h o l e s t e r o l , a n dt r i g l y c e r id e s w e r e m e a s u r e d a t b a s e l in e a n d a f t e r6 , 12 , 1 8 a n d 2 4 m o n t h s .

Statist ical AnalysisC o n t i n u o u s v a r i a b le s a n d t h e i r d i ff e r e n c e s f r o mb a s e l i n e t o 2 4 m o n t h s w e r e a n a l y z e d u s i n gd e s c r i p t i v e s t a t i s t i c a l m e a s u r e s i n c l u d i n g t h ea r i t h m e t i c a l m e a n , s t a n d a r d d e v i a t io n , m e d i a n ,q u a r ti le s , m i n i m u m a n d m a x i m u m . D i c h o to -m o u s v a r i ab l e s w e r e a n a l y z e d b y c o n t i n g e n c y

t a b l e s a n d p r e - p o s t s h i f t t a b l e s . F o r e x p l o r a t i v et r e a t m e n t c o m p a r i s o n s t -t es ts f o r i n d e p e n d e n ts a m p l e s t o a n a l y z e t h e c h a n g e s f r o m b a s e l in e t o2 4 m o n t h s b e t w e e n t h e t h r e e g r o u p s s t u d i e d w e r ep e r f o r m e d . T h e l e v e l o f s i g n if i c a n c e w a s s e t a tc~ = 0 .0 5 . A l l t e s t s a r e o f d e s c r i p t i v e c h a r a c t e r o n l ya n d t h e re f o r e , n o a - a d j u s t m e n t w a s c o n s i d er e d .T r e a t m e n t e m e r g e n t a d v e r s e e v e n t s w e r e c o d e da c c o r d i n g to t h e W H O / B f A r M ( A d v e r s e R ea c ti o nT e r m i n o lo g y ) th e s a u r u s a n d a n a l y z e d o n p r e -f e r r e d te r m a n d o n b o d y s y s t e m l ev e l.

D a t a A n a ly s i sA t o t a l o f 29 9 p a t i e n t s w e r e r e c r u i t e d f r o m 3 2o u t p a t i e n t c e n t e rs in G e r m a n y a n d r a n d o m l ya s s i g n e d t o T A 1 2 0 0 , T A 6 0 0 o r P L A a c c o r d i n g t ot h e i r e n t r y s e q u e n c e f o l l o w i n g a c e n t r a l c o m p u -t e r i z e d r a n d o m i z a t i o n l is t. T h e i n i ti a l a i m w a s t ou s e a n i n t e n t i o n - t o - t r e a t s t a t i s t i c a l a n a l y s i s o ft h e s e p a t i e n t s , b u t m a j o r p r o b l e m s w e r e f a c e de v e n b e f o r e c o m p l e t i o n o f th e s t u d y i n c l u d i n g ah i g h r a t e o f d r o p - o u t s ( n - - 5 2) , w i t h d r a w a l d u e t oc o n c u r r e n t d is e a se ( n = 1 5 ) o r a d v e r s e e v e n t s( n = 3 ) , p r o t o c ol v io l at o rs ( n = 3 1 ) a n d p a t ie n t sw i t h p e r i p h e r a l v a s c u l a r d i s e a s e ( n = 2 9 ) . T h ep r i m a r y a n a l y s i s t h e r e f o r e i n c l u d e d 1 69 p a t ie n t s ,w h o h a d c o m p l e t e d th e 2 4 m o n t h t r ia l.

B e c a u s e o f m a j o r f l a w s i n t h e e l e c t ro p h y s i o l o -g i c a l a s s e s s m e n t i n a c o n s i d e r a b l e n u m b e r o fp a t i e n t s , a v a l i d t e s t o f t h e p r i m a r y h y p o t h e s i st h a t T A p r e v e n t s d i ab e t ic p o l y n e u r o p a t h y w a sn o t p o s s i b le . T h e r e f o r e , a s e c o n d a r y s u b g r o u pa n a l y s i s w a s p e r f o r m e d i n a c o h o r t o f p a t i e n t sf r o m w h i c h p a t i en t s w i t h p r o b a b l y i n v a l id o re x c e s s i v e ly v a r i a b l e r e s u lt s h a d b e e n e x c l u d e d .F o r t h i s p u r p o s e i n d e p e n d e n t c l i n i c a l n e u r o -p h y s i o l o g i s t s n o t i n v o l v e d i n t h e s t u d y w e r er e c r u i t e d t o a c t a s e x p e r t s t o e x c l u d e s e r ia l d a t ao f p a t ie n t s t h a t t h e y c o n s i d e r e d t o b e e x c e s s i v e l yv a r i a b l e o r n o t p l a u s i b le . A f t e r e x c l u s i o n b y t h i se x p e r t p a n e l o n l y 6 5 p a t i e n t s c o u l d b e i n c l u d e d i nthe f in a l ana lys i s (TA 1200 n = 18 , TA 600 n = 27 ,P L A n = 2 0).


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174 M. RELJANOVICet al.TABLE I Clinicalcharacteristics of patients suitable for analysis at entry

Placebo TA60 0 TA 1200Number 20 27 18Sex (Male/Female) 10/10 11/16 7 / 1 1Age (Years) 57.3 + 6.4 58.1 + 17.3 58.0 4- 5.5Bodymass index (kg/m2) 28.3 + 3.4 29.2 + 3.5 29.9 + 4.0Systolicblood pressure (mmHg) 137.74-10.5 141.3 4-17.8 140.6 4-18.6Diastolic blood pressure (mmHg) 82.0 4- 7.6 82.4 11.3 83.0 4- 8.9Smokers" 3 7 1HbAlc (%) at baseline 93 4- 2.2 88 1.5 9.1 4- 2.2HbAI (%) after24 months 9.14- 2.4 9.2 4- 2.2 8.0 4-1.5V a l u e s a r e m e a n + S D o r a n u m b e r o f p a t i en t s .

The baseline demographic data of thesepatients did not differ significantly between thegroups for an y of the variables listed (Table I).

R E S U L T S

Glycemic control The HbAlc levels changedfrom baseline to mo nth 24 from 9.1 +2.2% to8.0 + 1.5% in TA 1200, from 8.8 + 1.5% to 9.2 +2.2% in TA 600 an d from 9.3 + 2.2% to 9.1 2.4%in PLA. Comparisons of these changes did notshow any statistically significant differencesbetween the treatment groups.Peripheral nerve funct ion At entry into thestudy, there were no significant differences be-tween the groups for any of the four parametersstudied. After 24 months sural SNCV increasedsignificantly (all p-values com pared to PLA) inTA 1200 and TA 600 (both p < 0.05), su ral SNAPin TA 600 (p < 0.05) and in TA 1200 (p = 0.08).Tibial MNCV in creased significantly in TA 1200(p < 0.05). The ch anges in tibial MNDL d id notdiffer significantly between the three groupsafter 24 mo nt hs (Table l-I).

Furthermore, no significant differencesbetween the three groups were noted for thechanges of the NDS from baseline to 24 months(-0.2 -4- 2.9 point s in TA 1200, -0 .19 2.13 poin tsin TA 600, an d -0 .6 4- 3.1 poin ts in PLA).

Safety monotoring Treatment-emergent adv erseevents and laboratory tests showed no differ-ences between the gr oups as it is sho wn in TableIII. Furthermore the global assessment of toler-ability was very good and/or good in 100% ofthe patients in the PLA group, 89% in TA 600and 94% in TA 1200.DISCUSSIONIn this trial a beneficial and statistically significanteffect of TA on several attributes of nerve conduc-tion, particular ly sural SNCV, was ob served aftertwo years of treatment. The magnitude of im-pro veme nt in sural SNCVof 3 and 3.8 m/s for 600and 1200rag of TA, respectively, appears tosignify a clinically meaningful degree of improve-ment. I281 In additio n, it has been demo nstr atedthat 2-year treatment w ith 600 and 1200 mg of TAis safe, as it did not s how sig nificantly more sid eeffects than PLA treatment and was rated at verygoo d/g ood tolerability by almost all patients. Thelack of effect on the NDS is not surprising. First,the number of patients included in the finalanalysis was too small in view of the purpose ofthe NDS which was developed as a screeningmethod for epidemiological studies includinglarge group s of patients. Second, findi ng a favor-able effect on nerve conduction but not ondeficits is expected, because electrophysiologi-cal parameters are considered to be the most


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1 7 6 M . R E L J A N O V I C et a l .T A B L E H I T r e a t m e n t e m e r g e n t a d v e r s e e v e n t s b y b o d y s y s t e m s

Bo d y sy s t em l ev e l / W h o p re fe r red t e rm s T 1 2 00 (n = 1 0 1) T 6 0 0 (n = 1 0 0) PLA (n = 1 0 5)S k i n a n d a p p e n d a g e s d i s o r d e r sPru r i t u s 3 1 3

Sk i n u l ce ra t i o n 2 5 2M u s c u l o - s k e l e ta l s y s t e m d i s o r d e r sA r t h ra l g i a 5 6 8

A r t h ro s i s 3 5 3Back p a i n 9 1 9 1 8

C e n t r. a n d p e r i p h , n e r v o u s s y s t e m d i s o r d e r sC r a m p s l e g s 1 4 5D i zz i n es s 7 2 6H ea d ach e 1 6 1 1 1 2Pa raes t h e s i a 2 3 1A u t o n o m i c n e r v o u s s y s te m d i s o r d e r sG l a u c o m a 1 3 2H y p e r t e n s i o n 2 4 2

V i s i o n d i so rd e rsG l a u c o m a 1 3 2V i s i on a b n o r m a l 2 0 5

Psy ch i a t r i c d i so rd e rsS l eep d i s t u rb an c es 1 4 2G a s t r o i n t e s t i n a l s y s t e m d i s o r d e r s

A b d o m i n a l p a i n 1 0 5 7Co n s t i p a t i o n 3 1 1D i a r rh o e a 3 5 7D y s p e p s i a 6 5 3Fl a t u l en ce 3 2 4Gast r i t i s 1 4 4N a u s e a 7 4 2To o t h ach e 4 3 4

M et ab o l i c an d n u t r i t i o n a l d i so rd e rsH y p e r l i p a e m i a 2 2 6

C a r d i o v a s c u l a r d i s o r d e r sH y p e r t e n s i o n 2 4 2M y o e n d o p e r i c a r d i a l a n d v a l v e d i s o rd e r s

A n g i n a p ec t o r i s 6 9 5H e a r t r a t e a n d r h y t h m d i s o r d e r s

A r r h y t h m i a 2 4 1V ascu l a r (ex t raca rd i ac ) d i so rd e rsC r a m p s l e g s 1 4 5R e s p i r a t o r y s y t e m d i s o r d e r sBron chi t i s 15 12 9

C o u g h i n g 2 1 3Ph a ry n g i t i s 4 1 9Sinus i t i s 4 2 1U p p e r re sp . t ra c t i n fec t i o n 4 4 5

U r i n a r y s y s t e m d i s o r d e r sU r i n a ry t rac t i n fec t i o n 2 2 3B o d y a s a w h o l e - g e n e r a l d i s o r d e r sI n f l u e n z a -l i k e s y m p t o m s 1 6 1 8 1 9Pa i n 6 7 8

R e s i s ta n c e m e c h a n i s m d i s o r d e r sIn fec t i o n 3 6 2


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LIPOIC A CIDAN D NEUROPATHY 177a s s o c i a t e d w i t h e x p e r i m e n t a l d i a b e t i c n e u r o -pa thy . [21 I t ha s be e n de m on s t r a t e d tha t r e du c e dd i g i ta l n e r v e c o n d u c t i o n v e l o c i ty ( N C V ), n e r v eb loo d f low , a nd g lu t a th ione l e ve l s i n d i a be t i c r a tsa r e n o r m a l i z e d a n d in vitro l i p i d p e r o x i d a t i o n o fn e u r a l t i s s u e is r e d u c e d b y T A i n a d o s e - d e p e n -de nt ma nn er , [19"21 sug ge s t in g th a t the im pro ve -m e n t i n n e u r o v a s c u l a r ch a n g e s w e r e i n d u c e d b yi m p r o v i n g o x y g e n f r ee - ra d i c al s c a v e n g i n g a c t iv -i ty . O n e m e c h a n i s m o f r e d u c e d n e r v e b l o o d f l o wi s t he i nh ib i to r y e f f e c t o f supe r ox ide a n ion onva sod i l a t a t i on by s c e ve ng ing n i t r i c ox ide . S inc en i t ri c o x i d e s y n t h a s e i s r e d u c e d i n e x p e r i m e n t a ld i a b e ti c n e u r o p a t h y , I33] TA m igh t p r e ve n t t h i sinh ib i t i on by r e du c ing ox ida t ive st r es s . A r e c e n ts t u d y h a s a l s o d e m o n s t r a t e d t h a t t r e a t m e n tw i t h T A m a y c o r r e c t d e f i c i t s i n n e u r o p e p t i d e s( ne u r ope p t ide Y - a nd subs t a n c e P - l i ke a c t iv i t y ) i nsp ina l c o r d o f d i a be t i c r a t s , i nd i c a t ing tha t t hec o m p o u n d m a y b o o s t n e u r o t r o p h i c s u p p o r t . ~231F u r t h e r m o r e , T A h a s b e e n s h o w n t o i n c r e a s em y o c a r d i a l g l u c o s e u p t a k e / u t i l i z a t i o n a n dc a r d i a c ou t pu t , [34] e nha nc e e ndo ne u r i a l g luc oseu p t a k e , e n e r g y m e t a b o l i s m , a n d m y o - i n o s i t o lc o n t e n t, 351 i m p r o v e n e u r a l o r e n d o t h e l i u m -m e d i a t e d r e l a x at i o n i n t h e c o r p u s c a v e r n o s u m , 36Jp r e v e n t d y s f u n c ti o n o f e n d o t h e l i u m - d e p e n d e n th y p e r p o l a r i z i n g f ac t o r (E D H F) a n d N O s y s t e m sin the m e se n te r i c va sc u la tu r e , [37] pa r t i a l l y p r e ve n td i a b e t e s - i n d u c e d i m p a i r m e n t s o f a n t i o x i d a t i v ed e f e n s e , g l u c o s e i n t e r m e d i a r y m e t a b o l i s m v i ag lyc o lys i s , a nd e ne r g y s t a tu s i n l e ns ] 3 sl a nd toi n c r e a s e t h e N A D + / N A D H r a t i o , s u p e r o x i d ed i sm u ta se , a nd c a t a l a se a c t iv i t i e s i n s c i a t i cne r ve . [39] A d m in i s t r a t i o n o f l ow dose s o f TA /- ~-l i no l e n i c a c id c on juga t e c o r r e c t s t he ne r ve c on -duc t ion a nd ne r ve b lood f low de f i ci t s [4]a s w e l l a ssc i a t i c ne r ve c on te n t s o f ne r ve g r ow th f a c to r ,subs t a n c e P , a nd ne u r op e p t ide y [411 in d i a be t i cr a t s , sugge s t ing a syne r g i s t i c a c t i on o f t he sec o m p o u n d s . A n o t h e r m o d e o f a ct io n o f a - l ip o i ca c i d i n t h e e x p e r i m e n t a l s e t t i n g i n c l u d e s asup p r e s s ion o f t he a c t iva t ion o f t he f r e e r a d i c a l-s e ns i t i ve t r a nsc r ip t ion f a c to r N F - ~ B in c u l tu r e dend oth e l ia l ce ll s. [421 In te rac t ion of ad va nc ed

g l y c a t io n e n d p r o d u c t s (A G E s) w i t h t h e i re ndo the l i a l su r f a c e re c e p to r s ( R A G Es) ge ne r a t e sin t r a c e l lu l a r ox ida t ive s t r e s s , r e su l t i ng in a c t iva -t i o n o f N F -n B w h i c h t r a n s lo c a t e s i n t o t h e n u c l e u sa n d i n d u c e s t h e e x p r e s s i o n o f e n d o t h e l i a l g e n ep r o d u c t s s u c h a s e n d o t h e li n - 1 a n d t i s s u e fa c t o rtha t a re inc reased in d iabe tes . [42J Suc h a p ro tec t iono f c e ll u l ar a n t i o x i d a t iv e d e f e n s e m e c h a n i s m s b ya - l ip o i c a c i d t h a t p r e v e n t s e n d o t h e l i a l d y s f u n c -t i on in vitro v i a s u p p r e s s i o n o f N F -~ B a c t i v a t io nc ou ld a l so be r e l e va n t i n t he d i a be t i c ne r ve . I n ap r e l i m i n a r y s t u d y 3 - d a y o r a l t r e a t m e n t w i t h6 0 0 m g o f T A r e d u c e d N F - n B a c t i v a t i o n i np e r i p h e r a l b l o o d m o n o n u c l e a r ce ll s t h a t w a spa r a l l e l e d by a de c r e a se i n ox ida t ive s t r e s s i np l a s m a o f d ia be t i c pa t i e n t s w i th n e ph r o pa thy , 431O the r r e c e n t s tud i e s i n Type 2 d i a be t i c pa t i e n t sind i c a t e t ha t i . v . o r o r a l t r e a tm e n t w i th TA f o rs e v e r a l d a y s o r w e e k s m a y i m p r o v e i n s u l i nsens it ivity, 44"451 glu co se effectiv enes s, 46] a ndpar am ete rs o f inc reased oxid a t ive s t ress . [47] Th us ,t h e r e i s a b u n d a n t e v i d e n c e f r o m e x p e r i m e n t a ls t u d i e s s u g g e s t i n g a m a j o r p a t h o g e n e t i c ro l e o fox ida t ive s t r e s s i n d i a be t i c ne u r opa th y .

I n c o n c l u s i o n , t h e p r e s e n t r e s u lt s a l o n g w i t ht h o s e o f t h e r e c e n t s t u d i e s u s i n g a p p r o p r i a t e l yh ig h do se s o f TA (_> 600 m g pe r da y ) i nd i c a t e t ha t2 - ye a r t r e a tm e n t m a y e xe r t f a vo r a b le e f f e c t s onp e r i p h e r a l n e r v e f u n c t i o n i n d i a b e t ic p a t i e n t sw i t h po ly ne u r o pa thy . I t is o f pa r t i c u l a r i n t e r e s tt ha t no s ign i f i c a n t a dve r se r e a c t ions i n a s soc i a t i onw i t h t h e d r u g w e r e o b s e r v e d i n t h i s l o n g - t e r mt r e a tm e n t . To f u r the r subs t a n t i a t e t he r e su l t s o ft h e a f o r e m e n t i o n e d s t u d i e s a l a rg e s c a le c o n -t r o l l e d pha se I I I t r i al ( N A TH A N 1 ) i s be ing c on -d u c t e d i n N o r t h A m e r ic a a n d E u r o p e a c c o r d in gt o t h e r e c o m m e n d a t i o n s o f t h e P e r i p h e r a l N e r v eSo ciety . [29]

AcknowledgmentsT h i s s tu d y w a s s u p p o r t e d b y g r a n t s f r o m A S T AM e d i c a A G , F r a n k f u r t a m M a i n , G e r m a n y . T h ea u t h o r s t h a n k P r o f e s s o r D a n Z i e g l e r a n d P e t e rJ . D yc k f o r va lua b le d i s c us s ions .


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17 8 M. RELJANOVIC et al .P A R T I C I P A N T S I N T H E A L A D I N I I S T U D YP r i n c i p a l i n v e s t i g a t o r s H . M e h n e r t , K . R e t t ,M u n i c t i ( d i a b e t o l o g y ) , C . R e i c he l , Z w i c k a u ( n e u -r o l o g y ) ; s t u d y d i r e c t o r : M . L o b i s c h , F r a n k f u r t / M . ;s t u d y c o - o r d i n a t o r : K . S c h f i t t e ; q u a l i t y a s s u r a n c en e u r o l o g y : R . M a l e s s a , W e i m a r , M . R e l j a n o v i c ,Z a g r e b ; m o n i t o r i n g : E . - C . T i c i n e l l i , F r a n k f u r t / M ,M . A p a c e c h e a , A . A d a m c z y k , K F M M f i nc h e n ;s t a t i s t i c s : D . N e h r d i c h , F r a n k f u r t / M .

I n v e s t i g a t o r s , s t u d y s i te s ( p a t i e n t r e c r u i t m e n t )P . A d l e r , N f i r n b e r g ; M . A n d e r s , B e r l in ;R . B e l l m a n n , B e r l i n; H . C a r b o n i , B e r l in ; R . D i e t z e ,l n g o l s t a d t ; G . D r e p h a l , L e i p z i g ; J. E b e r t , B e r li n ;K . -H . , E b e r th , H o y e r s w e r d a ; E . E b n e r, R e g e n s b u r g ;R . E r n s t , W i e s b a d e n ; F a l g e , N f i r n b e r g K . F u n k e ,P o t s d a m ; G . G e r l a c h , M e i n i n g e n ; G . G r o h ,Z w i c k a u ; M . H a h n , L e i p z ig ; H e l m , N i i r n b e r g ;C h r . H e ~ l a n a n n , B e r l i n - P a n k o w ; R . H u n g e r l a n d ,B a s s u m ; E . I m h o f , I n g o l s t a d t ; V . J u n g ,W a l d k r a i b u r g ; M . K l u g e , B e r l i n ; R . K o s c i e l n y ,A p o l d a ; M . K r a m a r ; S . K r a n e i s , B e r n b u r g ; S . L u k a s ,H a l l e ; K 61 n; R . M i i ll e r, L a u c h h a m m e r - O s t ; M . P a h l ,B e r l i n ; D . P i g a r e k , E r f u r t ; P . S o n n e n s c h e i n ,N i i r n b e r g ; G . S c h e d o n , B e r l i n ; M . S t / i n d e l , B e r l i n ;K . W i n n , H a n n o v e r ; B . W i t z s c h e l , M o r i t z b u r g .

N e u r o l o g i s t s ( n e u r o g r a p h y ) Z . B a d a l , I n g o l s t a d t ,E . B a n z d o r f , M e i n i n g e n ; U . D a r n s t a e d t , B e r n b u r g ;W . D i r k s , H a n n o v e r ; P . D r e i g i g , B e r l i n ; R . M . E h r e t ,B e r li n ; A . H a g e n , H a l l e ; K. K e m p k e s , W i e s b a d e n ;K r a u s e , L e i p z i g ; J . L u t z , L e i p z i g ; G . M a r k ,R e g e n s b u r g ; M . M e i n k e , B e r l in ; H . M u n z e l ,B r i n k u m ; V . P i g a r e k , E r f u r t ; P l a u l , W e i m a r ;G . R e i c h e l , Z w i c k a u ; K . R o s c h e r , R a d e b e u l ;B . S a c h s , G r o g e n h a i n ; A . S c h u l z , B e r l in ; M . S t a f fe l ,N f i r n b e r g ; B. Z i e n e r t , H o y e r s w e r d a ; M . Z o m a k ,P o t s d a m ; Z o t t e r , A l t 6 t t i n g .

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insulin compared to conventional treatment and risk ofcomplications in patients w ith typ e II diabetes. (UKPDS33). Lancet , 352; 837-853.[3] D. Z iegler, M. H anefeld, K.J. Ruhnau, H.P . Meiflner,M. Lobisch,K. Schfitte,EA. Gries and The ALADINStudyGroup (1995) Treatment of symptom atic diabetic peri-pheral neu.ropathywith the antioxidant ~-lipoic acid. A 3-week m ulticentre randomized controlled trial (ALAD INStudy). Diabetologia,38: 1425-1433.[4] D. Ziegler, P. Mayer, H. Miihlen and EA. Gries (1993)Effekte einer Therapie m it r~-Lipons/iure gegenfiberVitamin B1 bei der diabetischen Neuropathie. Diabetesund S to f twechsel , 2: 443-448.[5] M. K iha ra, J.D . Schme lzer and J.F. Poduslo (1991)Aminoguanidine effects on nerve blood flow, vascularpermeability, electrophysiology, and oxygen free radi-cals. Proceedings o f the N at ional Acad emy o f Sc iences , 88:6107-6Ill.[6] E.A. Masson an d A.J.M. Boulton (1990) Aldose reductaseinhibitors in the treatment of DN P. A review of therationale and clinical evidence. Dru g s , 39: 190-202.

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