International Journal of Toxicology最新文献

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a serotonin receptor agonist, in clinical development for the treatment of major depression and other psychiatric disorders. A critical safety concern for serotonergic compounds is their potential to induce seizures, as a severe manifestation of serotonin toxicity. The objective of this study was to evaluate the seizure liability of 5-MeO-DMT in a canine model. Beagle dogs (n = 8) were surgically instrumented for continuous telemetric recording of electroencephalography (EEG) and electromyography (EMG), coupled with behavioral video monitoring. Following a baseline period, animals were intranasally administered with control vehicle or escalating doses of 5-MeO-DMT (0.5, 1.0, and 1.5 mg/kg/day), once daily for nine consecutive days. Plasma samples for determination of pharmacokinetic parameters were collected from a satellite group (n = 3). Intranasal administration of 5-MeO-DMT resulted in centrally mediated and dose-dependent behavioral signs, such as head shaking, salivation, repetitive movements, dilated pupils, increased muscle tone, and tremors. A majority of these signs had a rapid onset and offset, which correlated with the peak plasma levels and resolved within 1 hour post-dose, and they were consistent with serotonergic agonism of 5-MeO-DMT. The continuous EEG recording revealed no evidence of seizures or epileptiform discharges at any dose levels throughout the study. In a canine model, considered sensitive to serotonergic drug-induced seizures, daily intranasal administration of escalating doses of 5-MeO-DMT did not induce seizures or epileptiform activity, even at doses causing significant physiological signs of serotonergic stimulation. These results provide robust critical safety information for a low seizure liability of 5-MeO-DMT.

Oligonucleotide therapeutics (ONTs) are a growing class of nucleic acid-based therapies with the potential to treat a variety of diseases through several different mechanisms of action (MoA). The most prevalent MoA entails the inhibition of therapeutically relevant levels of protein expression via mRNA degradation, exemplified by numerous approved ONTs. ONTs have unique physicochemical properties, pharmacokinetic characteristics, and MoAs that are distinct from other drug classes. The result can be a disconnect between the administered dose, plasma drug concentrations, pharmacodynamics, and toxicity. Thus, ONT development poses unique scientific and regulatory challenges that are not fully addressed by current International Council for Harmonisation (ICH) guidelines. The complexity of ONT development has recently been recognized with the acceptance of the new ICH topic proposal "ICH S13-Nonclinical Safety Evaluation of Oligonucleotide-based Therapeutics." In preparation for the ICH S13 Step 2 public consultation period, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) DruSafe ONT Working Group convened to identify and discuss key considerations for ONT development, and to communicate areas where regulatory clarity and harmonization are most needed. Specifically, these include strategies to assess off-target toxicities, safety pharmacology, general toxicity studies, First-In-Human dose selection, genotoxicity studies, reproductive and developmental toxicity studies, carcinogenicity assessments, and the appropriate use of a surrogate molecule in development. The intended goals of this paper are to provide a means for communicating input towards the ICH process and to provide a resource for assisting with the public review of the draft ICH S13 Guidance.

BackgroundConventional ketamine hydrochloride solutions are acidic and hyperosmotic, limiting their tolerability for subcutaneous (SC) delivery. BB106 is a novel ketamine formulation using the multitude of sulfobutylether-beta-cyclodextrin (SBECD) anionic substitutions as ionic counterions to achieve a new ketamine-SBECD salt in solution at near-physiologic pH and isotonicity, thereby enabling SC administration. To support its development for pain and neuropsychiatric indications, we conducted nonclinical toxicology studies in rats and minipigs.MethodsA 2-week repeated-dose SC injection study in rats and a 4-week continuous SC infusion study in Göttingen minipigs were performed, each with a 2-week recovery phase. Assessments included clinical observations, body weights, food consumption, ophthalmology, electrocardiography, clinical pathology, toxicokinetics (TK), and histopathology.ResultsBB106 was well-tolerated in both species. No mortality or dose-limiting systemic toxicity occurred. Clinical signs were consistent with ketamine pharmacology (eg, transient ataxia) and resolved after dosing. Local site reactions were minimal, histologically mild, and reversible. No treatment-related lesions were observed in any of the systemic tissues examined (including liver, kidney, bladder, and brain). TK analyses confirmed consistent systemic exposure without accumulation. SBECD itself produced no adverse effects at the exposure levels tested.ConclusionRepeated SC bolus injections in rats and continuous SC infusion in minipigs demonstrated favorable local and systemic safety profiles for BB106. These findings support its feasibility as an alternative to intravenous ketamine for pain and psychiatric disorders. To our knowledge, this is the first toxicology report of SC administration of an SBECD salt formulation and the results support continued consideration as a potential medicine.

Traditional food production systems are constrained by limited arable land, climate change, and environmental pressures, necessitating the exploration of alternative protein sources. Mycoprotein from Fusarium compactum (F. compactum) MM-135 has shown promise due to its balanced amino acid profile, high dietary fiber, and low-fat content. Previous studies, including a 14-day dietary exposure study, have shown safety at high doses up to 150,000 ppm. This study further evaluated the subchronic toxicity and teratogenicity of mycoprotein from F. compactum MM-135, testing higher doses than previously reported. In the 90-day oral toxicity study, rats were fed diets containing 50,000, 100,000, or 200,000 ppm of mycoprotein with no adverse effects. The NOAEL was 200,000 ppm (15.26 g/kg/day in males and 16.20 g/kg/day in females). In the teratogenic study, pregnant rats were exposed to the same doses from gestation days 6 to 15. No adverse effects on maternal pregnancy or fetal development were observed, with an NOAEL of 200,000 ppm (16.53 g/kg/day). These results confirm that mycoprotein from F. compactum MM-135 is safe at the tested dose of 200,000 ppm, exceeding the safety threshold established in prior studies, and support its potential as a sustainable alternative protein source.

Parkinson's disease (PD) is characterized by the abnormal aggregation of α-synuclein, which can originate in the gut and propagate to the brain. Recent evidence suggests a correlation between metabolic disorders, particularly diabetes, and PD pathogenesis through the gut-brain axis. Methylglyoxal (MGO), a glucose-derived metabolite produced by gut bacteria such as Proteus mirabilis, is implicated in protein misfolding and glycation. This study investigated whether MGO induced α-synuclein aggregation in intestinal enteroendocrine cells and explored the underlying mechanisms. Mouse enteroendocrine STC-1 cells were treated with MGO (0.01-1 mM) for 36 h, and changes in α-synuclein aggregation, neuronal markers, and relevant signaling pathways were assessed. MGO at 1 mM significantly reduced cell viability and neuronal marker expression, and concentrations of 0.1 and 1 mM increased α-synuclein aggregation. MGO also inhibited SIRT1 expression, leading to increased Hif-1α transcription and reduced expression of autophagy-related proteins Beclin1 and LC3B. These changes were accompanied by mitochondrial dysfunction, as evidenced by decreased Bcl2, increased cytochrome C expression, and reduced levels of the antioxidant factor HO-1. Our findings provide the first evidence that MGO directly induces α-synuclein aggregation in enteroendocrine cells via the SIRT1-Hif-1α-autophagy pathway dysregulation, establishing a potential mechanistic link between gut microbiome-derived metabolites and PD pathogenesis. These results suggest that intestinal glycation may be a critical target for preventing α-synuclein pathology originating in the gut.

The Tg.rasH2 mouse is a validated bioassay system for evaluation of carcinogenic potential, and it is confirmed to be sensitive to both genotoxic and nongenotoxic carcinogens. This is also one of the models specified in ICH S1B Guidance, enabling 6-month carcinogenicity studies as an alternative to traditional 2-year bioassays. We conducted a 26-week carcinogenicity study at our test facility on Tg.rasH2 mice sourced from CLEA Japan Inc., in a process to generate historical control database. Although historical control data have been published for these mice sourced from Taconic Biosciences Inc., USA, there is a dearth of published literature citing spontaneous incidence of neoplastic findings in Tg.rasH2 mice sourced from CLEA Japan. We have therefore presented the spontaneous tumor incidence in our study and compared it with the previously published tumor incidence for Tg.rasH2 mice sourced from Taconic, USA. The comparison reveals a similarity of tumor incidence between the mice from these two sources.

The rasH2^TM mouse model has become the primary alternative to a 2-year mouse carcinogenicity study in safety testing of human pharmaceuticals. In this publication, we present the neoplastic incidence for 2291 control males, 2191 control females, 575 MNU-treated males, 559 MNU-treated females, and 210 urethane-treated males and females in rasH2^TM carcinogenicity studies conducted from 2012 to 2024 as well as survival, body weights, and selected non-neoplastic microscopic findings for control and positive control mice. Inclusion of a positive control group is recommended to ensure regulatory acceptance. Survival of controls at the end of 26 weeks was approximately 96% with similar percentages of survivors in the 13-week urethane-treated positive controls in contrast to a survival percentage of approximately 17% in MNU-treated positive controls. Malignant neoplasms accounted for most early deaths in control and positive control mice. Major neoplasms in control mice included Harderian gland adenomas, bronchioloalveolar adenomas and carcinomas, and splenic hemangiosarcomas, while the predominant neoplasms in MNU-treated mice included squamous cell papillomas and carcinomas of the nonglandular stomach and malignant lymphomas. The percentage of urethane-treated mice developing bronchioloalveolar neoplasms was over 98% in both sexes. When compared to control mice, MNU-treated mice had lower mean body weights while urethane-treated mice had higher mean body weights. Major non-neoplastic findings in control mice were subcapsular cell hyperplasia (51.78% to 89.41%) and skeletal muscle myopathy (77.17% to 80.71%). Other non-neoplastic findings included retinal degeneration in MNU-treated mice (∼87% in both sexes) and bronchioloalveolar hyperplasia in urethane-treated mice (≥53% in both sexes).

Diabetes and hypertension often coexist and need complex pharmacological management. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is widely used for glycemic control, and telmisartan, an angiotensin II receptor blocker, is the preferred treatment for hypertension. Thus, we have conducted a 1-month exploratory combination safety and toxicity study in male Wistar Han rats. Animals were administered 100 mg/kg/day of sitagliptin or telmisartan individually, or in combination by oral gavage. We have evaluated effects on body weight, feed intake, clinical chemistry, and hematology parameters, and microscopic examination of liver, kidney, adrenal glands, heart, lungs, lymphatic organs, and gastrointestinal tract. The combination showed a decrease in body weight gain, feed intake, hematocrit, reticulocytes, WBCs, serum triglycerides, AST, total protein, globulin, and heart weight, and increased serum levels of urea, phosphorous, magnesium, potassium, and kidney weight. Co-administration showed an additive effect on decrease in WBC counts, potentiating the effects on decreased serum triglycerides and increased phosphorous levels and kidney weights, and a synergistic effect on serum AST levels. Sitagliptin attenuated the changes caused by telmisartan on reticulocyte counts, serum creatinine levels, and liver and thymus weights. Administration of the individual compounds caused a reduction in spleen weight, though the combination had no effect. Sitagliptin, telmisartan, or combination dosing showed no significant organ toxicity upon histopathological examination. It appears that co-administration of telmisartan and sitagliptin is well tolerated in rats. Three-month toxicity studies, in both genders, with full toxicokinetic profiling and thorough tissue examination, will be necessary to support the combination's toxicity profile.

Although Bisphenol A (BPA) is still used in consumer products, concerns about its toxicity led to the adoption of structurally related replacement products such as Bisphenol F (BPF) and Bisphenol S (BPS). Unfortunately, comparing the biological responses to BPA and BPA substitutes in vivo can be challenging, as the available information is often derived from different studies using various animal strains and experimental protocols. To address this issue, we directly compared the impacts of BPA, BPF, and BPS in the same in vivo exposure study. Briefly, 8-week-old male Fischer rats were exposed to BPA, BPF, or BPS (at five different doses) and to 17α-ethinylestradiol (positive control for estrogenicity) by gavage for 28 consecutive days. Rat health, dietary intakes, and weight gains were monitored, 24-hour urine samples were collected, and blood and tissues were harvested at the terminal necropsy. The impacts of BPA, BPF, and BPS on rat weight gains, organ weights and histology, liver enzymatic activities, hematology, clinical chemistry, and serum hormone levels were relatively modest and mostly limited to the highest doses administered. However, bisphenol cross-contamination observed in urine samples from the vehicle control group may have interfered with the evaluation of their effects at lower doses. Although BPA, BPF, and BPS exposures all shared similarities with the 17α-ethinylestradiol positive control group, their impacts on serum hormone levels and endocrine-responsive tissues also presented noticeable differences. This suggests that BPA, BPF, and BPS may interfere with endocrine functions through slightly different molecular mechanisms.