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Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
BDQ at steady state prolongs the QTc interval by approximately 12 mS237 but has not been clearly associated with serious dysrhythmias. It may also be associated with gastrointestinal disturbance, arthralgia, headache, and dizziness. Phospholipidosis observed in some preclinical toxicity studies has not been observed in humans to date. The drug currently has a black box warning due to unexplained excess mortality in clinical trials.
Phosphatidate Phosphohydrolase Activity in the Liver
Published in David N. Brindley, John R. Sabine, Phosphatidate Phosphohydrolase, 2017
The interaction of the drugs with phosphatidate inhibits the action of the phosphohydrolase, while simultaneously stimulating the activity of phosphatidate cytidylyltransferase (Sections IV.D and V). In the liver these amphiphilic cations mainly increase the accumulation of phosphatidate, whereas in other tissues increases in the production of CDP diacylglycerol, phosphatidylglycerol, and phosphatidylinositol can also be observed. Phospholipidosis is further characterized by marked increases in the accumulation of lysobisphosphatidate. This lipid is synthesized in the secondary lysosomes104,105 by the enzymic transfer of fatty acids from phosphatidylinositol to phosphatidylglycerol or lysophosphatidylglycerol. Lysobisphosphatidate is a characteristic marker for secondary lysosomes and its accumulation is a good indicator of the stage of development of the phospholipidosis.
Bedaquiline
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Jeffrey A. Tornheim, Kelly E. Dooley
Bedaquiline and its M2 metabolite are cationic amphiphilic drugs, and both accumulate within cells. In in vitro models, both cause phospholipidosis, though the clinical relevance of this preclinical finding is unknown (Mesens et al., 2007).
Small-molecule BACE1 inhibitors: a patent literature review (2011 to 2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Frederik Rombouts, Ken-ichi Kusakabe, Chien-Chi Hsiao, Harrie J. M. Gijsen
Since 2011, several important evolutions have marked the field of BACE1 inhibitors. In view of the numerous cases of toxicity observed in clinical trials, focus has increased on safety. CatD inhibition and associated ocular toxicity have been avoided by targeting the S3 pocket, while BACE2 inhibition has been reduced by targeting the 10S loop, flap loop and S2ʹ pockets. Liver toxicity has been avoided by shifting to novel chemotypes that are less prone to generate reactive metabolites, and cardiac toxicity has been minimized by carefully controlling the pKa of the amidine and overall lipophilicity. In some cases, the latter parameters could also be modulated to avoid phospholipidosis. The combination of safety requirements, the influence of structure-based drug design and an increasingly crowded IP situation have pushed the field into an unusually complex chemistry space, but also are a testimony to the creativity of medicinal chemists across the industry. The failure of all clinical trials in the BACE field, in addition to the numerous failures with amyloid-clearing antibodies, have however made most players diversify their AD portfolios to other approaches such as targeting tau, and abandon BACE1 inhibition as a strategy for targeting amyloid beta in brain and treating AD.
Three-dimensional liver models: state of the art and their application for hepatotoxicity evaluation
Published in Critical Reviews in Toxicology, 2020
Xihui Zhang, Tianyan Jiang, Dandan Chen, Qi Wang, Leshuai W. Zhang
Different from steatosis characterized with neutral lipid accumulation, phospholipidosis (PLD) is another hepatic disorder with phospholipid accumulation in the lysosomes, likely attributing to the reduced expression or activity of intracellular phospholipase by the drug compounds. At least fifty cationic amphiphilic drugs (CAD) that can introduce PLD are currently available in the market (Andreas et al. 2010). Drug induced phospholipidosis (DIP) was successfully recapitulated in the rat hepatocyte spheroid system treated with amiodarone and amitriptyline (Takagi et al. 2016). Loratadine, a histamine antagonist that is capable of inducing PLD in vivo, however, is a non-PLD inducer in an in silico model and a monolayer cultured in vitro model (Kasahara et al. 2006; Hanumegowda et al. 2010). Despite the negative response using traditional in vitro method, loratadine treated hepatocyte spheroids showed a significant increase of intracellular phospholipid. The follow-up CYP450 inhibition studies showed that desloratadine, a metabolite of loratadine, was the actual compound behind for PLD induction (Takagi et al. 2016). Therefore, metabolic activation is one of the advantages of hepatic spheroid system for improved prediction of DIP. Previously, we utilized primary mouse hepatocyte spheroids to investigate the enhanced effect of nanocarriers on DIP. As shown in Figure 6, we demonstrated that when some CAD (ifenprodil) were loaded into PEGylated graphene oxide (PEG-GO), phospholipid accumulation was further potentiated compared to free drugs in hepatocyte spheroids (Zhang et al. 2018). As a result, although cell-based assays have been proposed by several reviews (Teresa and Jose 2012; Garcia et al. 2017), the liver spheroid model may be superior to cells cultured on flat substrata for PLD screening and prediction, not only suitable for small molecules but also for nanomaterials.
Myeloid bodies is not an uncommon ultrastructural finding
Published in Ultrastructural Pathology, 2022
Hae Yoon Grace Choung, Jerome Jean-Gilles, Bruce Goldman
Not uncommonly, myeloid bodies (MB) are seen in biopsies of those without clinical evidence of FD. Similar morphologic changes have been reported in multiple case reports in other settings, notably, secondary to iatrogenic causes of phospholipidosis.1–7 To further understand the significance of MBs in those without FD, we performed the first biopsy-based single-center study of renal biopsies with incidental findings of MBs.