Ketoconazole (KC), a potent cytochrome P450 (CYP) 3A inhibitor, is hydrolyzed by arylacetamide deacetylase (AADAC) in the liver to N-deacetylketoconazole (DAK). Both KC and DAK are known to inhibit CYP3A in human liver microsomes, and DAK accumulates extensively in the liver. We investigate the impact of AADAC on KC-induced drug-drug interactions (DDI) in vivo. DAK inhibited Cyp3a-mediated triazolam hydroxylation in mouse liver microsomes, whose potency was lower than KC (Ki was 0.11 ± 0.03 μM vs 0.008 ± 0.002 μM). Upon KC administration (20 mg/kg, p.o.) to wild-type mice, KC was cleared from the liver within 8 h, whereas DAK remained after 24 h. These findings suggested a smaller impact on DDI in Aadac knockout mice than in wild-type mice. However, the plasma AUC of triazolam (0.5 mg/kg, p.o.) following KC preadministration was significantly higher in Aadac knockout mice than in wild-type mice, indicating that accumulated hepatic DAK in wild-type mice does not affect triazolam hydroxylation. This can be explained by preferential DAK accumulation in lipid-rich organelles, limiting its effective cytosolic concentration to inhibit Cyp3a. In conclusion, Aadac attenuated KC-related DDIs by increasing DAK, which preferentially accumulated in intracellular organelles and thus had a limited impact on cytosolic Cyp3a inhibition.

Purpose: This retrospective study assessed the presence of adverse events during moderate sedation for pediatric dental procedures performed in a dental clinic. Methods: Dental treatment completed with sedation between June 2014 to November 2024 was assessed for the presence of any adverse events (AEs). AEs were classified by the modified Tracking and Reporting Outcomes of Procedural Sedation (TROOPS) scale and an adverse event list from the Pediatric Sedation Research Consortium (PSRC). Results: There were 923 completed patient sedation records between the ages of 2 and 16 years from 9 different sedation regimens within the dental clinic included in this study. Overall, the proportion of adverse events was low (4.55%) with an increase in AE with the intranasal dexmedetomidine/orally administered midazolam (odds ratio [OR]=4.7, P<0.01) and a decrease in AE with triazolam (OR equals 0.2, P<0.01). No adverse events required medical intervention. Conclusions: Overall, adverse event proportions were low with pediatric dental moderate sedation supporting the safety of this modality of treatment. More studies are needed to assess adverse events and adverse event scales in pediatric dental sedation.

Prolonged immersion in a reheated bathtub can cause extensive thermal alteration and produce intracranial findings that mimic traumatic lesions on postmortem computed tomography (PMCT). Here, we report a bath-related fatality in a woman in her late 60s in which PMCT demonstrated a crescent-shaped epidural collection along the right parietal convexity. The collection exhibited layered components, consisting of a fat-attenuation upper layer and a dependent low-attenuation layer with a small amount of gas. PMCT also demonstrated diffuse bilateral ground-glass opacities, bilateral pleural effusions, and left pneumothorax, as well as fluid accumulation in the paranasal sinuses and airway fluid with foam. At autopsy, extensive epidermal stripping and blistering with heat rigor were observed, and red frothy fluid was present within the airway. Autopsy revealed a brick-colored epidural deposit (approximately 15 g) without skull fracture, consistent with heat-coagulated blood. Toxicological analysis detected triazolam and mirtazapine in the blood. Drowning was considered highly likely; however, definitive confirmation was limited by severe systemic thermal alteration. This case highlights a forensic diagnostic pitfall in which heat hematoma-like epidural changes following prolonged hot-water immersion may mimic traumatic epidural hematoma on PMCT, underscoring the importance of integrating scene information, toxicology, PMCT, and autopsy findings.

Triazole-containing compounds will result in the production of various pharmacologically effective drugs. Epilepsy is a severe neurological disorder primarily managed by controlling seizures using antiepileptic drugs, which are often related with side effects in rare circumstances and can be life-threatening. Triazolam and Alprazolam are both drugs containing a triazole ring, and these are well-established drugs that are used in the treatment of epilepsy. In the five-membered azole ring, triazole ring containing compounds consist of two carbon and three nitrogen atoms. Triazole, a heterocyclic compound, which contains at least two distinct elements in the ring that includes three nitrogen atoms and two carbon atoms as a part of the five-membered azole chain. The nitrogenous heterocyclic moiety triazole, which is commonly called pyrrodiazole, has the chemical formula C2H3N3. The triazole-containing derivatives with two different isomers are 1, 2, 3-triazoles and 1, 2, 4-triazoles. Triazole-containing compounds can be synthesized by various methods such as substitution reactions, ring opening, and rearrangement. Among these isomers of triazole, drugs containing 1,2,4-triazole possess different pharmacological properties such as antifungal, antineoplastic, antibacterial, antimycobacterial, and antiepileptic properties. 1,3,4-thiadiazole-linked 1,2,4-triazoles and 1,2,4-triazole-3-thione derivatives are important targets for potent anticonvulsant drug candidates in both clinical and preclinical studies. Many synthetic compounds have a structural characteristic of a 1, 2, 4-triazole ring with diverse therapeutic efficacy. 1,2,4-triazoles are a key scaffold in a large number of triazole derivatives that produce diverse pharmacological effects. This review focuses on the pharmacological significance and the synthesis of triazole derivatives in medicinal chemistry.

Triazolam (TRZ) is a representative benzodiazepine sedative-hypnotic drug that has gradually been abused due to the increasing societal pressures. To further provide a theoretical basis for the rationale use of TRZ and obtain more information for its metabolic process, in this study, human CYP3A4 was employed as the metabolic enzyme to investigate the metabolic mechanism of TRZ by multiple computational methods. Here, three types of substrate-binding conformations related to the diversity of TRZ metabolites are identified (pose A, pose B and pose C). The "sandwich" structure and the π-π stacking between TRZ and F304/porphyrin ring may be the key factors in dominating three substrate-binding conformations. Furthermore, we discovered pose A is the predominant binding mode, with Cα-H serving as the key metabolic site and CYP3A4-catalyzed Cα-H hydroxylation follows a hydrogen abstraction-rebound mechanism. More importantly, in hydroxylation process, the spin states of iron can regulate the metabolic reaction rate of TRZ and the highest rate of metabolism (5.96 s-1) is found in the quartet spin states. Based on our findings, it can be suggested that rational incorporating aromatic groups into TRZ could improve its metabolic stability. Meanwhile, the transition of the heme iron from a low-spin to a high-spin state appears to accelerate TRZ metabolism, potentially leading to the accumulation of α-OH triazolam in vivo, which may pose risks to human health. These results could enhance our understanding of CYP3A4-mediated regioselective metabolism of TRZ and provide a theoretical foundation and new perspective for studies on the metabolism of other triazole drugs.

Ensuring analyte stability is essential for accurate forensic and clinical detection of sedative-type drugs. This study systematically evaluated the stability of 22 sedative-type drugs and metabolites in human urine under controlled conditions varying by pH (4.0, 7.0), temperature (25°C, 4°C, -20°C), and freeze-thaw cycles (5 cycles), using a fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. While compounds such as midazolam, clobazam, and zolpidem remained highly stable, others-including alprazolam, triazolam, and lorazepam-exhibited notable degradation, particularly under acidic pH and elevated temperature. Flunitrazepam and clonazepam showed distinct degradation with the formation of 7-amino metabolites at neutral pH. Notably, this transformation occurred only in urine and not in phosphate-buffered saline, suggesting a urine-specific mechanism. These findings highlight the importance of compound-specific preservation strategies. In scenarios where analyte identity or sample pH cannot be verified promptly, immediate refrigeration or freezing (ideally at -20°C), along with minimizing freeze-thaw cycles, is strongly recommended to preserve sample integrity and ensure reliable toxicological interpretation.

Benzodiazepines (BZDs) are widely used in the treatment of psychiatric disorders, but their association with suicidal/self-injurious behavior is conflicting. This study investigated the relationship between BZDs and suicidal and self-injurious behavior, by analyzing data from the FDA Adverse Event Reporting System. We analyzed FDA Adverse Event Reporting System data from January 2004 and March 2025, to analyze adverse events (AEs) associated with suicidal and self-injurious behavior in BZDs. Thirty-eight BZDs were initially identified via the WHO Anatomical Therapeutic Chemical Code System. After excluding 26 BZDs with insufficient psychiatric disorder-related AEs (<50 reports), 12 (diazepam, chlordiazepoxide, oxazepam, potassium clorazepate, lorazepam, bromazepam, clobazam, alprazolam, flurazepam, triazolam, temazepam, and midazolam) were retained for disproportionality analysis using zolpidem as a control. Reporting odds ratios (RORs) were calculated, and subgroup analysis assessed risk variations by age and gender. Among 52,767 psychiatric disorders AEs, 9474 (17.95%) involved suicidal and self-injurious behaviors. Compared to zolpidem, diazepam (ROR = 1.38), chlordiazepoxide (ROR = 1.62), oxazepam (ROR = 2.14), lorazepam (ROR = 1.11), alprazolam (ROR = 1.64), flurazepam (ROR = 3.26) triazolam (ROR = 1.68), and temazepam (ROR = 1.72) showed significantly elevated risks, while clobazam (ROR = 0.46) and midazolam (ROR = 0.37) demonstrated protective effects. Subgroup analyses revealed higher risks in females using diazepam, oxazepam, lorazepam, alprazolam and temazepam. Adults <65 years who used potassium clorazepate, lorazepam, clobazam, alprazolam, or triazolam faced a significantly higher suicide-related risk than those ≥65 years. Compared to zolpidem, BZDs demonstrate varied suicide-related risks, which necessitated personalized risk-benefit evaluations and increased monitoring for high-risk agents such as flurazepam and alprazolam.

The human cytochrome P450 3A4 (CYP3A4) enzyme, which is expressed in the liver and the intestines, catalyzes the metabolism of numerous drugs. The induction of CYP3A4 by the pregnane X receptor (PXR) represents a significant problem in pharmacotherapy. Since the metabolic properties of CYP3A substrates and the recognition of PXR ligands differ between humans and rats, there are limitations to reproducing human CYP3A4 induction in rat studies. Here, we developed a double-humanized rat model for CYP3A and PXR to mimic drug-drug interactions in humans using a rat model. The model was created using a combination of mammalian artificial chromosome-based chromosome engineering, bacterial artificial chromosome-based transgenic technology, and genome editing. The resulting double-humanized rat model for CYP3A and PXR (huCYP3A-PXR rat) was treated with rifampicin, a human PXR ligand. This treatment increased CYP3A4 mRNA expression in the liver and intestine and enhanced the hydroxylation activities of triazolam, a CYP3A4 substrate. Pretreatment with rifampicin resulted in a reduction of triazolam plasma concentrations and an increase in its metabolites after oral administration. Furthermore, ketoconazole, a CYP3A4 inhibitor, led to an increase in triazolam plasma concentrations and a decrease in its metabolites in huCYP3A-PXR rats regardless of pretreatment with rifampicin. These results suggest that huCYP3A-PXR rats could predict human CYP3A4 induction and inhibition in vivo. This innovative model, in which PXR and CYP3A are humanized, is expected to be a valuable tool for studying drug-drug interactions, including a combination of inducers and inhibitors, and to be integrated into the preclinical drug-development pipeline in future.