Publications by authors named "Helga H J Gerets"

Article Synopsis
  • High off-target promiscuity and potent cytotoxicity in drug development can lead to a high failure rate, making safety assessment critical for compounds like novel plasmepsin X (PMX) inhibitors for malaria treatment.
  • A total of 249 PMX compounds were tested through various assays, revealing a correlation between high cytotoxicity in liver cells and poor tolerability in animal studies, often associated with specific receptor activities.
  • A structured approach using in vitro assays is necessary to identify harmful targets early and improve the chances of selecting safer compounds for further testing.
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Quinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture, we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.

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Historically, identifying carcinogens has relied primarily on tumor studies in rodents, which require enormous resources in both money and time. models have been developed for predicting rodent carcinogens but have not yet found general regulatory acceptance, in part due to the lack of a generally accepted protocol for performing such an assessment as well as limitations in predictive performance and scope. There remains a need for additional, improved carcinogenicity models, especially ones that are more human-relevant, for use in research and regulatory decision-making.

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A cross-industry survey was conducted by EFPIA/IQ DruSafe in 2018 to provide information on photosafety evaluation of pharmaceuticals after implementation of ICH S10. This survey focused on the strategy utilized for photosafety risk assessment, the design of nonclinical (in vitro and in vivo) and clinical evaluations, the use of exposure margins in risk assessment, and regulatory interactions. The survey results indicated that a staged approach for phototoxicity assessment has been widely accepted by regulatory authorities globally.

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Drug-induced liver injury (DILI) is a patient-specific, temporal, multifactorial pathophysiological process that cannot yet be recapitulated in a single in vitro model. Current preclinical testing regimes for the detection of human DILI thus remain inadequate. A systematic and concerted research effort is required to address the deficiencies in current models and to present a defined approach towards the development of new or adapted model systems for DILI prediction.

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The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized.

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Sixteen training compounds selected in the IMI MIP-DILI consortium, 12 drug-induced liver injury (DILI) positive compounds and 4 non-DILI compounds, were assessed in cryopreserved primary human hepatocytes. When a ten-fold safety margin threshold was applied, the non-DILI-compounds were correctly identified 2h following a single exposure to pooled human hepatocytes (n=13 donors) in suspension and 14-days following repeat dose exposure (3 treatments) to an established 3D-microtissue co-culture (3D-MT co-culture, n=1 donor) consisting of human hepatocytes co-cultured with non-parenchymal cells (NPC). In contrast, only 5/12 DILI-compounds were correctly identified 2h following a single exposure to pooled human hepatocytes in suspension.

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Assessing the potential of a new drug to cause drug-induced liver injury (DILI) is a challenge for the pharmaceutical industry. We therefore determined whether cell models currently used in safety assessment (HepG2, HepaRG, Upcyte and primary human hepatocytes in conjunction with basic but commonly used endpoints) are actually able to distinguish between novel chemical entities (NCEs) with respect to their potential to cause DILI. A panel of thirteen compounds (nine DILI implicated and four non-DILI implicated in man) were selected for our study, which was conducted, for the first time, across multiple laboratories.

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Today, obtaining mechanistic insights into biological, toxicological, and pathological processes is of upmost importance. Researchers aim to obtain as many as possible data from one cell sample to understand the biological processes under study. Multiplexing, which is the ability to gather more than one set of data from the same sample, fulfills completely this objective.

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Recently, the effect of binocular central retinal lesions on the expression of immediate early genes in the visual system of adult cats was demonstrated using in situ hybridization and immunocytochemistry. The present study was undertaken to quantify cat c-fos mRNA expression differences in the cat primary visual cortex after sensory deafferentation. Prior to quantification, DNA fragments obtained using reverse transcription-polymerase chain reaction (RT-PCR) in combination with rapid amplification of complementary DNA ends (RACE) were cloned and sequenced.

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