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T N MATERIALS AND METHODS INTRODUCTION P AND TREATMENT OF TOXOPLASMA GONDII L

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L

a c k o f a c t iv it y o f a r t e m e t h e r f o r p r o p h y l a x i s

AND TREATMENT OF TOXOPLASMA GONDII

a n d

P

n e u m o c y s t i s c a r in i i in f e c t io n s in r a t

BRU N -PA SCA U D M .*, CHAU F.*, D E R O U IN F.** & G IRARD P.M .*,***

S u m m ary :

Artemisinin and its derivatives have been found effective in vivo against Plasmodium and in vitro against Toxoplasma gondii and Pneumocystis carinii. W e tested the activity of artemether for prophylaxis and treatment in the rat model of concurrent T. gondii and P. carinii infection. Artemether at doses of 18 and

10 0 mg/kg administered (s.c.) in prophylaxis did not prevent toxoplasmosis or pneumocystosis, while trimethoprim-

sulfamethoxazole (reference treatment) w as effective for prevention of both infections. Similar results were obtained in curative studies.

These results do not support the use of artemether for prevention or treatment of toxoplasmosis or pneumocystosis.

KEY WORDS : Toxoplasma gondii, Pneumocystis carinii, artemether, prophylaxis, treatment.

R é s u m é : In e f f i c a c i t éd e la r t é m e t h e r d a n s la p r é v e n t i o n e tl e TRAITEMENT DE LA TOXOPLASM OSE ET DE LA PNEUMOCYSTOSE CHEZ LE RAT CO-INFECTÉ

L'artemisinine et ses dérivés ont une activité anti-Plasmodium in vivo et une activité anti-Toxoplasma gondii et anti -Pneumocystis carinii in vitro. L'artémether a été évalué en prophylaxie et en traitement d e la toxoplasmose et d e la pneumocystose chez le rat co-infecté.

Contrairement au triméthoprime-sulfaméthoxazole (traitement de référence), l'artémether, aux doses d e 18 ou 100 m g/kg (administré p a r voie sous-cutanée) ne permet ni la prévention ni le traitement d e la pneumocystose et de la toxoplasmose.

MOTS CLÉS : Toxoplasma gondii, Pneumocystis carinii, artemether, prophylaxie, traitement.

IN T R O D U C T IO N

N

ew approaches for therapy and prophylaxis o f toxoplasm osis and pneum ocystosis are urgently needed becau se o f the high fre­

quency o f side effects associated with the administra­

tion o f sulfonam ides and folates inhibitors. In this context, artemisinin and its derivatives may be o f potential interest as these compounds, which have acti­

vity against P la sm o d iu m in experim ental models and in humans (Peters et al., 1986; White, 1994) have been also found effective in vitro against T. g o n d ii and P. c a r in ii (Merali & M eshnick, 1991; Ou-Yang et al.,

* INSERM Unité 13, Hôpital Bichat-Claude Bernard, 170, boulevard Ney, 75877, Paris Cedex 18, France.

** Laboratoire de Parasitologie-Mycologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75475 Paris Cedex 10.

*** Service des Maladies Infectieuses et Tropicales, Hôpital Rothschild, 33, boulevard de Picpus, 75012, Paris, France.

Correspondence: Monique Brun-Pascaud. Tel.: 33 1 40 25 86 05.

Fax: 33 1 40 25 86 02.

This study was done in accordance with prevailing regulations regarding care and use o f laboratory animals in European Commu­

nities (Jo u rn a l officiel des Comm unautés Européennes, 18 Décembre 1986, L358).

1990). However, Chang et al. (1988) reported that arteether was ineffective in the treatm ent o f acute toxoplasm osis, but no data is available for prophylaxis of toxoplasm osis or pneumocystosis. In this study, we took advantage o f the use o f a rat model o f concur­

rent T. g o n d ii/ P. c a r in ii (Brun-Pascaud et al., 1994) to evaluate the efficacy o f artemether for treatment and prevention o f both infections.

MATERIALS A N D M ETH O D S

T

he experim ental design has been described in detail elsew here (Brun-Pascaud et al., 1994).

Briefly, P. c a r in ii infection was induced in Wistar rats by 25 mg o f cortisone acetate (Hydrocor­

tiso n e R o u ssel®; H o ech st-R o u ssel, Paris, F ran ce) injected subcutaneously twice w eekly and a low-pro- tein (8 %) diet (Usine Alimentation Rationelle, Ville- moisson, France). After 5 w eeks o f immunosuppres­

sion , rats w ere in o cu la te d in tra p e rito n e a ly w ith 107 tachyzoites o f the virulent RH strain o f T. g on d ii.

For prophylactic experim ents, rats were treated from the initiation o f the corticosteroid treatment. In the refe­

rence prophylactic group, rats received p e r os trime-

Parasite, 1996, 3 , 187-189

Note de recherche 187

Article available athttp://www.parasite-journal.orgorhttp://dx.doi.org/10.1051/parasite/1996032187

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BRUN-PASCAUD M . CHAU F , DEROUIN F. & GIRARD P M

th o p rim -su lfa m e th o x a z o le (TM P-SM X) (Bactrim ® , Pediatric suspension; Roche, Neuilly-sur-Seine, France) 5 days per w eek then every day after T. g o n d ii ino­

culation at daily dose o f 20 and 100mg/kg respectively, and rats in the control group received no therapy. All surviving rats w ere sacrificed after 7 w eeks o f corti­

costeroid administration.

As preliminary experim ents show ed that a high dose (lOOmg/kg, s.c., three times a w eek) o f artemether (Paluther® ; R h o n e -P o u len c R orer D om a, Antony, France) induced acute toxicity, artemether was sub- cutaneously (s.c.) administered using three different schedules as follows: i) 18mg/kg/day 2 days per w eek th e n ev e ry day a fter T. g o n d i i in o c u la tio n , it) 18 mg/kg/day 5 days per w eek and Hi) 100 mg/kg/day 2 days per w eek then every day after T. g o n d ii ino­

culation in prophylactic experiments. In curative exp e­

riments, the same daily dosages w ere administered every day from the second day following the intrape- ritoneal inoculation o f T. g o n d ii until death or sacri­

fice.

P. c a r in ii cyst counts w ere determined in lung tissue after enzymatic digestion and Toluidine blue O stai­

ning. T. g o n d ii infection was quantified in target organs by an indirect im m unofluorescence assay following tissue culture (Brun-Pascaud et al., 1994).

P. c a r in ii cysts counts and T. g o n d ii parasitic burdens w ere processed using one-w ay analysis o f variance, and each interesting pair o f groups was compared using Bonferroni’s adjusted ¿test (Godfrey, 1985). Dif­

ferences in values w ere considered significant if the P value was < 0.05 or 0.05 divided by the num ber of tests made. Data w ere expressed as m eans ± 1 stan­

dard deviation.

RESULTS

R

esults o f prophylactic experim ents are sum­

m arized in T a b le I. A ctive in fe c tio n w ith P. ca r in ii and T. g o n d ii was found in all control rats. 15 o f 17 rats treated with artemether died within 8 days (range 4-8, mean: 5.8 ± 1.1) post T. g o n d ii ino­

culation and all rats exhibited active infection with T. g o n d ii and P. c a r in ii even at the higher dosage. In contrast, all rats treated with TMP-SMX w ere alive 14 days after T. g o n d ii inoculation and w ere then sacrificed: neither pleural fluid effusion nor T. g o n d ii was found in organs and the level o f P. c a r in ii cyst counts reflected a latent infection as usually dem ons­

trated (Brun-Pascaud et al., 1994).

No curative effectiveness o f artem ether could also be demonstrated: 8 o f 10 treated rats died at 6.1 ± 2.6 post T. g o n d ii inoculation. The means T. g o n d ii burdens w ere log 4.2 ± 0.8 and log 4.7 ± 0.4 in lung, log 2.1 ± 1.2 and 1.6 ± 1.6 in brain, 6.2 ± 0.6 and 4.5 ± 2.6 in spleen and log 5.7 ± 1.6 and 5.4 ± 2.1 in liver, the P. c a r in ii counts w ere log 5.4 ± 0.8 and 5.0 ± 0.7 in rats treated resp ectiv ely w ith 18 mg/kg/day and 100 mg/kg/day. T. g o n d ii and P. c a r in ii infections were

Groups Untreated controls

Prophylactic treatm ent“

Artemether Artemether

18 mg/kg 100 mg/kg

TMP-SMX 20-100 mg/kg

Treatment day/week 2/week 5/week 2/week 5/week

(Number of rats) (10) (6) (5) (6) (5)

Day o f death or sacrifice death death death death sacrifice

post T. gon dii infection 5.7 ± 2.8 6.2 ± 0.5 5.7 ± 1.0 7.5 ± 3.7 14

(number o f rats) (8/10) (4/6) (5) (6) (5)

Pleural fluid volume (ml) 5.5 ± 1.7 3.2 ± 1.7 5.4 ± 2.2 3.3 ± 2.0 0

T. g on dii (log 10)

pleural fluid 2.1 ± 1.8 2.2 ± 1.5 3.4 ± 0.8 2.6 ± 2.0

lung 4.7 ± 0.8 4.7 ± 0.4 4.6 ± 0.5 4.5 ± 0.9

brain 2.2 ± 1.1 0.8 ± 1.7 3.8 ± 0.7 2.7 ± 1.6 0*

spleen 4.7 ± 0.9 4.7 ± 0.8 5.5 ± 0.4 5.6 ± 1.0 0*

liver 5.9 ± 0.4 5.8 ± 0.4 6.1 ± 0.3 6.4 ± 0.2 0*

P. carin ii (log 10)

lung 6.3 ± 0.8 5.3 ± 0.9 6.6 ± 0.3 5.7 ± 1.0 2.6 ± 0.6*

a Drugs were given daily after T. gon dii inoculation. * p < 0.001 vs untreated controls.

Table I. — Prophylactic activity o f artemether against P. carinii and T. gondii infections.

188 Note de recherche Parasite, 1996, 3, 187-189

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bm m éim i/ToxopiA SM A gondii and Pneumocystis u s m i

not any different compared to untreated controls. TMP- SMX reference com bination was fully effective on both infections, all rats were alive after 14 days o f treatment;

at autopsy, tissue cultures for T. g o n d ii w ere negative in all organs, and the mean num ber o f P. c a r in ii cysts was log 3.6 ± 0.3.

C O N C L U S IO N

O

ur results show that artemether was ineffec­

tive fo r the treatm ent or p rev en tio n o f T. g o n d ii and P. ca r in ii infections, even using the higher dosages that can be tolerated in rats. These results, which are in agreement with those reported by Chang and Pechere (1988) with the related compound arteether in the treatment o f acute murine toxoplas­

mosis, are rather disappointing in regard to the excel­

lent in vitro activity o f these com pounds (Holfels et al., 1994; Ou-Yang et al., 1990), and do not support the use o f these drugs in humans for treatment or pre­

vention o f both toxoplasm osis and pneumocystosis.

ACKNOWLEDGEMENTS

W

e thank Rhô ne-Poulenc Rorer Doma for the kind supply o f artemether. This study was supported in part by a grant from the Agence Nationale pour la Recherche sur le SIDA.

REFERENCES

Br u n-Pa sc a u d M ., Ch au F., Sim o n po l i A .M ., Gir a r d P .M ., Dero u inF. & Po cid a loJ.J. Experimental evaluation of com­

bined prophylaxis against murine pneumocystosis and toxoplasmosis. Jo u rn a l o f Infectious Diseases, 1994, 170, 653-658.

Ch an g H R. & Pech er eJ.C. Arteether, a Qinghaosu deriva­

tive, in toxoplasmosis. Transactions o f The Royal Society o f Tropical M edecine a n d Hygiene, 1988, 82, 867.

Go d f r e y K . Comparing the means of several groups. New England Jo u rn a l o f Medecine, 1985, 313, 1450-1456.

Ho lfelsE., Mc a u leyJ., Ma c k D., Mil h o u sW.K. & Mc le o d R.

In vitro effects of Artemisinin ether, Cycloguanil hydro­

chloride (alone and in combination with Sulfadiazine), Quinine sulfate, Mefloquine, Primaquine phosphate, Tri­

fluoperazine hydrochloride, and Verapamil on Toxoplasma gondii. Antimicrobial Agents a n d Chemotherapy, 1994, 38,

1392-1396.

Merai.i S. & Mesh n ick S.R. Susceptibility of Pneumocystis carin ii to artemisinin in vitro. A ntim icrobial Agents a n d Chemotherapy, 1991, 35, 1225-1227.

Ou- Yang K ., Kru g E .C ., Mark J . & Beren s R.L. Inhibition of growth of Toxoplam a gon dii by Qinghaosu and deriva-

Parasite, 1996, 3, 187-189

tive. Antim icrobial Agents a n d Chemotherapy, 1990, 34, 1961-1965.

Peters W ., Ze-Lin L, Ro b in so n B.L. & Wa rh urstD.C. The che­

motherapy of rodent malaria. XL. The action of artemisinin and related sesquiterpenes. Annals o f Tropical M edecine a n d Parasitology, 1986, 80, 483-489.

Wh ite N.J. Artemisinin: current status. In Artemisinin. Tran­

sactions o f The Royal Society o f Tropical M edecine an d Hygiene, 1994, 88, S1/1-65.

Reçu le 19 décembre 1995 Accepté le 6 février 1996

N ote d e recherche 189

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