IntroductionSpaceflight may accelerate degradation of active pharmaceutical ingredients, raising concerns about medication stability during long-duration missions. This study assessed the potency of active pharmaceutical ingredients in a convenience sample of medications flown to the International Space Station alongside lot-matched terrestrial control samples.MethodsSpaceflight-exposed samples and terrestrial control samples were analyzed using ultra-high-performance liquid chromatography with tandem mass spectrometry. At the time of analysis, all medications were beyond their labeled expiration dates following prolonged storage and delayed laboratory testing. Medications included caffeine, diazepam, diphenhydramine, epinephrine, ketamine, lidocaine, naloxone, and promethazine in solid and liquid formulations. Percent difference between exposed and control samples was calculated, and absolute potency was evaluated relative to 95 to 105% and 80 to 120% ranges. Regression analyses examined associations of changes in the potency of active pharmaceutical ingredients with days in space and days expired.ResultsMost samples from both groups fell outside the 95 to 105% range. However, >90% remained within the broader 80 to 120% range. Average percent differences between spaceflight-exposed and ground control samples were generally within ±5% for most medications, suggesting limited relative potency differences despite prolonged spaceflight exposure. Epinephrine exhibited the most consistent reductions, averaging 10% lower potency than control samples. Regression analyses identified medication-specific associations with days expired and days in space but did not show a consistent pattern of spaceflight-associated potency loss.ConclusionWithin the limitations of this lot-matched, post-storage comparison, International Space Station exposure was not associated with large relative potency changes for most medications studied. Epinephrine represented the clearest exception and may require medication-specific stabilization strategies for long-duration space exploration missions.

Polysubstance use is rising and linked to heightened overdose rates and increased treatment challenges, further exacerbated by increasing detection of adulterants (e.g., xylazine) in the street drug supply. Harm reduction groups provide sterile syringes in exchange for used ones, creating a unique opportunity to characterize prevalent polysubstance combinations and inform translational and preclinical research We analyzed residues from used syringes (N=3,168) obtained from several harm reduction organizations in Jefferson County, KY (Jan-Dec 2025) for the presence of substances using gas chromatography mass spectrometry (GC-MS). We classified compounds as adulterants (e.g., diphenhydramine [DPH]/Benadryl), byproducts/precursors of synthesis (e.g., 4-ANPP), and recreational drugs (e.g., meth). We excluded byproducts/precursors and determined the most frequent substance and pairs/trios containing one or more recreational substance. Results. Of 3,168 syringes, 2,522 (79.61%) tested positive for substances. Out of those positive, the top recreational substances were meth (n=1,387; 54.99%), fentanyl (n=1,220; 48.37%), and heroin (n=653; 25.89%). Top adulterants were DPH (n=1021; 40.48%), dimethyl sulfone (n=749; 29.69%), and lidocaine (n=736; 29.18%). The most common pairs were DPH+fentanyl (n=670; 26.57%), lidocaine+fentanyl (n=659; 26.13%), dimethyl sulfone+meth (n=621; 24.62%), and fentanyl+heroin (n=484; 19.19%). The most common trios were DPH+lidocaine+fentanyl (n=369; 14.63%), DPH+fentanyl+heroin (n=327; 12.97%), lidocaine+fentanyl+heroin (n=297; 11.77%), diphenhydramine+xylazine+fentanyl (n=273; 10.82%), and meth+lidocaine+fentanyl (n=262; 10.39%). Our findings highlight evolving patterns of multiple-opioid and opioid-stimulant polysubstance use, generating insights that can be rapidly applied to strengthen clinical, preclinical, and translational polysubstance research. These insights allow for investigations into biobehavioral mechanisms and consequences of emerging use patterns, accelerating development of novel therapeutics.

We previously described an integrated in vitro liability assay for seizure, a new approach methodology (NAM) to reduce toxicity due to central nervous system (CNS) liability in drug discovery and development. Here we report the development of SAR (structure activity relationships) to guide drug design away from this liability. SAR test compounds were selected from the Enamine REadily AccesibLe (REAL) database using pharmacophore features and similarity to previous test compounds (amoxapine, diphenhydramine, quetiapine, 4-AP, linopirdine) or to ion channel positive reference compounds (bepridil, NS1619, quinidine, verapamil, XE991). These 88 compounds (10 parent compounds and 78 structurally related derivatives) were screened by automated electrophysiology in cell lines expressing human KV2.1, NaV1.2, the α1β2γ2 GABAA or α4β2 nicotinic receptors to generate IC50 values. Across all four ion channels, the derivative compounds exhibited increased, equivalent or reduced potency compared with the parent compounds, providing a complex and rich dataset for SAR. Regarding individual pharmacophoric features, statistical analysis identified 12 features significantly associated with activity at the α4β2 nicotinic receptor; 4 of these were also significantly associated with activity at KV2.1. Selected parent compounds (amoxapine, diphenhydramine, quetiapine) and structural analogues were screened for seizure-like activity in human induced pluripotent stem cell neurons using microelectrode array. The seizure-like phenotype was altered with the derivatives, as expected from the respective ion channel IC50 values. These data provide insight into specific substructures associated with seizure-like drug toxicity, offering the opportunity to avoid CNS liability in the development of novel compounds, saving time, money and resources.

IntroductionRituximab, an anti-CD20 monoclonal antibody used in B-cell malignancies, is associated with infusion-related reactions (IRRs) during the initial infusion. Standard premedication includes acetaminophen, corticosteroids, and a histamine-1 (H1) antagonist, typically diphenhydramine. Second-generation H1 antagonists offer similar efficacy with less sedation. Some institutions also incorporate histamine-2 (H2) antagonists despite limited supporting evidence. This study evaluated whether dual H1/H2 antagonist premedication reduces IRRs compared with H1-antagonist monotherapy when given with standard premedication.MethodsThis retrospective study reviewed health records of adults with a hematologic malignancy who received their first rituximab infusion at Brown University Health system between January 1, 2022 and June 30, 2025. Patients received premedication with either an H1-antagonist alone or dual H1/H2 receptor-antagonists with acetaminophen and a corticosteroid. The primary endpoint was IRR incidence during or within 24 h of infusion initiation. Secondary endpoints included IRR severity, incidence of grade 3-4 IRRs across subgroups, and time to IRR onset.ResultsAmong 299 patients (mean age 65; 55% male), 62% had aggressive lymphoma, 28% indolent lymphoma, and 10% leukemia. Baseline features included bone marrow involvement (38%), bone disease (39%), advanced-stage nodal disease (54%), B symptoms (48%), and >2 extranodal sites (28%). IRRs occurred in 38% of patients receiving dual H1/H2 antagonist premedication versus 36.5% with H1-antagonist monotherapy, with no difference in grade 3-4 IRRs. Most IRRs occurred 30 to 60 min after infusion initiation.ConclusionDual H1/H2-antagonist premedication was not associated with differences in the incidence or severity of rituximab IRRs compared with H1-antagonist monotherapy in addition to standard premedication.

Postpartum depression (PPD) is a highly prevalent but under-reported and undertreated disorder that affects mothers and infants alike. The management of PPD has to be thoughtfully catered to limit the exposure of infants to harmful drugs. This network meta-analysis (NMA) was conducted to assess the efficacy of pharmacological interventions for the prevention and treatment of PPD. We searched PubMed/MEDLINE, EMBASE, Scopus, Google Scholar, Cochrane databases and clinical trial registries to find studies to be included, and data were extracted. Random effects Bayesian NMA was performed using Markov chain Monte Carlo simulations. A network graph was built, the rank probability of each treatment was determined, and the surface under the cumulative rank probability curve was calculated. The risk of bias assessment, including publication bias, was assessed. Data from 54 studies, including 7,438 participants, were included for this NMA. No pharmacological intervention demonstrated robust superiority over placebo for the treatment of PPD, though wide credible intervals (CrI) and limited sample sizes preclude definitive conclusions. Trazodone (-1.6; 95% CrI: -2.7 to -0.41) and diphenhydramine (-1.4; 95% CrI: -2.5 to -0.20) are the two treatments that showed an efficacy superior to placebo in the prevention of PPD as seen by symptom severity scores. There was no publication bias, as observed by the funnel plot and Egger's regression test. Based on single small trials, trazodone and diphenhydramine showed statistically superior efficacy to placebo in preventing PPD. Safety considerations in the perinatal and breastfeeding context must be carefully evaluated before these agents are considered in clinical practice.

Emerging contaminants of concern (CECs) are increasingly detected in tropical riverine systems, yet their prioritization remains challenging due to data gaps, complex mixtures, and limited integration of ecological and human health perspectives. This study proposes an integrated framework to identify priority CECs by combining occurrence data, ecological risk quotients (RQ), human health hazard quotients (HQ), and a novel prioritization index (PI). Thirty-four (34) multiclass CECs, including pharmaceuticals, hormones, and plasticizers, were quantified in four rivers in Johor, Malaysia using optimized solid-phase extraction coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Caffeine (1511-6085 ng/L), paracetamol (32-7408 ng/L), and bisphenol A (344-837 ng/L) dominated the contaminant profiles. Most pharmaceuticals posed negligible ecological risk, while bisphenol A showed low ecological risk under worst-case exposure (0.01 < RQ < 0.1). In contrast, human health assessment indicated substantial risks from bisphenol A and bisphenol S, particularly for children (HQ > 1). Integration of ecological thresholds (PNEC) and reference doses (RfD) identified bisphenol analogues as highest-priority contaminants, followed by estrone, lidocaine, dexamethasone, and diphenhydramine. The framework demonstrates that concentration-based assessments may underestimate risk and supports toxicity-weighted prioritization for monitoring and regulation in tropical aquatic systems.

Fentanyl and its analogs pose considerable dangers to public health and safety, and the development of simple tests that can detect these harmful substances accurately and rapidly could control their currently unchecked spread and thereby safeguard lives. Here, we use systematic evolution of ligands by exponential enrichment (SELEX) to isolate an aptamer that displays a rare blend of high affinity and broad cross-reactivity to 139 fentanyl analogs, alongside excellent specificity against nontarget interferents, including cutting agents, adulterants, and other drugs of abuse. We demonstrate the utility of this aptamer by developing a single-step colorimetric dye-displacement assay that can detect diverse fentanyl analogs within seconds with a simple mix-and-read format. The analog coverage of our assay rivals that of commercial immunoassay-based fentanyl tests while offering better specificity against substances that commonly trigger false positives in those tests, such as diphenhydramine, lidocaine, and methamphetamine. Our findings indicate that aptamers may be fundamentally better suited for achieving broad but specific detection of structurally related classes of molecules relative to other commonly used receptors, such as antibodies, due to their excellent and controllable binding properties, among other benefits, including low cost and high stability.

Hypersensitivity reactions to glucagon-like peptide-1 receptor agonists (GLP-1RAs) are uncommon but clinically significant given their expanding use for obesity and type 2 diabetes. Tirzepatide, a dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and reports of allergic reactions remain limited. We present this case to highlight the diagnostic utility of intradermal testing and supervised drug challenge in confirming drug-specific hypersensitivity and identifying a safe therapeutic alternative within the same drug class. We report a 25-year-old woman with class I obesity (BMI 32.25) who developed hypersensitivity reactions after dose escalation of tirzepatide initiated for weight management. She tolerated 3 months of sequential dose escalations from 2.5 mg through 7.5 mg without adverse reaction, losing approximately 20 lbs. during this period. Following her first 10 mg dose, she developed episodic lip angioedema and generalized urticaria over the subsequent 4 days, without respiratory or gastrointestinal symptoms. Symptoms persisted despite intramuscular diphenhydramine, a 5-day course of prednisone, and two emergency department visits with intravenous steroids, ultimately resolving only after tirzepatide discontinuation. Laboratory evaluation conducted approximately 8 months prior to the reaction, following a separate self-limited episode of lip swelling unrelated to tirzepatide, had demonstrated normal total IgE, normal C1 esterase inhibitor protein and function, and normal complement levels, effectively excluding hereditary and acquired angioedema. H. pylori urea breath testing obtained, and allergy evaluation (which excluded food and seasonal allergies) was negative. Percutaneous skin testing to tirzepatide was negative; however, intradermal testing at 1:10 dilution was positive (8 mm wheal, 8 mm flare), confirming drug hypersensitivity. Intradermal testing to semaglutide was negative. A supervised subcutaneous challenge with semaglutide 0.25 mg was well tolerated, and the patient was cleared to initiate semaglutide under endocrinology oversight. The patient has since continued semaglutide without recurrence. This case illustrates tirzepatide-specific hypersensitivity and highlights the diagnostic value of intradermal testing and supervised challenge in guiding safe continuation of therapy with alternative GLP-1RAs.

Sedating antihistamines (sAH) are widely used as premedication to prevent infusion-related reactions (IRRs). Subcutaneous daratumumab (DARA-SC) is administered in a shorter time than its intravenous form. Therefore, sedation caused by sAH after DARA-SC administration may also pose a concern. We investigated the efficacy and safety of sAH and non-sedating antihistamines (nsAH) premedication. This multicenter, retrospective, observational study was conducted from six hospitals in Japan. Data from the electronic medical records of consecutive patients with multiple myeloma who received DARA-SC injection between 19 May 2021 and 31 December 2022 was analyzed. The incidence of IRR and drowsiness was investigated as efficacy and safety endpoints, respectively. Differences in incidence between patients treated with nsAH and those treated with sAH were compared. Thirty-one patients in the nsAH group and 130 patients in the sAH group were evaluated. All patients in the nsAH group were treated with levocetirizine, while patients in the sAH group were treated with dexchlorpheniramine or diphenhydramine. The incidence of IRRs was 0% (0/31) in the nsAH group and 1.5% (2/130) in the sAH group. The incidence of drowsiness was 6.5% (2/31) in the nsAH group and 7.7% (10/130) in the sAH group. These differences were not statistically significant. This study showed that levocetirizine is not obviously inferior in efficacy and safety relative to sAH in preventing IRRs and drowsiness. Therefore, levocetirizine can be considered as a substitute for patients for whom the use of sAH is not acceptable.

Nitric oxide (NO), stimulated by the muscarinic receptor agonist acetylcholine (ACh) released from the endothelium via mitochondrial acetyl-CoA production, appears to contribute to physiological flow-mediated vasodilation. Diphenhydramine (DPH), a muscarinic receptor antagonist, may interfere with ACh-induced NO-mediated vasodilation. However, whether DPH affects ACh-induced, NO-mediated vasodilation remains unknown. This study aimed to examine the effect of DPH on ACh-induced, NO-mediated vasodilation and its underlying mechanisms, including muscarinic receptor subtypes. The effects of diphenhydramine, M3 muscarinic receptor antagonist 4-diphenylacetoxyl-N-methylpiperidine methiodide (4-DAMP), and nitric oxide synthase (NOS) inhibitor N[w]-nitro-l-arginine methyl ester (l-NAME) on ACh-induced vasodilation in endothelium-intact aortas were examined. Furthermore, the study evaluated the effects of DPH on vasodilation induced by the non-receptor-mediated endothelium-dependent vasodilator calcium ionophore A23187 and sodium nitroprusside in endothelium-intact aortas. The influence of DPH on ACh-induced cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, calcium elevation, and nitrite (NO metabolite) production was further assessed in endothelium-intact aortas and human umbilical vein endothelial cells. DPH markedly inhibited ACh-induced vasodilation, whereas l-NAME almost abolished it. Pretreatment with 4-DAMP nearly eliminated the DPH-mediated inhibition of ACh-induced vasodilation. DPH slightly inhibited vasodilation induced by calcium ionophore A23187 and sodium nitroprusside. The DPH-induced inhibition of ACh-induced vasodilation was greater than the inhibition observed with calcium ionophore A23187 or sodium nitroprusside. DPH inhibited ACh-induced cGMP formation, eNOS phosphorylation, endothelial calcium elevation, and nitrite production. Overall, these results suggest that supratherapeutic DPH concentrations inhibit ACh-induced, NO-mediated vasodilation, likely primarily through inhibition of endothelial M3 muscarinic receptors.

Chemogenetics allows the controllable manipulation of brain circuits upon delivery of a selective activating ligand, and has been invaluable in dissecting brain circuits underlying many behaviours. The Gαi/o-coupled designer muscarinic receptor hM4Di is an especially versatile tool for on-demand inhibition, and has proven effective not only in fundamental neuroscience but also as a therapeutic transgene in preclinical models of epilepsy and other CNS disorders. Indeed, by placing the circuit modulation under the control of an exogenous ligand, chemogenetics mitigates the potential risk of overdosage intrinsic to viral-vector mediated gene therapy. An obstacle to clinical translation, however, is the absence of an activating ligand with favourable biodistribution and side effect profile. Here we show that mutation of hM4Di at two sites (S85 and Y416) imparts full and potent agonism to the widely used over-the-counter antihistamine diphenhydramine. We complement medium-throughput screening in human embryonic kidney cells with in vitro electrophysiological characterization in neuronal circuits, and reveal the interaction of diphenhydramine with key residues using cryo-electron microscopy. Administration of diphenhydramine to mice expressing the modified receptor in the ventral hippocampus reversibly modulated anxiety-related behaviour and attenuated the severity of chemoconvulsant-induced seizures. We further demonstrate on-demand seizure suppression in a chronic epilepsy model. G protein-coupled Receptors Activated by Non-Prescription Agents (GRANPAs) lower the barrier to clinical translation of a powerful chemogenetic approach to brain circuit manipulation.

In this study, a poly(bromophenol blue) (poly(BPB))-coated CoSn(OH)6 cubic particles -modified pencil graphite electrode (poly(BPB)@CoSn(OH)6/PGE) was developed, and its electrochemical activity towards diphenhydramine (DPHN) oxidation was systematically investigated. Cyclic voltammetric studies revealed that the oxidation of DPHN at the modified electrode is governed by a diffusion-controlled process, indicating strong interaction between DPHN molecules and the poly(BPB) film. The incorporation of the CoSn(OH)6 cubic structure enhances electron transfer kinetics by increasing the density of electroactive sites and facilitating charge transport across the electrode interface. This cooperative interaction between the conductive polymer and metal hydroxide structure results in a significant amplification of the oxidation response. Under optimized conditions, the proposed electrode exhibited a linear response in the concentration range of 1.0-500.0 µM with a detection limit (LOD) of 0.30 µM. Although the analytical performance is comparable to previously reported systems, the present work provides deeper insight into the role of polymer-metal hydroxide interfaces in governing electrochemical sensing behavior. The sensor also demonstrated acceptable selectivity and applicability in pharmaceutical, biological, and environmental samples. These findings highlight the importance of interfacial design in improving electrochemical performance and offer a useful framework for developing advanced hybrid sensing platforms.