D I A G N O S I S , T R E A T M E N T A N D C O N T R O L O F FILARIASI*
ACKNOWLEDGEMENTS
W ith s i n c e r e t h a n k s t o t h e p a t i e n t s , t h e M i n i s t r i e s o f H e a l t h , t h e i n v e s t i g a t o r s a n d all w h o c o n t r i b u t e d t o t h e a m o c a r z i n e d e v e l o p m e n t .
R E F E R E N C E S
LECAILLON J . B . , DUBOIS J . P . , AWADZI K . , POLTERA A . A . , GINGER C D . Brit. J. din. Pharmac, 1990a, 30, 625-628.
LECAILLON J . B . , DUBOIS J . P . , SOULA G . , PICHARD E.., POLTERA A . A . , GINGER C D . Brit. J. din. Pharmac, 1990b, 30, 629-633.
POLTERA A . A . , ZEA-FLORES G . , GUDERIAN R . , BELTRANENA F . , PROANO R . , MORAN M., ZAK F . , STRIEBEL H . P . Lancet, 1991, 337, 5 8 3 - 5 8 4 . POLTERA A . A . (Editor). Trap. Med. Parasitol., 1991, 42 (suppl. III).
239-318.
IVERMECTIN LEVELS VARY I N TISSUES AND SPECIES
O K O N K W O P.O.*, N W O Y E I.* AND O G B U O K I R I J . E . *
KEYWORDS : ivermectin, chemotherapy, resistance, bioavailability, filariasis.
onchocerciasis.
SUMMARY
Ivermectin (IVM) is high in faeces, not found in urine but low in skin, saliva and bteastmilk of man. Plasma levels vary according to species.
Binding to plasma proteins varies also. Resistance of some farm ani
mal nematodes to the avermectins have been reported. A small per
centage of patients show poor reduction in skin mf after yearly treatment with Ivermectin. W e suggest that tissue bioavailability of free drug must be ascertained before interpreting animal models and che
motherapy programs.
I N T R O D U C T I O N
I
vermectin has a c h i e v e d m u c h attention in veterinary medic i n e b e c a u s e o f an e x c e l l e n t reputation as an endocitide.
T h e r e have b e e n reports o f resistence o f s o m e n e m a t o d e s in farm a n i m a l s t o i v e r m e c t i n (Craig, 1 9 9 3 ) . I n t e r e s t i n g l y , a small population o f individuals do not r e s p o n d t o ivermectin with reduction o f dermal microfilariae in mass c h e m o t h e r a p y programs. Filaria w o r m s in rodent m o d e l s o f filariasis (Wanji, 1 9 9 2 ) are also insentive to ivermectin. T h e r e have b e e n n o e x p l a n a t i o n s for t h e s e p h e n o m e n a . O n e p o s s i b l e e x p l a n a tion is variable bioavailability in s p e c i e s a n d tissues.
In this c o m m u n i c a t i o n w e h a v e m e a s u r e d ivermectin levels in tissues. Variations in the tissue effects o f anti-filarial drugs may b e related to in situ tissue bioavailability o f the drug.
M A T E R I A L A N D M E T H O D S
I
v e r m e c t i n is m e a s u r e d routinely in o u r laboratory b y an HPLC m e t h o d ( K l o t z et al., 1 9 9 0 ; K r i s h n a a n d K l o t z , 1993). T h e m e t h o d c a n d e t e c t 0.5 n g / m l with an interassay a n d intrassay variability averaging 3.6 % a n d 5.6 % r e s p e c t i -* University o f Nigeria T e a c h i n g Hospital, P M B 1 1 2 9 Enugu, Nigeria.
v e l y . T h e a s s a y t i m e is 10 m i n u t e s . All h u m a n s u b j e c t s g r a n t e d i n f o r m e d c o n s e n t . T h i s s t u d y r e c e i v e d r e q u i s i t e a p p r o v a l f r o m t h e E t h i c a l C l e a r a n c e C o m m i t t e e o f t h e University o f Nigeria T e a c h i n g Hospital.
R E S U L T S A N D D I S C U S S I O N
O ver the last four years w e have b e e n distributing iver- m e c t i n a n n u a l l y in a c o m m u n i t y h y p e r e n d e m i c for o n c h o c e r c i a s i s ( O k o n k w o et al., 1 9 9 1 ) . In this area w h e r e the g u i n e a s a v a n n a h a n d forest merge, there are typical skin lesions as well as e y e lesions.
T a b l e I lists s o m e p h a r m a c o k i n e t i c i n d e c e s in ten o n c h o c e r ciasis patients. T h e r e are w i d e individual variations in t h e s e p a r a m e t e r s . In this small p o p u l a t i o n o f patients, there are t w o p h a r m a c o g e n e t i c g r o u p s : Early Tmax (time to r e a c h m a x i m u m p l a s m a c o n c e n t r a t i o n ) - high Cmax ( m a x i m u m p l a s m a c o n c e n t r a t i o n ) g r o u p a n d l a t e Tm a x- l o w Cmax g r o u p . W e are investigating w h e t h e r the p e r s o n s with l o w levels o f ivermectin in b l o o d after the n o r m a l r e c o m m e n d e d 1 5 0 u g / k g c o r r e s p o n d w i t h t h o s e w h o s h o w l o w reduction in dermal and o c u l a r microfilariae.
Table 1. - Pharmacokinetic parameters of ivermectin in plasma of patients with onchocerciasis.
W e h a v e previously s h o w n that ivermectin b i n d s to p l a s m a p r o t e i n s ( O k o n k w o et al., 1 9 9 3 ) . T h e avidity o f b i n d i n g varies a c c o r d i n g to s p e c i e s if physiological c o n c e n t r a t i o n s are u s e d for in vitro c o n c e n t r a t i o n s . O n the a v e r a g e h u m a n serum a l b u m i n b i n d s 9 5 %, b o v i n e s e r u m a l b L i m i n 8 0 %, o v a l b u m i n 7 5 % a n d alpha 1 a c i d g l y c o p r o t r e i n < 5 0 % o f total b l o o d ivermectin. F r e e u n b o u n d drug is the o n l y phy
siologically active entity. T h u s levels a n d types o f proteins m a y largely d e t e r m i n e free drug levels. H y p o a l b u m i n i a a n d r a i s e d r e a c t i v e p r o t e i n s are often s e e n in parasitic i n f e c t i o n s . T h e T j / 2 o f i v e r m e c t i n s h o w s w i d e v a r i a b i l i t y in m a n y s p e c i e s , cattle 1.8, s h e e p 2.7, d o g 1.8, s w i n e 0 . 5 , rab
bit 0 . 8 , m a n 2.3 ( d a y s ) .
In m a n a n d s o m e farm a n i m a l s f a e c e s are the richest s o u r c e o f largely unaffected ivermectin. T h i s is most important in g u t d w e l l i n g n e m a t o d e s b u t o f little r e l e v a n c e for filaria w o r m s l o c a t e d in the lymphatic circulation or in skin l o c a tions. T h e drug c a n b e m e a s u r e d in saliva a n d breastmilk.
T h e levels in milk are l o w ( F i g u r e 1 ) a n d w e h a v e a d v o c a t e d ( O g b u o k i r i et al. in p r e s s ) that the restriction during lactation s h o u l d b e modified t o a l l o w the g e n e r a l i m p r o v e m e n t in well b e i n g after ivermectin distribution to e x t e n d to b a b i e s a n d their m o t h e r s .
Figure 2 is the c o m p a r i s o n o f the fractional e x t r a c t i o n o f ivermectin from p l a s m a in saliva, b r e a s t m i l k a n d skin. Skin
Pnrnsite. 1994. 1. I S
-27Article available athttp://www.parasite-journal.orgorhttp://dx.doi.org/10.1051/parasite/199401s1027
DIAGNOSIS, TREATMENT AND CONTROL O F FILARIASIS
with a h e t e r o g e n e i t y o f p r o t e i n s a n d lipids s h o u l d c o n t a i n l o w a m o u n t s o f ivermectin.
O u r o b s e r v a t i o n s are important in interpreting drug effects not only with ivermectin but with other filaricides in all forms of filariasis. T h e crucial question is w h e t h e r the drug should impinge o n the vital organelles o f the w o r m o r are host fac
tors m o r e responsible for drug induced w o r m killing (Schulz- Key et al., 1 9 9 3 ) . Is t h e adult 0. volvulus l e s s s e n s i t i v e b e c a u s e o f l o w ivermectin in the n o d u l e ? Are s o m e animal filaria m o d e l s unsuitable b e c a u s e the particular s p e c i e s s h o w low c o n c e n t r a t i o n at the target site ? W e also have s h o w n that in man there may b e a p h a r m a c o g e n e t i c basis for hand
ling o f ivermectin.
Figure 1. - Ivermectin in breastmilk.
Figure 2 . - Ivermectin concentration* in relation to plasma
* represents comparison between plasma and fluid or tissue levels in case of skin (mg skin/wt).
ACKNOWLEDGEMENT
T h e s t u d i e s r e p o r t e d h e r e w e r e s u p p o r t e d b y g r a n t s f r o m t h e C E C a n d T D R / W H O .
R E F E R E N C E S
CHIJIOKE C P . and OKONKWO P. : Adverse events following mass ivermectin therapy for onchocerciasis. Transactions Royal Society for Tropical Medicine and Hygiene, 1 9 9 2 , 86, 2 8 4 - 2 8 6 .
CRAIG T. : Anthelmintic Resistance. Veterinary! Parasitology. 1 9 9 3 , 46, 1 2 1 - 1 3 1 .
KLOTZ U., OGBUOKIRI J . E . and OKONKWO P. : Ivermectin binds avidly to plasma proteins. European Journal of Clinical Pharmacology, 1 9 9 0 , 39, 6 0 7 - 6 0 8 .
KRISHNA D.R. and KLOTZ U. : Determination o f Ivermectin in Human Plasma by High-performance Liquid Chromatography. Drug Research, 1 9 9 3 , 43, 5 , 6 0 9 - 6 1 1 .
OGISUOKTRI J . E . , OZLIMDA E . and OKONKWO P. : Low levels o f ivermec
tin are found in human breastmilk. European Journal of Clinical Pharmacology, accepted for publication.
OKONKWO P., OGBUOKIRI J . E . , Ofoegbu E . and Klotz U. : Protein bin
ding and ivermectin estimations in patients with onchocerciasis.
Clinical Pharmacology and Therapeutics, 1 9 9 3 , 5 3 , 4 2 6 - 4 3 0 . OKONKWO P., АКРА A., IHEKWABA A., NWAGHO D . , UMEH R., ADIBUA S.,
EZIKE V . , OGBUOKIRI J . E . : Studies on onchocerciasis in forest- savannah mosaic areas o f Nigeria. I. Investigations in Gbaragu, Oji River. Annals of Tropical Medicine and Parasitology, 1 9 9 1 , 85, 6 1 7 - 6 2 3 .
SCHULZ-KEY H., SOBOSLAY P.T. and HOFFMANN W. : Ivermectin media
ted immunity. Parasitology Today. 1 9 9 3 , 8, 1 5 2 - 1 5 3 .
WANJI S. : Un nouveau modèle pour la thérapeutique de l'oncho- cercose : la filaire à microfilaire dermique Monanema martini.
Thèse de Doctorat, Université de Montpellier, 1 9 9 2 , 1 9 9 p.
EFFECT OF REPEATED IVERMECTIN TREATMENT O N T H E EVOLUTION AND PROGRESSION OF OCULAR PATHOLOGY I N ONCHOCERCIASIS
BANLA M.*, HELLING G**, H E U S C H K E L C**, W O L F H.**, S O B O S L A Y P.T.**, LÜDER C.G.K.**, P R I T Z E S.*** A N D S C H U L Z - K E Y H.**
C O N C L U S I O N
T
h e m a n n e r in w h i c h s p e c i e s a n d i n d e e d i n d i v i d u a l s h a n d l e i v e r m e c t i n m a y vary c o n s i d e r a b l y . T h e r e s p o n s e o f t h e parasite d e p e n d s therefore o n its l o c a t i o n i.e. skin, n o d u l e , b l o o d o r l y m p h a t i c s a n d n u m e r o u s h o s t s factors ( S c h u l z - K e y et al., 1 9 9 3 ) a n d levels o f free drug impinding o n vital o r g a n e l l e s o f t h e w o r m . P h a r m a c o k i n e t i c p a r a m e - ters a n d free drug w o r m levels s h o u l d b e investigated for animal m o d e l s o f filariaris a n d n e w filaricides.K E Y W O R D S : onchocerciasis, ocular pathology, ivermectin.
T
n W e s t Africa, c o n t r o l o f o n c h o c e r c i a s i s by t h e _ Onchocerciasis Control Programme (OCP) relies on both vector eradication and chemotherapy (Remme et al., 1990a, 1990b). Ivermectin, the drug of choice, is highly effective against microfilariae of Onchocerca volvulus ; a single oral dose achieves a rapid elimination and a long lasting sup- pression of microfilaridermia (Greene et al., 1985). Such efficacy and the moderate adverse reactions following treat-* Centre Hospitalier de Région, Sokodé, Togo.
** Institute o f T r o p i c a l M e d i c i n e , U n i v e r s i t y o f T ü b i n g e n , Wilhelmstr. 2 7 , 7 2 0 7 4 Tübingen, Germany.
*** Deutsche Gesellschaft für Technische Zusammenarbeit (gtz), Eschborn, Germany.
