Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, October 2000, p. 2836-2841, Vol. 44, No. 10
Laboratoire d'Immunologie et Parasitologie,
UFR Sciences Pharmaceutiques, F-34060 Montpellier Cedex
2,1 and Laboratoire de Chimie de
Coordination du CNRS, F-31077 Toulouse Cedex 4,2
France
Received 17 April 2000/Returned for modification 19 June
2000/Accepted 14 July 2000
The in vitro potentiation of artemisinin by synthetic manganese
porphyrin complexes has been recently reported (F. Benoit-Vical, A. Robert, and B. Meunier, Antimicrob. Agents Chemother. 43:2555-2558, 1999). Since the activity of artemisinin and synthetic antimalarial endoperoxides is related to their interaction with heme (S. R. Meshnick, A. Thomas, A. Ranz, C. M. Xu, and H. Z. Pan, Mol.
Biochem. Parasitol. 49:181-190, 1991), an improvement of their
efficiency may be expected in the presence of a synthetic
metalloporphyrin having the same activating role as endogenous heme.
With the aim to boost the activity of antimalarial endoperoxide drugs,
we were thus led to evaluate the in vitro and in vivo potentiation of natural and synthetic drugs of this family by a nontoxic and cheap metalloporphyrin. The potentiation of artemisinin, Artemisinin is a sesquiterpene
lactone containing an endoperoxide that is critical for its
pharmacological activity as an antimalarial drug. Artemisinin 1 and its
hemisynthetic derivative artemether 2 (Fig.
1) are currently used to treat severe or
multidrug-resistant Plasmodium falciparum malaria, including
cerebral malaria. A synthetic compound with an endoperoxide function
like arteflene, Ro 42-1611 (19), also exhibits strong
antimalarial activity. Artemisinin derivatives are active during the
intraerythrocytic stage of infection. The inhibition of hemozoin
formation by artemisinin 1 has been proposed (25) but is
still controversial (1). It has been proposed that the
intraparasitic heme liberated during hemoglobin digestion might play an
important role in the selective toxicity of artemisinin toward the
parasite (24), and the reductive activation of artemisinin 1 or other endoperoxide-based antimalarial drugs by Fen heme
is probably a key point in the mechanism of action of these drugs
(8, 23, 33). In the presence of synthetic heme models such
as the iron or manganese complexes of
meso-tetraphenylporphyrin, it was recently found that
artemisinin and many synthetic endoperoxides are able to generate
alkylating intermediates via formation of either C-centered radicals
(27, 32, 34) or other reactive species (5). For
these compounds, the same mechanism of reductive activation by the
synthetic metalloporphyrin or by heme itself gives rise to different
drug-derived reactive species which can behave as alkylating agents
with respect to heme or parasitic proteins. Such modifications of
essential molecules of the parasite should be responsible for the
antimalarial effect.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
In Vitro and In Vivo Potentiation of Artemisinin
and Synthetic Endoperoxide Antimalarial Drugs by
Metalloporphyrins
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
-artemether, and
arteflene (Ro 42-1611) by synthetic heme models is reported. In vitro
studies on the chloroquine-resistant Plasmodium falciparum FcB1-Columbia strain indicate a synergistic effect of the manganese complex of meso-tetrakis(4-sulfonatophenylporphyrin)
(Mn-TPPS) on the activity of artemisinin or -artemether, whereas
this heme model has no influence on the activity of arteflene. A
significant synergistic effect on rodent malaria was also observed in
vivo between artemisinin and Mn-TPPS using Plasmodium vinckei
petteri strain.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
View larger version (8K):
[in a new window]
FIG. 1.
Structures of the endoperoxide antimalarial drugs 1 through 3.
We therefore looked for a possible potentiation of artemisinin,
-artemether, and arteflene activity by an added synthetic metalloporphyrin, which could act as enhancer of the drug-endoperoxide activation step as well as the endogenous iron(II) heme. This procedure was carried out on one hand in P. falciparum-infected human erythrocytes and on the other hand in
murine malaria. In a previous study, the potentiation between
artemisinin and the iron and manganese complexes of
meso-tetrakis(4-sulfonatophenylporphyrin) (TPPS) and
meso-tetrakis(3,5-disulfonatomesityl porphyrin) (TMPS) was
evaluated in vitro (4). A synergistic effect was
found between artemisinin and Mn-TPPS but not with the iron
porphyrin analogue. In the present study, a similar behavior was
observed with -artemether in the presence of manganese porphyrin
complexes in vitro. However, the metalloporphyrins used had no effect
on the activity of the synthetic antimalarial drug arteflene. In vivo,
on Plasmodium vinckei petteri, we observed a significant synergistic effect of Mn-TPPS on the activity of artemisinin but a
decrease of the efficiency of -artemether in the presence of the
same metalloporphyrin. This apparent antagonistic effect can probably
be attributed to an increased activation of -artemether outside of
its target in the presence of Mn-TPPS, this phenomenon leading to a
lower concentration of "useful" drugs within the parasite.
| |
MATERIALS AND METHODS |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
|
|---|
Materials. The resin TEMEX, AG50W-X8, H+ form, was purchased from Touzart & Matignon (Vitry-sur-Seine, France). Artemisinin was purchased from Aldrich (Saint-Quentin Fallavier, France). Tetraphenylporphyrin and other commercially available chemicals were from Aldrich, Fluka (Saint-Quentin Fallavier, France) or Merck (Nogent-sur-Marne, France). Artemether and arteflene were gifts of Rhône-Poulenc-Rorer Doma (Antony, France) and Hoffmann-La Roche (Basel, Switzerland), respectively.
Porphyrin synthesis. The hydrophobic ligand meso-tetramesitylporphyrin and the corresponding hydrosoluble octasulfonated derivative H2-TMPS were prepared as previously described by Hoffmann et al. (15) and Song et al. (36), respectively. The hydrosoluble tetrasulfonated derivative H2-TPPS was prepared by modification of a published synthesis (38) as follows. To recover the sulfonated porphyrin from an aqueous solution containing a huge amount of salt, n-tetrabutylammonium chloride was added (3 eq. per sulfonate group). The porphyrin containing four tetrabutylammonium counterions was then extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and evaporated to dryness. This desalted porphyrin was then dissolved in water and passed over a column of strongly acid resin AG50W-X8 pretreated with 1 M NaOH to regenerate the sodium sulfonate groups. The eluted aqueous solution was evaporated, and the pure tetrasodium salt of H2-TPPS was dried under vacuum.
The manganese complexes Mn-TPPS and Mn-TMPS were prepared by reaction of the corresponding ligands with MnII(OAc)2·4H2O (1.1 eq.) in refluxing water for 2 h. After cooling, the reaction mixture was treated with resin AG50W-X8, Na+ form, and filtered. The metalloporphyrins were dissolved in a minimum amount of methanol, precipitated by addition of diethyl ether, filtered, and dried under vacuum. For Mn-TPPS, the UV-vis (water)
, in nanometers (
,
mM
1 × cm1), is 378 (58), 400 (59),
420sh, 466 (100), 516 (7), 564 (12), 596 (9). For Mn-TMPS, the UV-vis
(water) , in nanometers (, mM1 × cm1), is 378 (30), 400 (32), 420sh, 468 (80), 568 (6).
Parasites. The chloroquine-resistant P. falciparum strain FcB1-Colombia was cultured in vitro using standard techniques (39) in a 5% CO2 atmosphere at 37°C (3). Cultures were synchronized by combination of gelatin (Plasmagel; Roger Bellon, Paris, France) and 5% D-sorbitol lysis (Merck, Darmstadt, Germany) (20, 21).
Antimalarial activity. The in vitro antimalarial-drug-sensitivity microtest was adapted from the micromethod of Desjardins et al. (10). Drugs were tested three times in triplicate in 96-well plates with cultures at ring stage (synchronization interval, 16 h) at 0.5 to 1% parasitemia (hematocrit, 1%). For each test, the plates of parasite culture were incubated with drugs at decreasing concentrations for 32 h and 72 h because of the timing of the onset and cessation of DNA, RNA, and protein synthesis (14, 18). The first dilutions of artemisinin (Sigma, France) and metalloporphyrins were prepared in sterile dimethyl sulfoxide (Merck) and Milli-Q ultrapure water, respectively (1 mg/ml), and later dilutions were with RPMI 1640 (Life Technologies, Cergy Pontoise, France). Parasite growth was estimated by incorporation of [3H]hypoxanthine (Amersham-France, Les Ulis, France) (3). Concentrations inhibiting 50% of the parasite growth (IC50) were determined graphically in concentration versus percent inhibition curves for each endoperoxide drug and each metalloporphyrin after 32 h or 72 h of incubation, with [3H]hypoxanthine being added to the medium at 24 h and 56 h, respectively.
In vitro potentiation tests. The effect of the manganese porphyrin complexes on the IC50 of endoperoxides was determined by potentiation experiments as described in reference 22. Isobolograms were constructed by plotting a pair of fractional IC50s for each combination of endoperoxide and metalloporphyrin. Endoperoxide fractional IC50s were calculated by dividing the IC50 of each endoperoxide combined with the metalloporphyrin by the IC50 of the endoperoxide alone, and these data were plotted on the horizontal axis. The corresponding metalloporphyrin fractional IC50 was calculated by dividing its fixed concentration by the IC50 of metalloporphyrin alone and was plotted on the vertical axis (13). An isobologram as a straight diagonal indicates an additive effect. Curves above or below the diagonal indicate antagonistic or synergistic effects, respectively. Results too close to the diagonal are considered as additive.
In vivo drug potentiation. Cell line 106WH of P. vinckei petteri, kindly supplied by E. Deharo (Muséum National d'Histoire Naturelle, Paris, France), was maintained in mice by syringe passage. Female CD1 mice (6 weeks of age, 20 ± 2 g) were used in this study. The mice were kept at a temperature of 22 ± 3°C and provided with a standard diet and water. They were inoculated intraperitoneally with 2 × 107 infected erythrocytes on day 0. The 4-day test was carried out as previously described (26) and was repeated three times. For the determination of the 50% effective dose (ED50) values, groups of five mice were treated by intraperitoneal injection once daily for four consecutive days with a range of doses, beginning 3 h after infection on day 0. All experiments included a drug-free control group, three or four groups were treated with different doses of the endoperoxide, three groups were treated with different doses of Mn-TPPS administered alone, and three to five groups were treated with Mn-TPPS in combination with the endoperoxide (9, 31). For each endoperoxide drug, three independent experiments were made. Parasitemia was checked by Giemsa Diff-Quik (Dade Behring, Paris, France)-stained blood smears on day 4 (i.e., 24 h after the final treatment). The reduction of parasitemia in treated groups was calculated as a percentage of parasitemia of untreated control groups. The ED50 doses resulting in 50% decreases in parasitemia are expressed in milligrams per kilogram of body weight per day. The 95% confidence intervals were calculated by a statistical study. In order to evaluate the putative toxicity of Mn-TPPS, a group of healthy mice was treated with Mn-TPPS at 40 mg/kg of body weight/day for 4 days.
Statistical study. The multiple comparison procedure of the Dunnett test (11) permitted us to examine the differences in vivo between all treated groups in comparison with the control group (PC-pcsm software, version 6.0, 1992; Delta-soft, Meylan, France).
| |
RESULTS AND DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
|
|---|
IC50 values and in vitro potentiation tests.
The
IC50 values obtained for artemisinin, artemether,
arteflene, Mn-TPPS, and Mn-TMPS on P. falciparum FcB1 strain
are reported in Table 1. These
results indicate that, on the chloroquine-resistant P. falciparum FcB1-Columbia strain, artemether is 3.5-fold as efficient as the parent drug artemisinin (IC50, 0.1 nM,
compared to 0.35 nM after 32 h of incubation) and close to
500-fold as efficient as arteflene (IC50, 49 nM). The
IC50 values of Mn-TPPS and Mn-TMPS were also
determined and were found in the same range as previously reported
(4). In fact, these metalloporphyrins are both devoid
of significant antimalarial activity when used alone (IC50,
276 µM and 257 µM for Mn-TPPS and Mn-TMPS, respectively).
|
|
) or 72 h (
) of
incubation.
In vivo potentiation by Mn-TPPS. The ED50 values of artemisinin and artemether on the P. vinckei petteri-infected mice were 3 ± 2 mg/kg of body weight and 0.3 ± 0.2 mg/kg of body weight, respectively, which is consistent with values previously reported by Jaquet et al. (19) and Posner et al. (28) (drugs injected subcutaneously on Plasmodium berghei).
In the 4-day test, the ED50 values of Mn-TPPS were found to be 25 ± 10 mg/kg of body weight per day. Since Mn-TPPS was shown to enhance in vitro the antimalarial activity of both artemisinin and artemether when incubated with the P. falciparum FcB1 strain and is devoid of toxicity in several cell lines (e.g., HeLa human fibroblast [4] and MT-4 lymphocyte [37]), we decided to treat a group of healthy mice with Mn-TPPS for 4 days. At a dose of 40 mg/kg of body weight per day, (close to twice as high as ED50), the treated mice were still alive, with normal behavior, after a 2-month period. No visible effect on organs was noticed during autopsy. These data confirmed the absence of toxicity of Mn-TPPS in mice. The control-mouse group was inoculated with Plasmodium spp. and received no treatment but only physiological serum during the 4-day test. The mean parasitemia of untreated control mice on day 4 was found to vary from 32% to 63% (mean, 46%). No death occurred during the treatment. All but one (97%) of the nontreated control mice died between days 5 and 14. The results obtained for the potentiation of the drug by Mn-TPPS on P. vinckei petteri were analyzed by using the Dunnett statistical test. For
= 0.05 and in bilateral situations, the groups of mice treated by the peroxide drug alone or by the peroxide associated with Mn-TPPS have ED50 values statistically
different from those obtained with the untreated control group
(11).
The results obtained for the potentiation of artemisinin and artemether
by Mn-TPPS on P. vinckei petteri are reported in Fig. 3 and 4,
respectively. They are expressed as percentages of parasitemia inhibition with respect to the control group. The inhibition of parasitemia of the control group (line 1) is therefore 0%. In Fig. 3,
lines 2 to 4 and 5 to 7 report parasitemia inhibition in the presence
of increasing doses of artemisinin alone and Mn-TPPS alone,
respectively. Lines 8 to 10 report parasitemia inhibition in the
presence of 1 mg of artemisinin per kg of body weight per day and
increasing doses of Mn-TPPS (2, 10, and 20 mg/kg/day).
|
|
(inh
A + inh MnP)]/(inh A + inh MnP), where inh A is the
parasitemia inhibition value due to the applied dose of artemisinin
when used alone, inh MnP is the parasitemia inhibition value due to the
applied dose of Mn-TPPS when used alone, and inh (A + MnP) is the
parasitemia inhibition value due to artemisinin and Mn-TPPS used together.
When the subinhibitory dosage of 1 mg of artemisinin per kg of body
weight per day was associated with 10 or 20 mg of Mn-TPPS per kg of
body weight per day, the inhibition of parasitemia was 54% ± 7% and
55% ± 10%, respectively (lines 9 and 10 in Fig. 3), significantly
higher than that of mice treated with artemisinin used alone (15% ± 3% [Fig. 3, line 3]) or the inhibition of parasitemia expected in
the case of an additive effect (15% + 22% = 37%). The
potentiations reached in these cases, 46 and 49% (Fig. 3, lines 9 and
10), were two similar values. With 1 mg of artemisinin per kg of body
weight per day associated with 2 mg of Mn-TPPS per kg of body weight
per day, the potentiation was 25% (line 8). The decreased parasitemia
of mice treated with artemisinin associated with Mn-TPPS is consistent
with the in vitro potentiation of artemisinin by the metalloporphyrin
on the FcB1 strain.
The potentiation study of artemether reported in Fig. 4 is rather
puzzling. When 0.25 mg of artemether per kg of body weight per day was
associated with 2 or 10 mg of Mn-TPPS per kg body weight per day, in
the hypothesis of an additive effect of these two drugs, 84 or 91%,
respectively, of parasitemia inhibition was expected. In fact, only
42% ± 8% and 45% ± 10% of parasitemia inhibition was observed in
these cases (Figure 4, lines 8 and 10).
This reduced efficiency of artemether in the presence of the
metalloporphyrin did not correlate with the potentiation observed in
vitro (Fig. 2B). The living mice are obviously more complex than the in
vitro parasite culture medium, and artemether was found to be more
fragile than artemisinin, especially in acidic conditions
(34). It is also probable that artemether can be activated
by the metalloporphyrin outside the parasite, far from the target heme
or proteins, leading to a loss of "useful" artemether and then to a
decrease of efficiency when artemether and Mn-TPPS are associated. In
fact, different studies have shown that the results of antimalarial
assays obtained in vitro with drug associations are difficult to
extrapolate from one strain to another and from in vitro to in vivo
(12). For example, on one hand, the association of
artemisinin and mefloquine has been found to be additive in vitro on K1
and NF-54 strains (19). On the other hand, this association
exhibits a synergistic effect in vivo on P. berghei (7) and is widely used against multidrug-resistant
Plasmodium spp. in humans (17). Furthermore, it
was recently reported that rats might be better animal models than mice
for parasitical studies, due to the numerous differences between the
immunity systems of the latter and that of humans (6).
The main result of the present in vivo potentiation study is that the
artemisinin efficiency can be increased by ca. 50% in the presence of
a nontoxic and cheap manganese porphyrin complex, which is by itself
devoid of any antiplasmoidal activity. In addition, these results
confirm that the activation of artemisinin by heme or a heme model in
the present case is a key step in the mechanism of action of this
antimalarial trioxane.
| |
ACKNOWLEDGMENTS |
|---|
This work was supported by the CNRS (Programme "Physique et Chimie du Vivant") and by a grant from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (Director's Initiative Fund).
Rhône-Poulenc-Rorer Doma (Antony, France) and Hoffmann-La Roche
(Basel, Switzerland) are gratefully acknowledged for a gift of
-artemether (Paluther) and arteflene (Ro 42-1611), respectively. We
thank J. Bernadou (LCC-CNRS, Toulouse) for fruitful discussions and H. Maillols (Laboratoire de Technique Pharmaceutique Industrielle, UFR
Sciences Pharmaceutiques, Université Montpellier I, Montpellier, France) for her help with statistical analyses of the results. We are
grateful to J.-M. Bastide (Laboratoire d'Immunologie et Parasitologie,
UFR Sciences Pharmaceutiques, Montpellier, France) for his constant
interest throughout this work.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, F-31077 Toulouse Cedex 4, France. Phone: 33 5 61 33 31 46. Fax: 33 5 61 55 30 03. E-mail: bmeunier{at}lcc-toulouse.fr.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
|
|---|
| 1. | Asawamahasakda, W., I. Ittarat, C. C. Chang, P. McElroy, and S. R. Meshnick. 1994. Effects of antimalarials and protease inhibitors on plasmodial hemozoin production. Mol. Biochem. Parasitol. 67:183-191[CrossRef][Medline]. |
| 2. |
Asawamahasakda, W.,
I. Ittarat,
Y.-M. Pu,
H. Ziffer, and S. R. Meshnick.
1994.
Reaction of antimalarial endoperoxides with specific parasite proteins.
Antimicrob. Agents Chemother.
38:1854-1858 |
| 3. | Benoit, F., A. Valentin, Y. Pélissier, F. Diafouka, C. Marion, D. Kone-Bamba, M. Koné, M. Mallié, A. Yapo, and J. M. Bastide. 1996. In vitro antimalarial activity of vegetal extracts used in West African traditional medicine. Am. J. Trop. Med. Hyg. 54:67-71. |
| 4. |
Benoit-Vical, F.,
A. Robert, and B. Meunier.
1999.
Potentiation of artemisinin activity against chloroquine-resistant Plasmodium falciparum strains by using heme models.
Antimicrob. Agents Chemother.
43:2555-2558 |
| 5. | Cazelles, J., A. Robert, and B. Meunier. 1999. Characterization of the main radical and products resulting from a reductive activation of the antimalarial arteflene (Ro 42-1611). J. Org. Chem. 64:6776-6781[CrossRef][Medline]. |
| 6. |
Cêtre, C.,
C. Pierrot,
C. Cocude,
S. Lafitte,
A. Capron,
M. Capron, and J. Khalife.
1999.
Profiles of Th1 and Th2 cytokines after a primary infection by Schistosoma mansoni in the semipermissive rat host.
Infect. Immun.
67:2713-2719 |
| 7. | Chawira, A. N., D. C. Warhurst, B. L. Robinson, and W. Peters. 1987. The effect of combinations of qinghaosu (artemisinin) with standard antimalarial drugs in the suppressive treatment of malaria in mice. Trans. R. Soc. Trop. Med. Hyg. 81:554-558[CrossRef][Medline]. |
| 8. | Cumming, J. N., P. Ploypradith, and G. H. Posner. 1997. Antimalarial activity of artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action. Adv. Pharmacol. 37:253-297. |
| 9. |
Deloron, P.,
L. K. Basc,
B. Dubois,
C. Gaudin,
F. Clavier,
J. Le Bras, and F. Verdier.
1991.
In vitro and in vivo potentiation of chloroquine against malaria parasites by an enantiomer of amlodipine.
Antimicrob. Agents Chemother.
35:1338-1342 |
| 10. |
Desjardins, R. E.,
C. J. Canfield,
J. D. Haynes, and J. D. Chulay.
1979.
Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique.
Antimicrob. Agents Chemother.
16:710-718 |
| 11. | Dunnett, C. W. 1964. Biometrics 1964:482-491[CrossRef]. |
| 12. | Fleck, S. L., B. L. Robinson, and W. Peters. 1997. The chemotherapy of rodent malaria. Ann. Trop. Med. Parasitol. 91:33-39[Medline]. |
| 13. | Frappier, F., A. Jossang, J. Soudon, F. Calvo, P. Rasoanaivo, S. Ratsimamanga-Urveng, J. Saez, J. Schrével, and P. Grellier. 1996. Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells. Antimicrob. Agents Chemother. 40:1476-1481[Abstract]. |
| 14. | Graeser, R., B. Wernli, R. M. Franklin, and B. Kappes. 1996. Plasmodium falciparum protein kinase 5 and the antimalarial nuclear division cycles. Mol. Biochem. Parasitol. 82:37-49[CrossRef][Medline]. |
| 15. | Hoffmann, P., A. Robert, and B. Meunier. 1992. Preparation and catalytic activities of the manganese and iron derivatives of Br8TMP and Cl12TMP, two robust porphyrin ligands obtained by halogenation of tetramesitylporphyrin. Bull. Chem. Soc. Fr. 129:85-97. |
| 16. |
Hoffman, S. L.
1996.
Artemether in severe malaria still too many deaths.
N. Engl. J. Med.
335:124-126 |
| 17. | Hung, L. N., P. J. de Vries, L. T. D. Thuy, B. Lien, H. P. Long, T. N. Hung, N. V. Nam, T. K. Anh, and P. A. Kager. 1997. Single dose artemisinin-mefloquine versus mefloquine alone for uncomplicated falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 91:191-194[CrossRef][Medline]. |
| 18. | Inselburg, J., and H. S. Banyal. 1984. Synthesis of DNA during the asexual cycle of Plasmodium falciparum in culture. Mol. Biochem. Parasitol. 10:79-87[CrossRef][Medline]. |
| 19. | Jaquet, C., H. R. Stohler, J. Chollet, and W. Peters. 1994. Antimalarial activity of the bicyclic peroxide Ro 42-1611 (arteflene) in experimental models. Trop. Med. Parasitol. 45:266-271[Medline]. |
| 20. | Jensen, J. 1978. Concentration from continuous culture of erythrocytes infected with trophozoites and schizonts of Plasmodium falciparum. Am. J. Trop. Med. Hyg. 27:1274-1276. |
| 21. | Lambros, C., and J. P. Vanderberg. 1979. Synchronisation of Plasmodium falciparum erythrocytic stages in culture. J. Parasitol. 65:418-420[CrossRef][Medline]. |
| 22. |
Martin, S. K.,
A. M. J. Oduola, and W. K. Milhous.
1987.
Reversal of chloroquine resistance in Plasmodium falciparum by verapamil.
Science
235:899-901 |
| 23. |
Meshnick, S. R.,
T. E. Taylor, and S. Kamchonwongpaisan.
1996.
Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy.
Microbiol. Rev.
60:301-315 |
| 24. | Meshnick, S. R., A. Thomas, A. Ranz, C. M. Xu, and H. Z. Pan. 1991. Artemisinin (quinghaosu): the role of intracellular hemin in its mechanism of antimalarial action. Mol. Biochem. Parasitol. 49:181-190[CrossRef][Medline]. |
| 25. | Orjih, A. U. 1996. Haemolysis of Plasmodium falciparum trophozoite-infected erythrocytes after artemisinin exposure. Br. J. Haematol. 92:324-328[CrossRef][Medline]. |
| 26. | Peters, W. 1987. Chemotherapy and drug resistance in malaria, 2nd ed. Academic Press, London, United Kingdom. |
| 27. | Posner, G. H., C. H. Oh, D. Wang, L. Gerena, W. K. Milhous, S. R. Meshnick, and W. Asawamahasakda. 1994. Mechanism-based design, synthesis, and in vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin: the importance of a carbon-centered radical for antimalarial activity. J. Med. Chem. 37:1256-1258[CrossRef][Medline]. |
| 28. | Posner, G. H., M. H. Parker, J. Northrop, J. S. Elias, P. Ploypradith, S. Xie, and T. A. Shapiro. 1999. Orally active, hydrolytically stable, semisynthetic, antimalarial trioxanes in the artemisinin family. J. Med. Chem. 42:300-304[CrossRef][Medline]. |
| 29. | Price, R. N., M. Van Vught, F. Nosten, C. Luxemburger, A. Brockman, L. Phaipun, T. Chongsuphajaisiddhi, and N. White. 1998. Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria. Am. J. Trop. Med. Hyg. 59:883-888[Abstract]. |
| 30. | Radloff, P. D., J. Phillips, M. Nkeyi, D. Sturchler, M. L. Mitterlholzer, and P. G. Kremsner. 1996. Arteflene compared with mefloquine for treating Plasmodium falciparum malaria in children. Am. J. Trop. Med. Hyg. 55:259-262. |
| 31. | Rasoanaivo, P., S. Ratsimamanga-Urveg, H. Rafatro, D. Ramanitrahasimbola, G. Palazzino, C. Galeffi, and M. Nicoletti. 1998. Alkaloids of Hernandia voyronii: chloroquine-potentiating activity and structure elucidation of herveline D. Planta Med. 64:58-62[Medline]. |
| 32. | Robert, A., and B. Meunier. 1997. Characterization of the first covalent adduct between artemisinin and a heme model. J. Am. Chem. Soc. 119:5968-5969[CrossRef]. |
| 33. | Robert, A., and B. Meunier. 1998. Is alkylation the main mechanism of action of the antimalarial drug artemisinin? Chem. Soc. Rev. 27:273-279[CrossRef]. |
| 34. | Robert, A., and B. Meunier. 1998. Alkylating properties of antimalarial artemisinin derivatives and synthetic trioxanes when activated by a reduced heme model. Chem. Eur. J. 4:1287-1296[CrossRef]. |
| 35. | Somo-Moyou, R., M. L. Mittelholzer, F. Sorenson, L. Haller, and D. Sturchler. 1994. Efficacy of Ro 42-1611 (arteflene) in the treatment of patients with mild malaria. Trop. Med. Parasitol. 45:288-291[Medline]. |
| 36. | Song, R., A. Robert, J. Bernadou, and B. Meunier. 1998. Sulfonated and acetamidosulfonylated tetraarylporphyrins as biomimetic oxidation catalysts under aqueous conditions. Inorg. Chim. Acta 272:228-234[CrossRef]. |
| 37. | Song, R., M. Witvrouw, D. Schols, A. Robert, J. Balzarini, E. De Clercq, J. Bernadou, and B. Meunier. 1997. Anti-HIV activities of anionic metalloporphyrins and related compounds. Antivir. Chem. Chemother. 8:85-97. |
| 38. | Srivastava, T. S., and M. Tsutsui. 1973. Preparation and purification of tetrasodium meso-tetra(p-sulfophenyl)porphine. An easy procedure. J. Org. Chem. 38:2103-2103. |
| 39. |
Trager, W., and J. Jensen.
1976.
Human malaria parasite in continuous culture.
Science
193:673-675 |
Antimicrobial Agents and Chemotherapy, October 2000, p. 2836-2841, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Soh, P. N., Witkowski, B., Olagnier, D., Nicolau, M.-L., Garcia-Alvarez, M.-C., Berry, A., Benoit-Vical, F.
(2009). In Vitro and In Vivo Properties of Ellagic Acid in Malaria Treatment. Antimicrob. Agents Chemother.
53: 1100-1106
[Abstract] [Full Text] -
Fattorusso, E., Parapini, S., Campagnuolo, C., Basilico, N., Taglialatela-Scafati, O., Taramelli, D.
(2002). Activity against Plasmodium falciparum of cycloperoxide compounds obtained from the sponge Plakortis simplex. J Antimicrob Chemother
50: 883-888
[Abstract] [Full Text] -
Bhisutthibhan, J., Meshnick, S. R.
(2001). Immunoprecipitation of [3H]Dihydroartemisinin Translationally Controlled Tumor Protein (TCTP) Adducts from Plasmodium falciparum-Infected Erythrocytes by Using Anti-TCTP Antibodies. Antimicrob. Agents Chemother.
45: 2397-2399
[Abstract] [Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»