Efficacy of DB289 in Thai Patients withPlasmodium vivaxor Acute, UncomplicatedPlasmodiumfalciparumInfections

Yeramian, Patrick; Meshnick, Steven R.; Krudsood, Srivicha; Chalermrut, K; Silachamroon, Udomsak; Tangpukdee, Noppadon; Allen, James L.; Brun, Reto; Kwiek, Jesse J.; Tidwell, Richard R.; Looareesuwan, S

doi:10.1086/430928

Cited by 49 publications

(56 citation statements)

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“…In clinical trials involving patients with primary stage African trypanosomiasis, treatment with oral DB289 (100 mg, twice daily for 10 days) achieved cure rates of approximately 95% (Dr. Carol Olson, Immtech Pharmaceuticals Inc., personal communication). In clinical trials involving patients with Plasmodium vivax or acute, uncomplicated P. falciparum, treatment with oral DB289 (100 mg, twice daily for 5 days) achieved cure rates of 96% (Yeramian et al, 2005). Oral DB289 was also well tolerated, with no serious side effects (Yeates, 2003).…”

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confidence: 99%

“…Clinical trials in humans demonstrated oral DB289 to be well absorbed and efficiently converted to DB75. However, pharmacokinetic studies have indicated that DB75 plasma concentrations are highly variable among patients (Yeramian et al, 2005). Such variability could be due in part to interindividual differences in the extent of metabolic conversion of DB289 to DB75.…”

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confidence: 99%

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CYP4F Enzymes Are the Major Enzymes in Human Liver Microsomes That Catalyze the O-Demethylation of the Antiparasitic Prodrug DB289 [2,5-Bis(4-amidinophenyl)furan-bis-O-methylamidoxime]

Wang

Saulter²,

Usuki

et al. 2006

Drug Metab Dispos

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DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime] is biotransformed to the potent antiparasitic diamidine DB75 [2,5-bis(4-amidinophenyl) furan] by sequential oxidative O-demethyl-ation and reductive N-dehydroxylation reactions. Previous work demonstrated that the N-dehydroxylation reactions are catalyzed by cytochrome b 5 /NADH-cytochrome b 5 reductase. Enzymes responsible for catalyzing the DB289 O-demethylation pathway have not been identified. We report an in vitro metabolism study to characterize enzymes in human liver microsomes (HLMs) that catalyze the initial O-demethylation of DB289 (M1 formation). Potent inhibition by 1-aminobenzotriazole confirmed that M1 formation is catalyzed by P450 enzymes. M1 formation by HLMs was NADPHdependent, with a K m and V max of 0.5 M and 3.8 nmol/min/mg protein, respectively. Initial screening showed that recombinant CYP1A1, CYP1A2, and CYP1B1 were efficient catalysts of M1 formation. However, none of these three enzymes was responsible for M1 formation by HLMs. Further screening showed that recombinant CYP2J2, CYP4F2, and CYP4F3B could also catalyze M1 formation. An antibody against CYP4F2, which inhibited both CYP4F2 and CYP4F3B, inhibited 91% of M1 formation by HLMs. Two inhibitors of P450-mediated arachidonic acid metabolism, HET0016 (Nhydroxy-N-(4-n-butyl-2-methylphenyl)formamidine) and 17-octadecynoic acid, effectively inhibited M1 formation by HLMs. Inhibition studies with ebastine and antibodies against CYP2J2 suggested that CYP2J2 was not involved in M1 formation by HLMs. Additionally, ketoconazole preferentially inhibited CYP4F2, but not CYP4F3B, and partially inhibited M1 formation by HLMs. We conclude that CYP4F enzymes (e.g., CYP4F2, CYP4F3B) are the major enzymes responsible for M1 formation by HLMs. These findings indicate that, in human liver, members of the CYP4F subfamily biotransform not only endogenous compounds but also xenobiotics.As part of our search for new lead compounds for the treatment of African trypanosomiasis (African sleeping sickness) and other parasitic infections, aromatic dicationic compounds, such as DB75 [2,5-bis(4-amidinophenyl) furan], have been evaluated for efficacy in multiple models of infection. These diamidine-type compounds are effective against a broad range of pathogens in vitro, including Trypanosoma brucei, Leishmania spp., Pneumocystis carinii, and

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CYP4F Enzymes Are the Major Enzymes in Human Liver Microsomes That Catalyze the O-Demethylation of the Antiparasitic Prodrug DB289 [2,5-Bis(4-amidinophenyl)furan-bis-O-methylamidoxime]

Wang

Saulter²,

Usuki

et al. 2006

Drug Metab Dispos

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“…DB289 30 has originally been developed for the treatment of the first stage of African sleeping sickness. In a small (23 patients) Phase-II clinical trial against P. vivax and uncomplicated P. falciparum infections, pafuramidine 30 demonstrated 96% efficiency and good tolerability [172].…”

Section: Pafuramidine (Db289)mentioning

confidence: 99%

Antimalarial Drugs – What is in Use and What is in the Pipeline

Schlitzer¹

2008

Archiv der Pharmazie

131

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Malaria continues to be a potentially fatal threat to almost half of the world's population. In light of this threat, the armory to fight this disease is rather limited. Resistance against the most common and affordable antimalarials is widespread. Only few new drugs are in clinical development, most of them belong to long used classes of antimalarial drugs. This review will concisely cover the drugs which are currently in use, and describe the drug candidates which are in clinical evaluation.

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“…1), an orally bioavailable prodrug of furamidine II (Fig. 1), is currently in phase III trials for pneumocystis pneumonia and HAT [1, [3][4][5][6][7]. It has been suggested that DNA minor groove binding at AT rich sites is essential for the antimicrobial activity of dications [1].…”

Section: Introductionmentioning

confidence: 99%

Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents

Arafa

Ismail

Munde

et al. 2008

European Journal of Medicinal Chemistry

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A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove of DNA were synthesized and evaluated as antiprotozoal agents. Selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. The linear triaryl bis-guanidines 6a,b were prepared from their corresponding diamines 4a,b through the intermediate BOC protected bisguanidines 5a,b followed by acid catalyzed deprotection. The N-substituted guanidino analogues 9c-f were obtained in three steps starting by reacting the diamines 4a,b with ethyl isothiocyanatoformate to give the carbamoyl thioureas 7a,b. Subsequent condensation of 7a,b with various amines in the presence of EDCI provided the carbamoyl N-substituted guanidine intermediates 8a-f which can also be regarded as potential prodrugs for the guanidino derivatives. Compounds 9c-f were obtained via the base catalyzed decarbamoylation of 8a-f. The DNA binding affinities for the target dicationic bis-guanidines were assessed by T m values. In vitro antiprotozoal screening of the new compounds showed that derivatives 6a, 9c and 9e possess high to moderate activity against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.). While the prodrugs did not yield cures upon oral administration in the antitrypanosomal STIB900 mouse model, compounds 8a and 8c prolonged the survival of the treated mice.

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Efficacy of DB289 in Thai Patients withPlasmodium vivaxor Acute, UncomplicatedPlasmodiumfalciparumInfections

Abstract: DB289 is a promising new antimalarial compound that could become an important component of new antimalarial combinations.

Cited by 49 publications

References 11 publications

CYP4F Enzymes Are the Major Enzymes in Human Liver Microsomes That Catalyze the O-Demethylation of the Antiparasitic Prodrug DB289 [2,5-Bis(4-amidinophenyl)furan-bis-O-methylamidoxime]

CYP4F Enzymes Are the Major Enzymes in Human Liver Microsomes That Catalyze the O-Demethylation of the Antiparasitic Prodrug DB289 [2,5-Bis(4-amidinophenyl)furan-bis-O-methylamidoxime]

Antimalarial Drugs – What is in Use and What is in the Pipeline

Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents

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