Serum albumin and α-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor Imatinib

Beckmann, Svenja; Long, Ting; Scheld, Christina; Geyer, Rudolf; Caffrey, Conor R.; Grevelding, Christoph G.

doi:10.1016/j.ijpddr.2014.07.005

Cited by 34 publications

(30 citation statements)

References 81 publications

(116 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Results of pharmacokinetic studies with 57 showed that in cancer patients serum levels can be reached [520–1390 ng mL −1 (1.05–2.82 μ m ) at the standard dosage of 400 mg 57 per 24 h] that are within the range of concentrations demonstrated to kill adult and larval schistosomes within few days in vitro . Unfortunately, 57 showed no activity in animal models due to its interference with blood components . Additional studies have to determine whether activity loss is related to the compound itself or to the animal model chosen.…”

Section: Discussionmentioning

confidence: 99%

“…[162,164] However,i nv ivo experiments in mice or hamsters failed to show any effect on worm burden, pairing stability,o r egg production at ad ose of 100 mg kg À1 .B lood components such as serum albumina nd/or AGP decreased the efficacyo f 57. [165] AGP levels rise upon infection in humans up to five times, but in mice, and probablyo therr odents, the increase is 30-to 40-fold. In an experimental in vitro set-up with adult worms, the negative effect of AGP was reversed by adding erythromycin, which competed for AGP binding and rescued the lethal phenotype of 57.…”

Section: Kinase Inhibitorsmentioning

confidence: 96%

“… However, in vivo experiments in mice or hamsters failed to show any effect on worm burden, pairing stability, or egg production at a dose of 100 mg kg −1 . Blood components such as serum albumin and/or AGP decreased the efficacy of 57 . AGP levels rise upon infection in humans up to five times, but in mice, and probably other rodents, the increase is 30‐ to 40‐fold.…”

Section: Anthelmintic Drug Therapymentioning

confidence: 99%

“…AGP levels rise upon infection in humans up to five times, but in mice, and probably other rodents, the increase is 30‐ to 40‐fold. In an experimental in vitro set‐up with adult worms, the negative effect of AGP was reversed by adding erythromycin, which competed for AGP binding and rescued the lethal phenotype of 57 …”

Section: Anthelmintic Drug Therapymentioning

confidence: 99%

“…In summary, kinase inhibitors show remarkable activity against S. mansoni in vitro. However, there is still the need for further studies to address issues such as kinase selection, inhibitor/drug choice, AGP competition, and selectivity . Against the background of today′s knowledge, the development of kinase inhibitors acting against schistosomes appears feasible.…”

Section: Anthelmintic Drug Therapymentioning

confidence: 99%

See 4 more Smart Citations

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

et al. 2018

Self Cite

View full text Add to dashboard Cite

Chemotherapy based on repeated doses of praziquantel remains the most effective control strategy against schistosomiasis, a neglected tropical disease caused by platyhelminths of the genus Schistosoma spp. Its long-term use, however, raises serious concerns about drug resistance against praziquantel. Therefore, it is generally acknowledged that alternative treatment options are urgently needed. This Review summarizes data on relinquished drugs as well as recent advances in the area of antischistosomal compounds from a medicinal chemistry point of view. Furthermore, insights into the structure-activity relationships of each class of compounds are presented including in vitro and in vivo data, if available. Although many compounds have demonstrated good antischistosomal activity in vitro, they offer little promise to replace praziquantel. Nevertheless, the race to develop novel antischistosomal agents is ongoing.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Kinase Inhibitorsmentioning

confidence: 96%

Section: Anthelmintic Drug Therapymentioning

confidence: 99%

Section: Anthelmintic Drug Therapymentioning

confidence: 99%

Section: Anthelmintic Drug Therapymentioning

confidence: 99%

See 3 more Smart Citations

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

Derivatives of biarylalkyl carboxylic acid induce pleiotropic phenotypes in adult Schistosoma mansoni in vitro

et al. 2016

View full text Add to dashboard Cite

Schistosomes and other parasitic platyhelminths cause infectious diseases of worldwide significance for humans and animals. Despite their medical and economic importance, vaccines are not available and the number of drugs is alarmingly limited. For most platyhelminths including schistosomes, Praziquantel (PZQ) is the commonly used drug. With respect to its regular application in mass treatment programs, however, there is increasing concern about resistance development.Previous studies demonstrated that inhibitors used to treat non-parasitic human diseases may be useful to be tested for their effects on parasites. To this end, we focused on biarylalkyl carboxylic acids (BACAs) as basis, which had been shown before to be interesting candidates in the context of finding alternative approaches to treat diabetes mellitus. We tested 32 chemically modified derivatives of these substances (biarylalkyl carboxylic acid derivatives (BACADs)) for their effects on adult Schistosoma mansoni in vitro. Treatment with 18 BACADs resulted in egg production-associated phenotypes and reduced pairing stability. In addition, 12 of these derivatives affected vitality and/or caused severe tegument damage, gut dilatation, or other forms of tissue disintegration which led to the death of worms. In most cases (10/12), one derivative caused more than one phenotype at a time. In vitro experiments in the presence of serum albumin (SA) and alpha-acidic glycoprotein (AGP) indicated a varying influence of these blood components on the effects of two selected derivatives. The variety of observed phenotypes suggested that different targets were hit. The results demonstrated that BACADs are interesting substances with respect to their anti-schistosomal effects.

show abstract