Scientific Review of the Proarrhythmic Risks of Oligonucleotide Therapeutics: Are Dedicated ICH S7B/E14 Studies Needed for Low-Risk Modalities?

Oligonucleotide therapeutics (ONTs) represent a new modality with unique pharmacological and chemical properties that modulate gene expression with a high degree of target specificity mediated by complementary Watson-Crick base pair hybridization. To date, the proarrhythmic assessment of ONTs has been influenced by International Conference on Harmonization (ICH) E14 and S7B guidance. To document current hERG/QTc evaluation practices, we reviewed US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Approval Packages (source: PharmaPendium.

Analysis of dibenzo[def,p]chrysene-deoxyadenosine adducts in wild-type and cytochrome P450 1b1 knockout mice using stable-isotope dilution UHPLC-MS/MS.

The polycyclic aromatic hydrocarbon (PAH), dibenzo[def,p]chrysene (DBC; also known as dibenzo[a,l]pyrene), is a potent carcinogen in animal models and a class 2A human carcinogen. Recent investigations into DBC-mediated toxicity identified DBC as a potent immunosuppressive agent similar to the well-studied immunotoxicant 7,12-dimethylbenz[a]anthracene (DMBA). DBC, like DMBA, is bioactivated by cytochrome P450 (CYP) 1B1 and forms the reactive metabolite DBC-11,12-diol-13,14-epoxide (DBCDE).

Aryl hydrocarbon receptor-dependent stanniocalcin 2 induction by cinnabarinic acid provides cytoprotection against endoplasmic reticulum and oxidative stress.

The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor historically known for its role in xenobiotic metabolism. Although AhR activity has previously been shown to play a cytoprotective role against intrinsic apoptotic stimuli, the underlying mechanism by which AhR confers cytoprotection against apoptosis is largely unknown. Here, we demonstrate that activation of AhR by the tryptophan catabolite cinnabarinic acid (CA) directly upregulates expression of stanniocalcin 2 (Stc2) to elicit cytoprotection against apoptosis induced by endoplasmic reticulum stress and oxidative stress.

Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.

In the present study, we tested the hypothesis that the potent and selective dopamine-β-hydroxylase (DβH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs.

Identification of stanniocalcin 2 as a novel aryl hydrocarbon receptor target gene.

Proper hepatocyte function is vital for survival; thus, unrepaired destruction of the parenchymal tissue leading to liver decompensation is devastating. Therefore, understanding the homeostatic process regulating liver regeneration is clinically important, and evidence that the aryl hydrocarbon receptor (AhR) can promote cell survival after intrinsic apoptotic stimuli is integral to the regenerative process. The current study uses primary hepatocytes to identify survival mechanisms consistent with normal AhR biology.