Pancreatic ductal adenocarcinoma (PDAC) diagnoses are often accompanied by a number of physical and psychologic symptoms, including anxiety and depression. As a result, many patients are prescribed anxiolytics such as benzodiazepines (BZD) that have unintended effects on the tumor. Previous work from our lab has highlighted that structural differences between BZD compounds may be responsible for different clinical outcomes influenced by their effects on cancer-associated fibroblasts (CAF) within the PDAC tumor microenvironment (TME). In this study, we demonstrate that the commonly prescribed N-substituted triazolobenzodiazepine alprazolam (ALP) abrogates the production of proinflammatory cytokines, including CCL2, CXCL12, interleukin 6 (IL6), and IL8, in human CAFs. This phenotype is unique only to azole-containing BZDs, including midazolam. The ability of ALP to regulate proinflammatory cytokine production is maintained in vivo as ALP-treated mice bearing pancreatic tumors exhibited reductions in IL6 within the tumor interstitial fluid. Mechanistically, an unbiased phosphoproteomic approach revealed that ALP abrogates Toll-like receptor 4-mediated cytokine production in CAFs. These findings cumulatively support that ALP dampens CAF-mediated inflammatory signaling within the PDAC TME.

Hair analysis is a well-established matrix in forensic toxicology, offering a valuable alternative or complement to traditional matrices in diverse contexts, including drug-facilitated crimes (DFC), elder abuse, and accidental exposure in children. However, objective interpretation of hair drug concentrations remains challenging due to significant inter-study variability, even for identical compounds. This study included hair analysis results upon the prosecutor's request over six years in the Grenoble Forensic Laboratory in France. Hair analysis was performed using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) on Sciex® 5500QT and Waters® TQ-XS mass spectrometers, following the French Society of Analytical Toxicology (SFTA) guidelines. Hair proficiency quality testing ensured reproductive results. This compendium describes 38 cases with hair analysis, including child's exposure and chemical abuse involving both children and the elderly. The study population predominantly involved female victims (84.2%), aged 5 months to 90 years. At least one substance was detected in hair in 26 cases. In twelve cases, hair analyses supplemented blood or urine testing. Substances identified were cocaine, THC, and levamisole in child exposure cases; alprazolam, diazepam, loprazolam, and tiapride in chemical abuse; and mainly MDMA, cocaine, paroxetine, and THC in other cases. This compendium contributes valuable data to the literature, enhancing the interpretation of hair drug concentrations across a broad spectrum of cases characterized by diverse age ranges, hair characteristics, timeframes, and circumstances. This work provides critical comparative data for interpreting findings in forensic cases.

Drug-facilitated sexual assault (DFSA) may involve a diverse array of substances, including illicit drugs, prescription medications, and over-the-counter pharmaceuticals. Hair analysis has emerged as a valuable forensic tool, offering an extended window of detection spanning several months. However, interpreting drug concentrations in hair can be challenging in forensic cases, as there are still substantial disparities in drug concentration findings across studies, or even no data available in the literature. This compendium seeks to contribute to the understanding and interpretation of forensic cases involving hair analysis. This study included hair analysis results upon prosecutor request over 6 years in Grenoble Forensic Laboratory from 2019 to 2024. Segmental hair analysis was performed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on Sciex® 5500QT and Waters® TQ-XS mass spectrometers, following Society of Hair Testing guidelines. Screened substances included drugs of abuse, benzodiazepines, sedative medications, and gamma-hydroxybutyrate (GHB), depending on the case, following French Society of Analytical Toxicology guidelines. Hair proficiency quality testing ensured reproducible results. In this compendium, 22 authentic DFSA cases are described with hair analysis. The cohort predominantly involved female victims (95%) aged 13-47 years. Hair analysis was positive in nine cases (41%), revealing the presence of at least one psychoactive substance. Substances identified were alimemazine, alprazolam, bromazepam, cetirizine, clozapine, codeine, cyamemazine, hydroxyzine, oxazepam, zolpidem, and 3,4-methylenedioxymethamphetamine (MDMA). The chemical profile observed primarily included sedating and amnesic pharmaceuticals, but not only. This compendium adds valuable data in the literature for better hair drug concentration interpretation in forensic cases.

New psychoactive substances (NPS) continuously emerge on unregulated drug markets, while in vitro pharmacological profiling at primary targets (e.g., cannabinoid receptor 1) often remains the only means of effect characterization. In this proof-of-concept study, we evaluated a complementary untargeted in vitro metabolomics approach for its ability to distinguish centrally active drugs based on drug-specific alterations of the cellular metabolome. SH-SY5Y neuroblastoma cells were exposed for 18 h to two NPS (MDMB-4en-PINACA and 4-methylmethcathinone) as well as alprazolam, cocaine, and tramadol. Cell extracts were analyzed using normal- and reverse-phase high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (HPLC-QToF). Multivariate analyses revealed distinct metabolic signatures and clear separation from controls for all compounds except tramadol. These findings demonstrate the feasibility and discriminatory capacity of the established workflow, highlighting its potential as a complementary tool for pharmacological and toxicological characterization of emerging psychoactive substances.

Hair analysis is increasingly used in forensic toxicology; however, result interpretation may be influenced by cosmetic hair treatments. Although the effects of bleaching, dyeing, and thermal straightening have already been evaluated, data on permanent chemical hair straightening are scarce, particularly under in vivo conditions. This case report evaluates the impact of an alkaline-based permanent hair straightening procedure on the determination of an endogenous compound, gamma-hydroxybutyrate (GHB), and an exogenous drug, alprazolam, in hair. Hair samples were collected from a 39-year-old woman before and 1 month after undergoing chemical hair straightening based on ammonium thioglycolate. Adjacent hair strands corresponding to identical temporal windows were analyzed. GHB was quantified in 0.5-cm hair segments using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, whereas alprazolam was analyzed in 2-cm segments using a validated LC-MS/MS method for drugs of abuse and psychoactive pharmaceuticals. All analyzed segments were positive for GHB in both samples. After the straightening procedure, endogenous GHB concentrations showed a pronounced increase compared with pretreatment levels, with fold changes ranging from approximately 6 to 43 in corresponding segments. In contrast, alprazolam concentrations in segments corresponding to the reported period of drug intake decreased by approximately 1.7- to 2-fold following chemical straightening. This case report demonstrates that permanent chemical hair straightening can produce marked and analyte-dependent effects on hair drug concentrations. These findings emphasize the importance of systematic documentation of cosmetic hair treatments and careful interpretation of hair analysis results in forensic casework, particularly when analyte concentrations are low.

In the current poly-drug use context, the contribution of each detected drug to the cause of death in a fatal poisoning may be difficult to assess. In this study, we aimed to investigate whether the analysis of drug paraphernalia found at the death scene could assist in the cause-of-death determination. Over a period of about four years, drug paraphernalia were analysed whenever paraphernalia was available for the analysis and a drug-related death was suspected. A total of 134 syringes and other kinds of paraphernalia were analysed in 77 death cases. Amphetamine, buprenorphine, and alprazolam were the most common findings. One single substance was detected in 51% of the analysed items, but some items contained up to 5 different substances, typically amphetamine or buprenorphine together with a benzodiazepine. Of the cases in which drug paraphernalia were analysed, in 57%, at least one detected substance was finally implicated as the cause of death in fatal poisonings, and in 14%, the detected substance was assessed as a contributing factor to death. Analysis of drug paraphernalia generated completely new drug findings in only a few cases. Comparing the results of the analysis of drug paraphernalia recovered at the death scene with the results of post-mortem toxicology allows for better understanding of circumstances of death, and in some cases enables more accurate determination of the cause of death by identifying the freshly administered drugs. In cases with new psychoactive substances, the analysis of paraphernalia can provide information that could otherwise be difficult to obtain as the concentrations in biological samples can be low.

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.

A novel alprazolam analog was detected as an illegal additive in pressed candies marketed for sleep improvement using high-performance liquid chromatography (HPLC)-diode array detection (DAD). The compound was further isolated and purified via semi-preparative liquid chromatography, and its chemical structure was elucidated through high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy. The compound was identified as cyclopropylflualprazolam. Since alprazolam is a psychotropic controlled substance, this finding has garnered significant attention from regulatory authorities. It is recommended that cyclopropylflualprazolam be included in the screening list of prohibited substances in functional foods.