Experimental pharmacodynamic and kinetic studies related to new combination therapies against P. falciparum malaria
Author: Gupta, Seema
Date: 2007-03-02
Location: Föreläsningssalen, Welandersalen, B21, Infektionskliniken, Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Institutionen för medicin / Department of Medicine
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Thesis (702.6Kb)
Abstract
Artemisinin (ART) class of compounds are of special interest due to their
rapid onset of action and high activity against multidrug resistant
malaria. The major drawback in monotherapy with ART and its derivatives
is the high rate of recrudescent infection. Currently, the general
recommendation in treatment of falciparum malaria with artemisinins is a
combination with another antimalarial drug with relatively long
half-life.
Our study demonstrated for the first time that the highly unusual time-dependent disposition of ART in patients can be similarly solicited in the rat. Artemisinin is also a potent auto-inducer of drug metabolism in rats. The study suggests caution in the interpretation of repeat-dose rat toxicity studies with ART unless its pharmacokinetics is simultaneously monitored, since during multiple administrations, the exposure of the drug will not be constant.
ART-based combination therapies (ACT) have been shown to improve treatment efficacy and also control drug resistance in South-East Asia. Our study showed different degrees of synergism with combination of ART and the two Mannich bases, amodiaquine (AMD) and pyronaridine (PYR). AMD showed high degree of synergism as compared to PYR. Although AMD and chloroquine are 4-aminoquinolines, their interaction with ART is different. Chloroquine showed only addition. ART combination at clinically relevant concentration ratios showed additive to synergistic activity with atovaquone (ATQ) and clear synergism with quinine, and mefloquine. Since quinine and mefloquine both belong to the quinoline methanol class and show synergistic activity with ART, it may be concluded that artemisinins are synergistic with this group of compounds and possibly, with most, if not all, other members of the class 2 aryl amino alcohol antimalarial compounds.
A non-artemisinin based combination, Malarone® (ATQ and PRG) has been found to be active against multidrug resistant falciparum malaria. Recently, i t has been introduced as an alternative prophylactic drug for prevention of malaria in travelers to areas with chloroquine resistant falciparum malaria. However, little is known about the mechanism of synergistic interaction between atovaquone and proguanil. Our study evaluated in vitro pharmacodynamic interactions of ATQ, PRG and cycloguanil (CYC). ATQ- PRG combination showed addition to high synergism whereas ATQ-CYC combination showed antagonism at therapeutically relevant concentration ratios. Our results support that Malarone s effectiveness is due to synergism between atovaquone and proguanil and may not require the presence of cycloguanil.
Our study demonstrated for the first time that the highly unusual time-dependent disposition of ART in patients can be similarly solicited in the rat. Artemisinin is also a potent auto-inducer of drug metabolism in rats. The study suggests caution in the interpretation of repeat-dose rat toxicity studies with ART unless its pharmacokinetics is simultaneously monitored, since during multiple administrations, the exposure of the drug will not be constant.
ART-based combination therapies (ACT) have been shown to improve treatment efficacy and also control drug resistance in South-East Asia. Our study showed different degrees of synergism with combination of ART and the two Mannich bases, amodiaquine (AMD) and pyronaridine (PYR). AMD showed high degree of synergism as compared to PYR. Although AMD and chloroquine are 4-aminoquinolines, their interaction with ART is different. Chloroquine showed only addition. ART combination at clinically relevant concentration ratios showed additive to synergistic activity with atovaquone (ATQ) and clear synergism with quinine, and mefloquine. Since quinine and mefloquine both belong to the quinoline methanol class and show synergistic activity with ART, it may be concluded that artemisinins are synergistic with this group of compounds and possibly, with most, if not all, other members of the class 2 aryl amino alcohol antimalarial compounds.
A non-artemisinin based combination, Malarone® (ATQ and PRG) has been found to be active against multidrug resistant falciparum malaria. Recently, i t has been introduced as an alternative prophylactic drug for prevention of malaria in travelers to areas with chloroquine resistant falciparum malaria. However, little is known about the mechanism of synergistic interaction between atovaquone and proguanil. Our study evaluated in vitro pharmacodynamic interactions of ATQ, PRG and cycloguanil (CYC). ATQ- PRG combination showed addition to high synergism whereas ATQ-CYC combination showed antagonism at therapeutically relevant concentration ratios. Our results support that Malarone s effectiveness is due to synergism between atovaquone and proguanil and may not require the presence of cycloguanil.
List of papers:
I. Gupta S, Svensson US, Ashton M (2001). In vitro evidence for auto-induction of artemisinin metabolism in the rat. Eur J Drug Metab Pharmacokinet. 26(3): 173-8
Pubmed
II. Gupta S, Thapar MM, Mariga ST, Wernsdorfer WH, Bjorkman A (2002). Plasmodium falciparum: in vitro interactions of artemisinin with amodiaquine, pyronaridine, and chloroquine. Exp Parasitol. 100(1): 28-35
Pubmed
III. Gupta S, Thapar MM, Wernsdorfer WH, Bjorkman A (2002). In vitro interactions of artemisinin with atovaquone, quinine, and mefloquine against Plasmodium falciparum. Antimicrob Agents Chemother. 46(5): 1510-5
Pubmed
IV. Thapar MM, Gupta S, Spindler C, Wernsdorfer WH, Bjorkman A (2003). Pharmacodynamic interactions among atovaquone, proguanil and cycloguanil against Plasmodium falciparum in vitro. Trans R Soc Trop Med Hyg. 97(3): 331-7
Pubmed
I. Gupta S, Svensson US, Ashton M (2001). In vitro evidence for auto-induction of artemisinin metabolism in the rat. Eur J Drug Metab Pharmacokinet. 26(3): 173-8
Pubmed
II. Gupta S, Thapar MM, Mariga ST, Wernsdorfer WH, Bjorkman A (2002). Plasmodium falciparum: in vitro interactions of artemisinin with amodiaquine, pyronaridine, and chloroquine. Exp Parasitol. 100(1): 28-35
Pubmed
III. Gupta S, Thapar MM, Wernsdorfer WH, Bjorkman A (2002). In vitro interactions of artemisinin with atovaquone, quinine, and mefloquine against Plasmodium falciparum. Antimicrob Agents Chemother. 46(5): 1510-5
Pubmed
IV. Thapar MM, Gupta S, Spindler C, Wernsdorfer WH, Bjorkman A (2003). Pharmacodynamic interactions among atovaquone, proguanil and cycloguanil against Plasmodium falciparum in vitro. Trans R Soc Trop Med Hyg. 97(3): 331-7
Pubmed
Issue date: 2007-02-09
Rights:
Publication year: 2007
ISBN: 978-91-7357-066-4
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