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L e t t e r s t o t h e E d i t o r 299

to be particularly common with treatment of respiratory infections, it has arisen also

duri ng treat ment of bone and soft tissue infection. 6 v Prescribers should be aware of

this problem and should continue to observe patients clinically and microbiologically.

It is importa nt to remember that the prime determinant of therapeutic success is

early diagnosis, s Ou r patient was a youn g, otherwise healthy diabetic. It remains to be

seen whether ciprofloxacin therapy is as effective in elderly, often poorly controlled,

diabetic patients who more often present with this condition.

D e p a r t m e n t s o f O t o l a r y n g o l o g y J . E . O s b o rn e

a n d o f P h a r m a c o l o g y a n d C l i ni c a l P h a r m a c o l o g y t R . L . B l a i r

N i n e w e l ls H o s p i t a l P . D a v e y t

D u nd ee D D I 9 S Y , U . K .

e f e r e n c e s

I. Chandler JR. Pathogenesis and treatment of facial paralysis due to malignant otitis externa.

Ann Oto l Rhino l Laryngol

1972; 8I: 648-658.

a. Norden CW, Shinners E. Ciprofloxacin as therapy for experimental osteomyelitis caused

by Pseudomonas aeruginosa. J Infect D is 1985 ; I5I: 291-294.

3. Greenberg RN, Tice AD, Marsh PK et al. Randomised trial of ciprofloxacin compared

with other antimicrobial therapy in the treatment of osteomyelitis. A m J M e d 82(Suppl

4A) : 266-269.

4. Elies W, Hermes H, Imm S. The role of gyrase inhibitors in affecting antibiotic

management in malignant otitis externa and other Pseudomonas-induced infections of the

ear.

Arch Oto Rhino Laryngol

1986; 243(5): 349 Abstr lO8.

5. Giamarellou H, Galankis N, Daphnis E, Stephanou J, Spirakis P. Treating acute and

chronic otitis with ciprofloxacin : a step toward a better prognosis ?

Rev Infect Dis

1988 ; IO :

S 2 5 1 - 2 5 2 .

6. Scully BE, Neu HC, Parry MF, Mandell W. Oral ciprofloxacin therapy of infections due

to Pseudomonas aeruginosa. Lancet i986; ii: 819-822.

7- Chapman ST, Speller DCE, Reeves DS. Resistance to ciprofloxacin.

Lancet

lO85; ii: 39.

8. Doroghazi RM, Nadol JB., Hyslop NE Jr.

et al.

Invasive external otitis : report of 2i cases

and review of the literature. A m J M e d 1981 ; 71 : 6o3-614.

A d d r e s s c o r r e s p o n d e n c e t o : M r J . E . O s b o r n e , G l a n C l w y d H o s p i t a l , B o d e l w y d d a n , R h y l , C l w y d ,

U . K .

e c o v e r y o f i m m u n o l o g i c a l c u t a n e o u s r e s p o n s i v e n e ss i n t h e a cq u i r e d

i m m u n e d e f i c ie n c y s y n d r o m e f o l lo w i n g tr e a t m e n t w i th p a p a v e r i n e

A c c e p t e d f o r p u b l i c a ti o n 29 S e p t e m b e r I988

Sir,

Tre atme nt of the acquired im mune deficiency syndr ome (A IDS ) is a matter o f lively

debate. Although more than 40 compounds are known to have some inhibitory effect

on the growth of the huma n immunodef iciency virus (HIV) in v i t r o / o n l y a few have

been tried clinically. Zidovudine has brou ght some improvemen t in patients with HI V

infection but this drug alone does not seem to be an entire solution to the problemfl

We wish to draw attention to our current experience with papaverine, an inhibitor

of cellular phosphodiesteras es. Th e drug, well kno wn as a non-specific smoo th muscle

relaxant, ~ has bee n shown to be active against measles virus in v i t ro . ~ We have found -

that papaverine also interferes with replication of HI V in hum an peripheral-b lood

mon onu clea r cells and in H9 cells. 6 In the H I V - H 9 cell system, papaverine blocked

HIV replication with complete disappearance of all viral proteins following an average

of 15 days exposure to the drug. In particular, the precurso r of the envelope protei n

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Letters to the Editor

g p 1 6 o w a s n o l o n g e r d e t e c t a b l e a f t e r 6 o h , s u g g e s t i n g e a r l y ac t i v it y o f p a p a v e r i n e o n

t h e s y n t h e s is o f H I V p r o t e in s .

T h e d r u g u n e q u i v o c a l l y i n h i b it e d r e v e r s e t r a n s c r i p t a se a c t i v it y a n d p 2 4 e x p r e s s io n

a t a c o n c e n t r a t i o n o f I O m g / 1 . A t al l c o n c e n t r a t i o n s t e s t e d , p a p a v e r i n e d i d n o t h a v e a n y

e f f ec t o n t h e p r o l i f e r a t i o n o f H 9 c e ll s.

F o l l o w i n g t h e s e e n c o u r a g i n g r e s u lt s

in vitro

w e s t a r t e d a n o p e n c l i n i c a l t r i a l w h i c h

h a s s o f a r i n v o l v e d t e n p e r s o n s a t d i ff e r i n g s ta g e s o f H I V i n f e c ti o n . W h i l e e i g h t o f

t h e m h a v e b e e n t r e a t e d f o r o n l y a f e w m o n t h s a n d i t is t o o s o o n t o d r a w c o n c l u s io n s

o n t h e e f f ec t o f t h e d r u g , t w o h a v e b e e n t a k in g p a p a v e r i n e f o r m o r e t h a n 2 4 m o n t h s .

T h e s e t w o p a t i e n t s w e r e d ia g n o s e d a s h a v i n g f u l ly d e v e l o p e d A I D S b e c a u s e o f

o p p o r t u n i s t i c i n f ec t io n s ( c e re b r a l to x o p l a s m o s i s a n d

Pneumocystis carinii

p n e u m o n i a )

b e f o r e s t a rt i n g t r e a t m e n t w i t h p a p a v e r i n e IO m o n t h s a f te r d ia g n o s is w h e n g e n e r al

d e t e r io r a t i o n i n h e a l th h a d a l r e ad y t a k e n p l a ce ( m a r k e d w e i g h t lo s s, l y m p h o c y t o p e n i a

w i t h I ' 5 I & / 1 a n d 2- 5 I o g / l ly m p h o c y t e s o f w h i c h 2 o a n d 3 0 % w e r e C D 4 + c el l s

r e s p ec t iv e l y ). E a c h p a t i e n t w a s g i v e n I 5 o m g p a p a v e r i n e o r a ll y (s l o w - r e le a s e

p r e p a r a t i o n ) s ix t i m e s a d ay . P h a r m a c o k i n e t i c s t u d ie s , b y m e a n s o f h i g h - p r e s s u r e

l iq u i d c h r o m a t o g r a p h y r e v e a l ed p e a k p l a s m a c o n c e n t r a t i o n s o f p a p a v e r i n e r a n g i n g

f r o m 0 7 to o ' 8 m g / 1 t o 2 h a f t e r t h e o r a l d o s e .

D e s p i t e t h e s e v a lu e s b e i n g m a r k e d l y l o w e r t h a n t h o s e n e e d e d t o a c h ie v e t h e a n t i -

H I V e ff ec ts o b s e r v e d

in vitro,

s e v e r a l f i n d i n g s i n t h e s e t w o p a t i e n t s s u g g e s t

in vivo

a c t i v it y o f t h e d r u g .

T w e n t y - f o u r m o n t h s a f t e r s t a r ti n g t r e a t m e n t w i th p a p a v e r i n e , b o t h p a t i e n ts w e r e i n

g o o d h ea l t h . N o o p p o r t u n i s t i c i n f ec t i o ns n o r o t h e r A I D S - r e l a t e d p h e n o m e n a w e r e

r e c o r d e d o v e r t h e p e r i o d o f t r e a t m e n t . B o d y w e i g h t i n c r e a s ed a f te r th e f i rs t 3 - 4

m o n t h s o f t r e a t m e n t a n d r e m a i n e d i n t h e n o r m a l r a n g e .

T o t a l l y m p h o c y t e c o u n ts a n d n u m b e r s o f C D 4 + c el l s r e c o v e r e d f ro m e x t r e m e l y

l o w v a l u e s t o l e ss d e p r e s s e d a n d s u s t a i n e d v a l u e s ( 3 .7 x IO 9 /1 a n d 4 5 x IO 9 /1

l y m p h o c y t e s w i t h 4 5 a n d 5 o % C D 4 + c e ll s r e s p e c t i v e ly ) . F o l l o w i n g a n i n s i g n i f ic a n t

i n it ia l d e c r e a s e , t h e c o n c e n t r a t i o n o f p 2 4 a n t i g e n i n t h e s e r u m d i d n o t c o r r e l a t e w i t h

t h e i m p r o v e d c l in i ca l s ta t e , h a v i n g f l u c t u a t e d o v e r t h e p e r i o d o f o b s e r v a t i o n .

N o a d v e r s e r e a c t i o n s o r s e r i o u s s i d e - e f f e c t s w e r e r e c o r d e d i n e i t h e r p a t i e n t , o n e o f

t h e m c o m p l a i n i n g o n l y o f h e a d a c h e i n t h e f ir st fe w d a y s o f t r e a t m e n t . B o t h c o n t i n u e d

t o r e s p o n d p o o r l y to m i c r o b i a l s k i n a n t i g e n s ( M u l t i te s t ) . W h e n i n o n e p a t i e n t ,

h o w e v e r , t h e d a il y d o s e o f p a p a v e r i n e w a s i n c r e a se d f r o m 9 o o t o I 35 O m g a fu l l

r e s p o n s e b e c a m e d e t e c t a b le f o r f o u r a n t i g e n s a f t e r 4 w e e k s o f t r e a t m e n t a t t h e n e w

d o s a g e . T h i s w a s a s tr i k i n g f i n d i n g s i n c e t h e r e c o v e r y o f s k i n r e s p o n s i v e n e s s , a s f a r a s

w e k n o w , h a s n e v e r b e e n r e p o r t e d i n a p a t i e n t w i t h A I D S s u c h a lo n g t i m e a f te r th e

i n it ia l d i ag n o s is . T h i s i m m u n o l o g i c a l i m p r o v e m e n t h a s a ls o b e e n c o n f i r m e d b y a r is e

i n t o t a l l y m p h o c y t e s a n d C D 4 + c e ll s ( f r o m 3 7 x I & / 1 t o 7 7 x IO 9/1 l y m p h o c y t e s a n d

f r o m 4 5 to

55

C D 4 + c e ll s) . I n t h i s p a t i e n t t h e s e r u m c o n c e n t r a t i o n s o f p a p a v e r i n e ,

w e r e a r o u n d 1.2 m g / 1 . A l t h o u g h m o r e

in vitro

a n d c l in i c a l s t u d i e s a r e n e e d e d , t h e

f in d i n g s r e p o r t e d h e r e s u g g e s t t h a t p a p a v e r i n e is w o r t h c o n s i d e r i n g a s a n a n t i r et r o v i r al

a g e n t .

T h e t h e r a p y o f H I V i n f e ct io n h a s p r o v e d d if fi cu l t b e c a u s e th e d r u g s s o f a r t r ie d h a v e

c o n s i s t e n t l y i n d u c e d s e v e r e s i d e - ef f e c ts , v,8 I n v i e w o f t h is , b e t t e r m a n a g e m e n t o f

p a t i e n t s m i g h t b e a c h i e v e d b y u s i n g s e v e r a l d i f f e r e n t d r u g s e i t h e r t o g e t h e r o r

a l t e r n a t e l y .

W h e n t h e a d m i n i s t r a t io n o f a n a n t ir e t ro v i r a l d r u g n e e d s t o b e s to p p e d b e c a u s e o f

s i d e- e f fe c ts , th e s u b s t i tu t i o n o f th e o r i g i n al c o m p o u n d w i t h a n o t h e r a n t i r et r o v i ra l

d r u g h a v i n g a l es s s e v e r e o r a d i f f e r e n t s p e c t r u m o f t o x i c i t y m i g h t b e h e lp f u l . T h i s

s u g g e s t io n is s u p p o r t e d b y t h e e m e r g e n c e o f se r io u s u n t o w a r d e f fe c ts o n r e d u c i n g t h e

d o s e o f zi d o v u d i n e . 9 P a p a v e r i n e m i g h t t h e n f in d a p l a c e as a n a l t e r n a t i v e i n a m u l t i d r u g

8/10/2019 Papaverine subida de cd4

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L e t t e r s to th e E d i t o r 3 o i

s t r a t e g y o f t r e a t m e n t , b e i n g e s p e c i a l ly s u i ta b l e f o r l o n g - t e r m t h e r a p y s i n c e i t s t o x i c i t y

s e e m s t o b e s l i g h t .

I s t i t u t o d i C l i n i c a d e l le D a n t e B a s s e t t i

M a l a t t i e I n f e t ti v e d e ll U n i v e r s it d d i V e r o na R o b e r to L u z z a t i

V e r o na I t a l y G i o v a n n i D i P e r r i

I s t i tu t o d e F a r m a c o l o g i a G i o r gi o S e g r e

d e l l U n i v e r s i t d d i S i e n a

S i e n a

I t a l y

I s t i tu t o d i M i c r o b i o lo g i a A d o l f o T u r a n o

d e l l U n i v e r s i t d d i B r e s c i a

B r e s c i a

I t a l y

e f e r e n c e s

I . A i d s / H f F e x pe r ime nt a l t r ea t me nt d irec tory. N e w Y o r k : A m e r i c an F o u n d a t i o n f or A I D S

R e s e a r c h ( A m F A R ) , I 9 8 8 .

2 . U s e o f A Z T i n H I V i n fe c ti o n s . R o u n d T a b l e , IV t h In t e rna t i ona l C onf e re nc e on AIDS,

Stockholm, I 2 - X 6 J une , I 9 8 8 .

3 . N i c k e r s o n M , V a s o d i l a t o r d r u g s . I n : The pha rmacological basis of therapeutics G o o d m a n ,

L S , G i l m a n A . e d s . N e w Y o r k : M a c m i l l a n , I 9 7 5 ; 7 35 .

4 . M i l l e r C A , C a r r i g a n D R . R e v e r s i b l e r e p r e s s i o n a n d a c t i v a t i o n o f m e a s l e s v i r u s i n f e c ti o n i n

n e u r a l c e l l s .

P r oc N a t l A c a d S c i U S A

I 9 8 2 ; 7 9 : I 6 2 9 - I 6 3 3 .

5 . B a s s e t t i D , T u r a n o A . P a p a v e r i n e ( R S 4 7 ). I n : , 4 I D S / H I V e x p er im e n ta l t re a tm e n t

directory, v o l. 2 . N e w Y o r k : A m e r i c a n F o u n d a t i o n f o r A I D S R e s e a r ch ( A m F A R ) , I 9 8 8 ;

7 9 - 8 0 .

6 . C a r u s o A , S c u r a G , B o n f a n t i C , L u z z a t i R , M a n c a N . , B a s s et ti D , T u r a n o A . P a p a v e r in e

i n h i b i ts H I V r e p l ic a t io n

in v i t ro. IV th Internat ional Conference on A I D S , Stockholm ,

I 2 - I 6

J une , I 9 8 8 .

7 . R i c h m a n D D , F i s c h l M A , G r ie c o M M , et al. T h e t o x i ci t y o f a z i d o t h y m i d i n e ( A Z T ) i n t h e

t r e at m e n t o f p a ti e n ts w i th A I D S a n d A I D S - r e l a t e d c o m p l ex . N e w E n gl J M e d I 9 8 7 ; 3 1 7 :

I 9 2 - I 9 9 7 .

8 . Y a r c h o a n R , P e r u o C F , T h o m a s R V

et al.

P h a s e I s t u d i e s o f 2 3 - d i d e o x y c y t i d i n e i n s e v e r e

h u m a n i m m u n o d e f i c i e n c y v i r u s i n f e c t i o n a s a s i n g l e a g e n t a n d a l t e r n a t i n g w i t h z i d o v u d i n e

( A Z T ) . Lanc e t I 9 8 8 ; i : 7 6 - 8 I .

9 . H e l b e r t M , R o b i n s o n D , P e d d l e B e t al. A c u t e m e n i n g o - e n c e p h a l i t i s o n d o s e r e d u c t i o n o f

z i d o v u d i n e .

Lanc e t

I 9 8 8 ; i: I 2 4 9 - I 2 5 2 .