Thrombopoietin mimetic reduces mouse lung inflammation and fibrosis after radiation by attenuating activated endothelial phenotypes.

Radiation-induced lung injury (RILI) initiates radiation pneumonitis and progresses to fibrosis as the main side effect experienced by patients with lung cancer treated with radiotherapy. There is no effective drug for RILI. Sustained vascular activation is a major contributor to the establishment of chronic disease.

Thrombopoietin mimetic stimulates bone marrow vascular and stromal niches to mitigate acute radiation syndrome.

Background: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice.

The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.

Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO).

Thrombopoietin mimetic stimulates bone marrow vascular and stromal niches to mitigate acute radiation syndrome.

Background: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating the regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is a key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice.

JNJ-10450232 (NTM-006), A novel non-opioid with structural similarities to acetaminophen, produces relatively long-lasting analgesia after a single dose in patients undergoing 3rd molar extraction.

JNJ-10450232 (NTM-006) is a non-opioid, non-NSAID analgesic and antipyretic compound with structural similarity to acetaminophen. Preclinical models show comparable analgesia relative to acetaminophen and no evidence of hepatotoxicity associated with overdose. Moreover, it was safe and generally well tolerated in a First-in-Human Study.

Metabolism and disposition of JNJ-10450232 (NTM-006) in rats, dogs, monkeys and humans.

JNJ-10450232 (NTM-006), a novel non-opioid, non-nonsteroidal anti-inflammatory drug with structural similarities to acetaminophen, demonstrated anti-pyretic and/or analgesic activities in preclinical models and humans and reduced potential to cause hepatotoxicity in preclinical species. Metabolism and disposition of JNJ-10450232 (NTM-006) following oral administration to rats, dogs, monkeys and humans are reported. Urinary excretion was the major route of elimination based on recovery of 88.

Preclinical safety assessment of JNJ-10450232 (NTM-006), a structural analog of acetaminophen, that does not cause hepatotoxicity at supratherapeutic doses.

JNJ-10450232 (NTM-006) is a new molecular entity that is structurally related to acetaminophen. A comprehensive non-clinical safety program was conducted to support first-in-human and clinical efficacy studies based on preclinical data suggesting that the compound has comparable or enhanced antinociceptive and antipyretic efficacy without causing hepatotoxicity at supratherapeutic doses. No hepatic toxicity was noted in a mouse model sensitive to acetaminophen hepatotoxicity or in rats, dogs, and non-human primates in 28-day repeat dose toxicity studies at and above doses/exposures at which acetaminophen is known to cause hepatotoxicity.

Development of a clinically relevant ex vivo model of cardiac ablation for testing of ablation catheters.

Introduction: Reliable ex vivo cardiac ablation models have the potential to increase catheter testing throughput while minimizing animal usage. The goal of this work was to develop a physiologically relevant ex vivo swine model of cardiac ablation displaying minimal variability and high repeatability and identify and optimize key parameters involved in ablation outcomes.

Methods And Results: A root cause analysis was conducted to identify variables affecting ablation outcomes.

First-in-human study to evaluate the safety, tolerability and pharmacokinetics of a novel analgesic and antipyretic drug with structural similarity to acetaminophen.

JNJ-10450232 (NTM-006) is a new molecular entity that comprises structural similarities to acetaminophen and provides comparable analgesia in animals and humans without causing the hepatotoxicity associated with acetaminophen overdose in preclinical models. This double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of JNJ-10450232 (NTM-006) following single (50-6000 mg) and multiple (250-2500 mg twice daily for 8 days) doses in healthy male volunteers. JNJ-10450232 (NTM-006) was absorbed within 1-3 h, except at high doses at which C was delayed and bimodal, while increases in AUC were more than dose proportional.

Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821).

The threat of a nuclear attack has increased in recent years highlighting the benefit of developing additional therapies for the treatment of victims suffering from Acute Radiation Syndrome (ARS). In this work, we evaluated the impact of a PEGylated thrombopoietin mimetic peptide, JNJ-26366821, on the mortality and hematopoietic effects associated with ARS in mice exposed to lethal doses of total body irradiation (TBI). JNJ-26366821 was efficacious as a mitigator of mortality and thrombocytopenia associated with ARS in both CD2F1 and C57BL/6 mice exposed to TBI from a cobalt-60 gamma-ray source.

Site-specific cancer risk following cobalt exposure via orthopedic implants or in occupational settings: A systematic review and meta-analysis.

In 2020, the European Commission up-classified metal cobalt as Class 1B Carcinogen (presumed to have carcinogenic potential) based primarily on data from rodent inhalation carcinogenicity studies. This up-classification requires an assessment under the Medical Device Regulations of cobalt cancer risk from medical devices. We performed a systematic review and meta-analysis to evaluate site-specific cancer risks with cobalt exposure from either total joint replacement (TJR) or occupational exposure (OC).

A systematic assessment of the epidemiologic literature regarding an association between acetaminophen exposure and cancer.

Introduced in the 1950s, acetaminophen is one of the most widely used antipyretics and analgesics worldwide. In 1999, the International Agency for Research on Cancer (IARC) reviewed the epidemiologic studies of acetaminophen and the data were judged to be "inadequate" to conclude that it is carcinogenic. In 2019 the California Office of Environmental Health Hazard Assessment initiated a review process on the carcinogenic hazard potential of acetaminophen.

Case Study 6: Deconvoluting Hyperbilirubinemia-Differentiating Between Hepatotoxicity and Reversible Inhibition of UGT1A1, MRP2, or OATP1B1 in Drug Development.

New molecular entities (NMEs) are evaluated using a rigorous set of in vitro and in vivo studies to assess their safety and suitability for testing in humans. Regulatory health authorities require that therapeutic and supratherapeutic doses be administered, by the intended route of administration, to two nonclinical species prior to human testing. The purpose of these studies is to identify potential target organ toxicity and to determine if the effects are reversible.

An integrated benefit-risk assessment of cobalt-containing alloys used in medical devices: Implications for regulatory requirements in the European Union.

In 2017, the European Union (EU) Committee for Risk Assessment (RAC) recommended the classification of metallic cobalt (Co) as Category 1B with respect to its carcinogenic and reproductive hazard potential and Category 2 for mutagenicity but did not evaluate the relevance of these classifications for patients exposed to Co-containing alloys (CoCA) used in medical devices. CoCA are inherently different materials from Co metal from a toxicological perspective and thus require a separate assessment. CoCA are biocompatible materials with a unique combination of properties including strength, durability, and a long history of safe use that make them uniquely suited for use in a wide-range of medical devices.

Carcinogenic assessment of cobalt-containing alloys in medical devices or cobalt in occupational settings: A systematic review and meta-analysis of overall cancer risk from published epidemiologic studies.

In 2020, the European Commission up-classified pure cobalt metal to a Category 1B hazard, based primarily on data from rodent inhalation carcinogenicity studies of metallic cobalt. The European Commission review did not evaluate cobalt-containing alloys in medical devices, which have very different properties vs. pure cobalt metal and did not include a systematic epidemiologic review.

A hazard evaluation of the reproductive/developmental toxicity of cobalt in medical devices.

Cobalt (Co) is an essential element with human exposure occurring from the diet, supplement ingestion, occupational sources, and medical devices. The European Chemical Agency (ECHA) recently voted to classify Co metal as a Reproductive Hazard Category 1B; presumed human reproductive toxicant due to adverse testicular effects in male rodents. A weight of evidence evaluation of the preclinical reproductive and developmental toxicity studies and available clinical data was performed to critically evaluate the relevance of this proposed classification for Co in medical devices.

Carcinogenic hazard assessment of cobalt-containing alloys in medical devices: Review of in vivo studies.

Cobalt (Co) alloys have been used for over seven decades in a wide range of medical devices, including, but not limited to, hip and knee implants, surgical tools, and vascular stents, due to their favorable biocompatibility, durability, and mechanical properties. A recent regulatory hazard classification review by the European Chemicals Agency (ECHA) resulted in the classification of metallic Co as a Class 1B Carcinogen (presumed to have carcinogenic potential for humans), primarily based on inhalation rodent carcinogenicity studies with pure metallic Co. The ECHA review did not specifically consider the carcinogenicity hazard potential of forms or routes of Co that are relevant for medical devices.

A comprehensive weight of evidence assessment of published acetaminophen genotoxicity data: Implications for its carcinogenic hazard potential.

In 2019, the California Office of Environmental Health Hazard Assessment initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of its genotoxicity. The objective of this analysis was to inform this review process with a weight-of-evidence assessment of more than 65 acetaminophen genetic toxicology studies that are of widely varying quality and conformance to accepted standards and relevance to humans. In these studies, acetaminophen showed no evidence of induction of point or gene mutations in bacterial and mammalian cell systems or in in vivo studies.

Infectious titres of human papillomaviruses (HPVs) in patient lesions, methodological considerations in evaluating HPV infectivity and implications for the efficacy of high-level disinfectants.

Background: Recent publications from a single research group have suggested that aldehyde-based high-level disinfectants (HLDs), such as ortho-phthalaldehyde (OPA), are not effective at inactivating HPVs and that therefore, patients may be at risk of HPV infection from medical devices. These results could have significant public health consequences and therefore necessitated evaluation of their reproducibility and clinical relevance.

Methods: We developed methods and used standardised controls to: (1) quantify the infectious levels of clinically-sourced HPVs from patient lesions and compare them to laboratory-derived HPVs, (2) evaluate experimental factors that should be controlled to ensure consistent and reproducible infectivity measurements of different HPV genotypes, and (3) determine the efficacy of select HLDs.

Dynamics of papillomavirus in vivo disease formation & susceptibility to high-level disinfection-Implications for transmission in clinical settings.

Background: High-level disinfection protects tens-of-millions of patients from the transmission of viruses on reusable medical devices. The efficacy of high-level disinfectants for preventing human papillomavirus (HPV) transmission has been called into question by recent publications, which if true, would have significant public health implications.

Methods: Evaluation of the clinical relevance of these published findings required the development of novel methods to quantify and compare: (i) Infectious titres of lab-produced, clinically-sourced, and animal-derived papillomaviruses, (ii) The papillomavirus dose responses in the newly developed in vitro and in vivo models, and the kinetics of in vivo disease formation, and (iii) The efficacy of high-level disinfectants in inactivating papillomaviruses in these systems.

Assessment of the biochemical pathways for acetaminophen toxicity: Implications for its carcinogenic hazard potential.

In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (≤4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects.

Application of the DILIsym® Quantitative Systems Toxicology drug-induced liver injury model to evaluate the carcinogenic hazard potential of acetaminophen.

In 2019, the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. The objective of the analysis herein was to inform this review by assessing whether variability in patient baseline characteristics (e.g.