Radioaktive Untersuchungen mit einem neuen Molluscicid

Duhm, Bernhard; Maul, W; Medenwald, H; Patzschke, K; Wegner, Lutz-Axel

doi:10.1515/znb-1961-0804

Cited by 14 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given orally, a substantial fraction of CLT is absorbed; it diffuses readily into all tissues and is rapidly metabolized (10,11). Absorption is more efficient when given in oil solution than in tablets (12).…”

Section: Discussionmentioning

confidence: 99%

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Tiffert

Ginsburg

Krugliak

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The increasing resistance of the malaria parasite Plasmodium falciparum to currently available drugs demands a continuous effort to develop new antimalarial agents. In this quest, the identification of antimalarial effects of drugs already in use for other therapies represents an attractive approach with potentially rapid clinical application. We have found that the extensively used antimycotic drug clotrimazole (CLT) effectively and rapidly inhibited parasite growth in five different strains of P. falciparum, in vitro, irrespective of their chloroquine sensitivity. The concentrations for 50% inhibition (IC50), assessed by parasite incorporation of [ 3 H]hypoxanthine, were between 0.2 and 1.1 M. CLT concentrations of 2 M and above caused a sharp decline in parasitemia, complete inhibition of parasite replication, and destruction of parasites and host cells within a single intraerythrocytic asexual cycle (Ϸ48 hr). These concentrations are within the plasma levels known to be attained in humans after oral administration of the drug. The effects were associated with distinct morphological changes. Transient exposure of ring-stage parasites to 2.5 M CLT for a period of 12 hr caused a delay in development in a fraction of parasites that reverted to normal after drug removal; 24-hr exposure to the same concentration caused total destruction of parasites and parasitized cells. Chloroquine antagonized the effects of CLT whereas mefloquine was synergistic. The present study suggests that CLT holds much promise as an antimalarial agent and that it is suitable for a clinical study in P. falciparum malaria. In the course of an investigation on the homeostasis of human red cells infected in vitro with the human malaria parasite Plasmodium falciparum, we found that clotrimazole (CLT), an imidazole derivative used as an antifungal agent (1), had a powerful growth-inhibiting effect on the parasite. The vast clinical experience, proven tolerance, and unique lack of acquired fungal resistance to CLT prompted a detailed investigation of its antimalarial effects in cultures of P. falciparum to assess its clinical potential. In this study, we report the in vitro effects of CLT on P. falciparum cultures by assessing the timeand concentration-dependent changes in parasite growth, parasite morphology, stage-specific development, and parasite replication. Materials and MethodsCultures. Five different laboratory strains of P. falciparum [A4 (2), W2, NF54, HB3, and FCR] were cultured in human erythrocytes by standard methods (3) under a low oxygen atmosphere. The culture medium was RPMI 1640, supplemented with 40 mM Hepes, 25 mg͞liter gentamicin sulfate, 10 mM D-glucose, 2 mM glutamine, and either 8.5% (vol͞vol) pooled human serum (A4 clone), or 10% heat-inactivated plasma (strains W2, NF54, HB3, and FCR). Culture media, with or without CLT, were changed daily, unless otherwise indicated. Parasites were synchronized at the ring stage with D-sorbitol (4) for all experiments. Initial parasitemias varied between 2% and 7% for the different e...

show abstract

Section: Discussionmentioning

confidence: 99%

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Tiffert

Ginsburg

Krugliak

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Historical in vivo studies found that the metabolism of the drug is extensive. 8,9 At 48 h after oral or intravenous (iv) dosing of radioactivity had been excreted. More than 10 labeled excretion products were detected on thin-layer chromatography of rat urine, as well as barely detectable levels of the parent compound, suggesting that nifurtimox was almost completely metabolized.…”

Section: ■ Introductionmentioning

confidence: 99%

“…More than 10 labeled excretion products were detected on thin-layer chromatography of rat urine, as well as barely detectable levels of the parent compound, suggesting that nifurtimox was almost completely metabolized. 8 A separate but contemporaneous study of unlabeled nifurtimox in rats, dogs, and humans showed that the amount of parent compound recovered in urine was approximately 0.5% of the administered dose. 9 Based on the levels and distribution of the radiolabel, the absorption and elimination of 35 S-labeled nifurtimox were found to be rapid, 8 but taken together with the observation that only very low levels of unchanged nifurtimox were found in urine in the unlabeled-drug study, 9 this early evidence supported the notion that nifurtimox is rapidly and extensively metabolized.…”

Section: ■ Introductionmentioning

confidence: 99%

Structural and Mechanistic Investigation of the Unusual Metabolism of Nifurtimox

Lang

Schulz

Piel

et al. 2022

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The oral antiparasitic drug nifurtimox has been used to treat Chagas disease for more than 50 years. Historical studies determined that very little nifurtimox is excreted unchanged, but contemporaneous preclinical studies of radiolabeled nifurtimox found almost all of the radiolabel was rapidly excreted, suggesting that metabolism is extensive. Attempts to study nifurtimox metabolism have had limited success, yet this knowledge is fundamental to characterizing the pharmacokinetics and pharmacodynamics of the drug. We conducted in vitro studies using hepatic and renal sources with 14 C-labeled nifurtimox as substrate and obtained samples of urine, plasma, and feces from rats administered 2.5 mg/kg [ 14 C]-nifurtimox, and samples of human urine and plasma from phase 1 clinical studies in which participants received a single dose of 120 mg nifurtimox. Analysis of metabolites was done by high-performance liquid chromatography (HPLC)high-resolution mass spectrometry (HRMS) and HRMS/MS with offline liquid scintillation counting of radiolabeled samples. Surprisingly, only traces of a few metabolites were identified from in vitro incubations with hepatocytes and subcellular fractions, but more than 30 metabolites were identified in rat urine, mostly with atypical mass changes. We developed an HRMS scouting method for the analysis of human samples based on the sulfur atom in nifurtimox and the natural abundance of 34 S, as well as a characteristic tandem mass spectrometry (MS/MS) fragmentation of nifurtimox and metabolites. Fragmentation patterns on HRMS/MS were used to propose structures for 18 metabolites (22 including stereoisomers), and based on these structures, the six most abundant products were synthesized and the structures of the synthetic forms were confirmed by HRMS and two-dimensional nuclear magnetic resonance (2D NMR). Overall, we determined that the metabolism of nifurtimox is almost certainly not mediated by typical hepatic and renal drug-metabolizing enzymes, and instead is rapidly metabolized mainly by reduction or nucleophilic attack, with some evidence of oxidation. Knowledge of the most abundant metabolites of nifurtimox affords the possibility of future studies to investigate levels of exposure and possible drug−drug interactions.

show abstract

“…Distribution studies in rodents with oral doses of 40 mg·kg −1 niclosamide ethanolamine (i.e. ~34 mg·kg −1 niclosamide) and 50 mg·kg −1 niclosamide demonstrate that tissue levels are highest in excretory organs (intestines, liver and kidney) and low to negligible levels are achieved in other tissues (such as the brain, heart and lungs) (Duhm et al, 1961 ; Tao et al, 2014 ).…”

Section: History and Mechanism Of Action Of Niclosamidementioning

confidence: 99%

Niclosamide—A promising treatment for COVID‐19

Singh¹,

Weiss

Goodman

et al. 2022

British J Pharmacology

View full text Add to dashboard Cite

Vaccines have reduced the transmission and severity of COVID‐19, but there remains a paucity of efficacious treatment for drug‐resistant strains and more susceptible individuals, particularly those who mount a suboptimal vaccine response, either due to underlying health conditions or concomitant therapies. Repurposing existing drugs is a timely, safe and scientifically robust method for treating pandemics, such as COVID‐19. Here, we review the pharmacology and scientific rationale for repurposing niclosamide, an anti‐helminth already in human use as a treatment for COVID‐19. In addition, its potent antiviral activity, niclosamide has shown pleiotropic anti‐inflammatory, antibacterial, bronchodilatory and anticancer effects in numerous preclinical and early clinical studies. The advantages and rationale for nebulized and intranasal formulations of niclosamide, which target the site of the primary infection in COVID‐19, are reviewed. Finally, we give an overview of ongoing clinical trials investigating niclosamide as a promising candidate against SARS‐CoV‐2.

show abstract

Radioaktive Untersuchungen mit einem neuen Molluscicid

Cited by 14 publications

References 0 publications

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Structural and Mechanistic Investigation of the Unusual Metabolism of Nifurtimox

Niclosamide—A promising treatment for COVID‐19

Contact Info

Product

Resources

About