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Objective: Distinctive stressors facing pregnant and postpartum individuals during the COVID-19 pandemic may have affected their emergency department (ED) care-seeking for behavioral health concerns and violence victimization. We tested whether the incidence of postpartum behavioral health and assault injury ED visits differed for individuals according to their months of postpartum pandemic exposure. Methods: We used statewide, longitudinally linked hospital and ED administrative claims data from California to classify all individuals with hospital deliveries between January 1, 2016, and December 31, 2020, according to their months of postpartum pandemic exposure. Outcomes comprised 12-month incidence of any ED visit for a psychiatric disorder, drug use disorder/overdose, alcohol use disorder/intoxication, or assault injury, defined using International Classification of Diseases-Clinical Modification, version 10 codes. Risk ratios compared the incidence of each outcome among people with 1-12 months of postpartum pandemic exposure to those with 0 months of exposure. Results: Compared to people with 0 months of postpartum pandemic exposure (n = 1,163,215), delivering people with 1-12 month' exposure (range: n = 26,836 to n = 273,561) were approximately equally likely to have a postpartum ED visit for a psychiatric disorder, drug use disorder, or alcohol use disorder, after adjusting for demographic differences (most p > 0.10). The incidence of assault injury was significantly lower among delivering individuals with 11 or 12 months of pandemic exposure (RRadj = 0.70 and 0.91, respectively; both p < 0.01) compared to those with 0 months. Conclusions: Contrary to expectations, the pandemic did not appear to have affected ED utilization for most behavioral health conditions among postpartum individuals, but assault injury ED visits declined.

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.

BACKGROUND: Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day. METHODS: Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment. RESULTS: Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed Cmax 44.0 ng/mL, t1/2 4.6 h, and AUC24 280.1 ng*hr/mL. CONCLUSIONS: Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI. IMPACT: Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates. Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment. The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials. We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.

BACKGROUND: PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-β (TGF-β) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591). PATIENTS AND METHODS: In vitro and in vivo preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed. RESULTS: PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, n = 42; P1B, n = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, n = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, n = 6; P1B, n = 2) achieved stable disease. CONCLUSIONS: Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the

TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200-2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.

BACKGROUND: While folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes. METHODS: This multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment. RESULTS: The intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0-1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2-1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering. CONCLUSIONS: This randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg. GOV IDENTIFIER: NCT03472508 (Registration Date: March 21, 2018).

OBJECTIVE: Multifocal motor neuropathy is a rare chronic immune-mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose-exposure-response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure. METHODS: Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double-blind, placebo-controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic-pharmacodynamic model. RESULTS: The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter-patient variabilities in multifocal motor neuropathy. Model-based simulations for various dosing regimens (0.4-2.0 g/kg every 2-4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength. INTERPRETATION: These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose-splitting provided similar outcomes while offering flexibility and convenience.

BACKGROUND: Amyloid beta protein (Aβ) is a treatment target in Alzheimers Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. METHODS: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. RESULTS: From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups. CONCLUSIONS: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. TRIAL REGISTRATION: NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

Developmental exposures to PCBs are implicated in the etiology of neurodevelopmental disorders (NDDs). This observation is concerning given the continued presence of PCBs in the human environment and the increasing incidence of NDDs. Previous studies reported that developmental exposure to legacy commercial PCB mixtures (Aroclors) or single PCB congeners found in Aroclors caused NDD-relevant behavioral phenotypes in animal models. However, the PCB congener profile in contemporary human samples is dissimilar to that of the legacy Aroclors, raising the question of whether human-relevant PCB mixtures similarly interfere with normal brain development. To address this question, we assessed the developmental neurotoxicity of the Fox River Mixture (FRM), which was designed to mimic the congener profile identified in fish from the PCB-contaminated Fox River that constitute a primary protein source in the diet of surrounding communities. Adult female C57BL/6 J mouse dams (8-10 weeks old) were exposed to vehicle (peanut oil) or FRM at 0.1, 1.0, or 6.0 mg/kg/d in their diet throughout gestation and lactation, and neurodevelopmental outcomes were assessed in their pups. Ultrasonic vocalizations (USVs) and measures of general development were quantified at postnatal day (P) 7, while performance in the spontaneous alternation task and the 3-chambered social approach/social novelty task was assessed on P35. Triiodothyronine (T3) and thyroxine (T4) were quantified in serum collected from the dams when pups were weaned and from pups on P28 and P35. Developmental exposure to FRM did not alter pup weight or body temperature on P7, but USVs were significantly decreased in litters exposed to FRM at 0.1 or 6.0 mg/kg/d in the maternal diet. FRM also impaired male and female pups' performance in the social novelty task. Compared to sex-matched vehicles, significantly decreased social novelty was observed in male and female pups in the 0.1 and 6.0 mg/kg/d dose groups. FRM did not alter performance in the spontaneous alternation or social approach tasks. FRM increased serum T3 levels but decreased serum T4 levels in P28 male pups in the 1.0 and 6.0 mg/kg/d dose groups. In P35 female pups and dams, serum T3 levels decreased in the 6.0 mg/kg/d dose group while T4 levels were not altered. Collectively, these findings suggest that FRM interferes with the development of social communication and social novelty, but not memory, supporting the hypothesis that contemporary PCB exposures pose a risk to the developing brain. FRM had sex, age, and dose-dependent effects on serum thyroid hormone levels that overlapped but did not perfectly align with the FRM effects on behavioral outcomes. These observations suggest that changes in thyroid hormone levels are not likely the major factor underlying the behavioral deficits observed in FRM-exposed animals.

OBJECTIVE: The purpose of this study was to determine the in vitro effects of a single exposure of bupivacaine on the mechanical properties of bovine cartilage explants at 3 weeks. DESIGN: Femoral condyle articular cartilage explants were aseptically harvested from juvenile bovine stifle joints before being exposed to chondrogenic medium containing 0.50% (wt/vol) bupivacaine, 0.25% (wt/vol) bupivacaine, or no medication (control) for 1 hour. Explants were then washed and maintained in culture in vitro for 3 weeks before testing. Cell viability, tensile and compressive mechanical properties, histological properties, and biochemical properties were then assessed. RESULTS: Explants exhibited a dose-dependent decrease in mean tensile Youngs modulus with increasing bupivacaine concentration (9.86 MPa in the controls, 6.48 MPa in the 0.25% bupivacaine group [P = 0.048], and 4.72 MPa in the 0.50% bupivacaine group [P = 0.005]). Consistent with these results, collagen content and collagen crosslinking decreased with bupivacaine exposure as measured by mass spectrometry. Compressive properties of the explants were unaffected by bupivacaine exposure. Explants also exhibited a trend toward dose-dependent decreases in viability (51.2% for the controls, 47.3% for the 0.25% bupivacaine-exposed group, and 37.0% for the 0.50% bupivacaine-exposed group [P = 0.072]). CONCLUSIONS: Three weeks after 1-hour bupivacaine exposure, the tensile properties of bovine cartilage explants were significantly decreased, while the compressive properties remained unaffected. These decreases in tensile properties corresponded with reductions in collagen content and crosslinking of collagen fibers. Physicians should be judicious regarding the intra-articular administration of bupivacaine in native joints.

In our paper, we encompass the topic of socioeconomic disparities intrinsic to drug pricing and look at ways to ensure that every individual in the United States can access antibiotics equally and equitably. In the United States, a multitude of individuals find themselves struggling with high, out-of-pocket costs for necessary antibiotics or medications.  These issues are generally caused by factors surrounding monopolistic drug markets, high costs for development, and the severity of disease that an individual is facing. We explore these challenges from a plethora of perspectives, such as; the role of specialty pharmacies, limited distribution networks, and the usage of psychotropic medications among youth with Autism Spectrum Disorders (ASD). High prices and restricted access of certain antibiotics for conditions like Hepatitis C highlight the systemic and intrinsic issues within the pharmaceutical industry and how it affects individuals who suffer from this disease or diseases similar to it. On a similar topic to that, ongoing shortages of ADHD medications continue to show the consistent and heavy impact of supply constraints amongst the pharmaceutical industry in the United States. We discuss potential solutions, including but not limited to, accelerating the approval of basic drugs, implementing ceiling prices to prevent high costs, and better integrating health-system specialty pharmacies. By concentrating on the need for policy reforms within the United States and collaboration amongst the various stakeholders that remain involved with drug pricing disparities, this study aims to offer a varied approach in reducing drug pricing disparities and making necessary medications accessible to every individual in the United States, regardless of socioeconomic or health status.

BACKGROUND: Reference to an intrinsic healing mechanism or an inner healer is commonplace amongst psychedelic drug-using cultures. The inner healer refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical body, for example, after sickness or injury. AIMS: Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived inner healing effects. METHODS: The item was issued to 59 patients after a single high (25 mg, n = 30) or placebo (1 mg, n = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression. RESULTS: Inner healer scores were higher after the high versus placebo dose of psilocybin (t = 3.88, p

This study demonstrates that changes in mindfulness predict subsequent changes in well-being in a data set including individuals who recently engaged in psychedelic use.

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose-response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose-response curves were examined. Mixed model analysis showed positive linear dose-response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73-88%) children, but not all, showed positive linear dose-response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose-response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose-response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121).

BackgroundIn U.S. states that legalized and commercialized recreational cannabis, cannabis sales in illegal markets are still sizable or even larger than those in legal markets. This study aimed to assess cannabis consumers' preferences for purchasing cannabis from legal and illegal markets and estimate the trade-offs under various policy scenarios.Methods963 adults were recruited, who used cannabis in the past year and lived in a state with recreational cannabis legalization. In a discrete choice experiment, participants chose purchasing cannabis from a legal dispensary or an illegal dealer with varying levels in product attributes including quality, safety, accessibility, potency, and price. Mixed logit models were used to analyze preferences.ResultsThe likelihood of choosing legal cannabis increased with a higher quality, the presence of lab test, a shorter distance to seller, a higher tetrahydrocannabinol level, and a lower price. The likelihood of choosing illegal cannabis increased with a higher quality, a shorter distance to seller, and a lower price. Among product attributes, quality and accessibility were perceived to be the most important for legal cannabis and price was perceived to be the most important for illegal cannabis. Policy simulations predicted that improving quality, ensuring safety, allowing delivery services, increasing dispensary density, and lowering prices/taxes of legal cannabis may reduce illegal cannabis market share.ConclusionsIn the U.S., cannabis consumers' preferences for illegal cannabis were associated with both legal and illegal cannabis product attributes. Policies regulating legal cannabis markets should consider potential spillover effects to illegal markets.

Steven-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is a rare immunologic hypersensitivity reaction to stimuli that presents as widespread eruption with mucocutaneous detachment and involvement of other organs. Multiple causes have been noted in literature, including numerous medications. In this report, we present a 52-year-old woman who arrived at the emergency department with a complaint of rash, malaise, and pruritus. She subsequently developed diffuse cutaneous and mucosal detachment. Work-up supported a diagnosis of SJS/TEN secondary to her thyroid replacement therapy, derived from desiccated pig thyroid glands. The patient's natural thyroid medication was discontinued and she responded well to appropriate treatment. This case is unique in that thyroid replacement therapy is not a commonly reported trigger of SJS/TEN. Providers should be aware of the potential for natural thyroid and other animal-derived natural medications to cause adverse reactions such as SJS/TEN.

Background: This study provides an overview of the clinical applications of drugs and their metabolites analysis in biological fluids and identifies commonly used analytical techniques for bioanalysis. Methods: Original open-access articles published between 31 October 2005 and 31 October 2020 in Google Scholar, MEDLINE, PubMed, and Embase were reviewed, and pertinent findings of the individual studies were pooled and presented using tables. This review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Results: Fifteen studies met the eligibility criteria and were included in the review. These studies show that qualitative identification and quantitative determination of drugs and their metabolites in biological fluids are important for therapeutic drug monitoring (TDM), pharmacokinetic and pharmacodynamic studies, drug abuse control, and forensic and toxicological analyses. Spectroscopic, electrochemical, and hyphenated and nonhyphenated chromatographic techniques are used to analyse drugs and their metabolites in biological fluids. However, hyphenated techniques are the preferred analytical methods because of their sensitivity, selectivity, accuracy, reproducibility, efficiency, and rapid analysis. Conclusion/Recommendations: Bioanalysis is important for pharmacokinetic and pharmacodynamic studies, therapeutic drug monitoring, forensic and toxicological analyses, and drug abuse control using different bioanalytical techniques. However, hyphenated techniques are the most commonly used bioanalytical techniques. Bioanalysis of drugs and their metabolites needs to be improved to provide good medical and pharmaceutical care to patients, to confirm forensic and toxicological cases, and to control drug abuse. [ABSTRACT FROM AUTHOR]

BACKGROUND: Vertigo is closely related to clinical neurological disorders. When neurons are damaged or dead, it may lead to abnormalities in the vestibular system and trigger vertigo symptoms. Therefore, it is necessary to explore and analyze the hotspots related to vertigo that are common in clinical neurology. OBJECTIVE: To analyze the vertigo-related histopathological changes in clinical neurology and the research hotspots worldwide using bibliometric methods. METHODS: The WanFang database and Web of Science core set database were searched by the first author to retrieve the research-related literature published from 2014-2023 on the treatment of common vertigo in clinical neurology. A bibliometric analysis of the number of publications, country/region, institution, keywords, co-cited literature, and highly cited literature was peformed using VOSviewer_1.6.19 software to summarize the research hotspots in this research field. RESULTS AND CONCLUSION: Web of Science core set database had the highest number of 174 publications in this field in 2022, and WanFang database had the highest number of 133 publications in this field in 2020. The top 3 countries with the highest number of publications are the United States, Germany, and China. The University of Munich, Germany is the international institution with the highest number of publications in this field, while Chengdu University of Traditional Chinese Medicine is the Chinese institution with the highest number of publications in this field. The results of keyword analysis showed that the research hotspot diseases in this field in China are mainly Meniere’s disease, cervical vertigo, senile vertigo, benign paroxysmal positional vertigo, isolated vertigo, and hypertensive vertigo, and the treatments include acupuncture, rehabilitation, medication (gastrodin, Banxia Baizhu Tianma Tang), and manipulative reduction. International research hotspot diseases in this field mainly include benign paroxysmal positional vertigo, vestibular disorders in new coronavirus cases, Meniere’s disease, vestibular schwannoma, acoustic neuromas, and vestibular migraines, etc., and the hotspot treatments are antivertiginous medications, antidepressant and anxiolytic treatments, and microsurgery. The results of literature co-citation analysis showed that for acute vestibular syndrome with persistent vertigo as the main symptom, three-step bedside ophthalmoscopy (HINTS: Head-Impact-Nystagmus-Strabismus Test) is more sensitive than early MRI in the diagnosis of combined strokes in patients with acute vestibular syndrome, which is the most peer-recognized method of detecting strokes in vestibular syndrome, whereas hormonal therapy is more effective to treat vestibular neuritis patients with paroxysmal vertigo as the main symptom. The results of highly cited literature analysis showed that, in the hot literature included in WanFang database in the past 10 years, acupuncture at Fengchi point and the acupuncture method of inducing resuscitation to improve posterior circulation ischemic vertigo have achieved certain results. The literature published in the past 3 years has indicated that Ginkgo biloba leaf extract+gastrodin, acupuncture+Banxia Baizhu Tang, betahistine+gastrodin, vestibular rehabilitation training+Epley Maneuver, all can improve the vertigo symptoms to different degrees. While there were no featured anti-vertigo drugs indicated in the literature in the Web of Science core set data in the recent 10 years, and most of them are based on traditional anti-vertigo drugs and microsurgery. However, there are a few case reports in the international literature in the last 3 years that found that COVID-19 infection may lead to vestibular neuritis and vertigo symptoms. The onset and progression of vertigo may be closely related to neuronal damage and regeneration. For example, viral infections, inflammatory stimuli, or other pathologic factors may lead to neuronal damage or death, thereby affecting the function of the vestibular system. Vertigo-related diagnosis and treatment standardization guidelines have been published both domestically and internationally. Currently, international guidelines recommend the combination of vestibular rehabilitation and physical rehabilitation for the treatment of vertigo, and Chinese guidelines recommend the combination of Chinese and Western medicine, reduction and acupuncture. However, the level of evidence is not very high, so a large number of large-sample, multicenter randomized controlled trials on anti-vertigo treatment are needed in the future. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) can lead to right ventricular hypertrophy, significantly increasing mortality rates. This study aims to clarify PH-specific metabolites and their impact on genomic and post-translational modifications (PTMs) in cancer, evaluating DHA and EPA's therapeutic potential to mitigate oxidative stress and inflammation. Methods: Data from 289,365 individuals were analyzed using Mendelian randomization to examine 1,400 metabolites' causal roles in PH. Anti-inflammatory and antioxidative effects of DHA and EPA were tested in RAW 264.7 macrophages and cancer cell lines (A549, HCT116, HepG2, LNCaP). Genomic features like CNVs, DNA methylation, tumor mutation burden (TMB), and PTMs were analyzed. DHA and EPA's effects on ROS production and cancer cell proliferation were assessed. Results: We identified 57 metabolites associated with PH risk and examined key tumor-related pathways through promoter methylation analysis. DHA and EPA significantly reduced ROS levels and inflammatory markers in macrophages, inhibited the proliferation of various cancer cell lines, and decreased nuclear translocation of SUMOylated proteins during oxidative stress and inflammatory responses. These findings suggest a potential anticancer role through the modulation of stress-related nuclear signaling, as well as a regulatory function on cellular PTMs. Conclusion: This study elucidates metabolic and PTM changes in PH and cancer, indicating DHA and EPA's role in reducing oxidative stress and inflammation. These findings support targeting these pathways for early biomarkers and therapies, potentially improving disease management and patient outcomes. [ABSTRACT FROM AUTHOR]

Objective: This study examined prescription trends for benign prostatic hyperplasia (BPH) drug therapy in Japan over the past decade, focusing on drugs rated as grade A according to Japanese clinical guidelines. Methods: Using the National Database Open Data, this study analyzed prescription data from the fiscal years of 2014 to 2021, tracking α1‐blockers, 5α‐reductase inhibitors, and phosphodiesterase type 5 inhibitors. We adjusted for demographics and calculated medication costs to determine prescribing patterns and changes in drug utilization. Results: Prescriptions for α1‐blockers increased from 9898 per 1000 males in 2014 to 12 613 in 2021. Prescriptions for 5α‐reductase inhibitors rose from 1441 per 1000 males in 2014 to 2310 in 2021. Tadalafil prescriptions saw a significant increase, from 900 in 2015 to 2520 in 2021. Despite these increases, the overall market size for BPH drugs decreased from 664 million dollars in 2014 to 279 million dollars in 2021, indicating a shift toward generic medications driven by healthcare policies. Conclusions: Although BPH medication prescriptions are increasing, driven by Japan's aging population and clinical guidelines, market dynamics are shifting owing to generic and government price adjustments. This analysis underscores the changing BPH treatment landscape in Japan, highlighting the importance of continuous evaluation of treatment efficacy and cost‐effectiveness in evolving healthcare policies and demographics. [ABSTRACT FROM AUTHOR]

There is a potential link between rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). The aim of this study is to investigate the molecular processes that underlie the development of these two conditions by bioinformatics methods. The gene expression samples for RA (GSE77298) and IPF (GSE24206) were retrieved from the Gene Expression Omnibus (GEO) database. After identifying the overlapping differentially expressed genes (DEGs) for RA and IPF, we conducted functional annotation, protein–protein interaction (PPI) network analysis, and hub gene identification. Finally, we used the hub genes to predict potential medications for the treatment of both disorders. We identified 74 common DEGs for further analysis. Functional analysis demonstrated that cellular components, biological processes, and molecular functions all played a role in the emergence and progression of RA and IPF. Using the cytoHubba plugin, we identified 7 important hub genes, namely COL3A1, SDC1, CCL5, CXCL13, MMP1, THY1, and BDNF. As diagnostic indicators for RA, SDC1, CCL5, CXCL13, MMP1, and THY1 showed favorable values. For IPF, COL3A1, SDC1, CCL5, CXCL13, THY1, and BDNF were favorable diagnostic markers. Furthermore, we predicted 61 Chinese and 69 Western medications using the hub genes. Our research findings demonstrate a shared pathophysiology between RA and IPF, which may provide new insights for more mechanistic research and more effective treatments. These common pathways and hub genes identified in our study offer potential opportunities for developing more targeted therapies that can address both disorders. [ABSTRACT FROM AUTHOR]

Background: Phenobarbital (PHB) has been shown to be an effective treatment of alcohol withdrawal syndrome (AWS), with multiple dosing strategies used (e.g., single-dose and symptom-triggered). Studies have often used tapered doses, typically following a front-loaded dose, despite PHB's long half-life which should lead to an ability to auto-taper. Objective: The purpose of this study was to compare clinical outcomes associated with two PHB dosing strategies (taper [T], no taper [NT]) for AWS. Methods: This retrospective cohort study compared adult patients admitted to the ICU from October 2017 to May 2019 who received an initial loading dose of PHB for AWS. The use of PHB was at the discretion of the clinician per our institutional guidelines. Prior to November 2018, patients were prescribed a PHB taper, while after this period, the taper was no longer recommended. The primary outcome was the proportion of patients requiring rescue PHB or adjunctive medications for AWS. Secondary outcomes included number of adjunctive agents used, prevalence of severe manifestations of AWS, ICU and hospital lengths of stay, and incidence of potentially significant drug interactions. Results: A total of 172 patients were included (T: n = 81, NT: n = 91). Baseline characteristics were similar between groups, including history of severe AWS and cumulative benzodiazepine dose pre-PHB. There was no difference in the primary outcome between groups (T: 70.4% vs NT: 59.3%, P = 0.152). The median number of adjunctive agents per patient, severe manifestations, and ICU and hospital length of stay did not differ between groups. Twenty-five patients (14.5%) had potentially significant drug interactions. Conclusion and Relevance: The use of a PHB loading dose without a taper may be comparable to a taper strategy on clinical outcomes. Prospective studies are needed to further delineate the optimal dose of PHB for AWS. [ABSTRACT FROM AUTHOR]

Objective: Simultaneous occurrence of psychological disorders such as obsessive-compulsive disorder (OCD) has been reported in patients with a history of substance abuse. We evaluated the occurrence and severity of OCD in opium and amphetamine users. Methods: In this cross-sectional study, patients with a history of opium use (n = 100) or with a history of amphetamine use (n = 100) were studied. The diagnosis of OCD was based on the Yale-Brown Obsessive Compulsive questionnaire. Results: Regarding the prevalence of OCD in the two groups of opium and amphetamine users, 36% and 22% suffered from very mild OCD, 48% and 36% from mild OCD, 13% and 27% from moderate OCD and 3% and 15% from severe OCD. The severity of OCD was independent of gender and marital status in both groups. In amphetamine users' group, OCD severity was linked to patients' age and time for drug usage. Conclusion: The severity of OCD is much more severe in amphetamine-dependent patients than in opium-dependent patients. In opioid-dependent patients, the severity of OCD is independent of gender, age, marital status, or duration of drug use, but in amphetamine-dependent patients, the severity of disorder is directly related to age and duration of amphetamine use. [ABSTRACT FROM AUTHOR]

In this study, it is examined how nanocellulose has been used in drug release so far. In the thinning, information is given briefly on controlled drug release and its importance, nanomaterials in controlled release, structure, and production of nanocellulose. Then, examples of the use of nanocellulose in drug release are given. The disadvantage of still having a slightly high production cost has been identified. However, it is understood that it is a very suitable material for drug release due to its abundance in nature, easy availability, and biocompatibility. Therefore, at the end of the study, it is recommended that nanocellulose of different sizes would be very useful for producing nanocellulose in different sizes and its applications in drug release and nanocellulose with other functional groups for drug release. In this respect, it is predicted that studies on nanocellulose as a natural product in terms of drug release will accelerate. [ABSTRACT FROM AUTHOR]

Introduction: Anaphylaxis is an acute life-threatening allergy, most commonly provoked by food, venom, or drugs. There is limited data regarding differences in symptomatology between anaphylaxis provoked by different triggers. This study aimed to assess sociodemographic characteristics, clinical symptoms, and management of anaphylaxis, according to triggers in adults. Methods: We conducted a cross-sectional study recruiting adult patients with anaphylactic reactions across 8 emergency departments (EDs) and 1 electronic medical service (EMS) in Canada. Univariate and multivariate regression models were used to evaluate symptoms involving all patients with the outcome of drug-induced anaphylaxis (DIA), venom-induced anaphylaxis (VIA), peanut-induced anaphylaxis (PIA), shellfish-induced anaphylaxis, tree-nut induced anaphylaxis (TIA) and nut-induced anaphylaxis (NIA). We assessed comorbidities associated with severe reactions, stratified by triggers listed above. Additionally, we evaluated the association of each trigger with treatment through regression models involving all patients with medications used as outcome and anaphylaxis triggers used as independent variables. Results: From April 2011 to November 2023, 1,135 adults presenting with anaphylaxis to EDs were recruited. The median age was 35.5 (interquartile range 25.3–51.1). Most of the patients presented with FIA (50.3%). Regarding symptomatology, hypotension was more likely associated with DIA (aOR = 1.20, 95% CI = 1.11–1.30, p < 0.01). When adjusted for age at reaction and male sex, alcohol was more likely associated (aOR = 1.51, 95% CI = 1.04–2.19, p = 0.035) with NIA. Regarding management, TIA was more likely associated with inpatient epinephrine (aOR = 2.05, 95% CI = 1.16–3.64, p = 0.014). DIA was less likely associated with outpatient antihistamine (aOR = 0.68, 95% CI = 0.48–0.89, p < 0.01) whereas TIA was more likely associated with outpatient antihistamine (aOR = 1.81, 95% CI = 1.03–3.19, p = 0.040). Conclusion: Our study underscores associations between specific triggers, clinical manifestations and managements, such as the potential link between TIA and throat tightness and hypotension and VIA. Identifying such associations can aid with the prompt diagnosis of anaphylaxis in patients presenting to the ED, leading to swifter treatment initiation and improving overall outcomes. [ABSTRACT FROM AUTHOR]

Artesunate (ART) is a classic antimalarial drug with high efficiency, low toxicity and tolerance. It has been shown to be safe and has good anti-tumor effect. Existing clinical studies have shown that the anti-tumor mechanisms of ART mainly include inducing apoptosis and autophagy of tumor cells, affecting tumor microenvironment, regulating immune response, overcoming drug resistance, as well as inhibiting tumor cell proliferation, migration, invasion, and angiogenesis. ART has been proven to fight against lung cancer, hepatocarcinoma, lymphoma, multiple myeloma, leukemia, colorectal cancer, ovarian cancer, cervical cancer, malignant melanoma, oral squamous cell carcinoma, bladder cancer, prostate cancer and other neoplasms. In this review, we highlight the effects of ART on various tumors with an emphasis on its anti-tumor mechanism, which is helpful to propose the potential research directions of ART and expand its clinical application. [ABSTRACT FROM AUTHOR]

Drug infusion therapy after surgery for urothelial carcinoma is an effective measure to reduce cancer recurrence rate. Hydrogels are drug carriers with good biocompatibility and high drug loading capacity, which can optimize the pharmacokinetics of drugs in the urinary system to improve the therapeutic effect. Compared with the traditional free drug in situ perfusion, the hydrogel drug loading system can still maintain effective drug concentration in the face of continuous urinary flushing due to its good mucosal adhesion effect. The significantly prolonged drug retention time can not only improve the therapeutic effect of drugs, but also reduce the discomfort and risk of urinary tract infections caused by frequent drug infusion, and improve patient compliance. In addition, the combination of hydrogel with nanoparticles and magnetic materials can also improve the mucosal permeability and targeting effect of the hydrogel drug loading system, so as to overcome the mucus layer of urinary epithelium and the physiological barrier of tumor and minimize the impact on normal tissue and cell functions. At present, the research of hydrogels for urothelial cancer treatment involves chemotherapy, immunotherapy, gene therapy, inhibition of metabolism and multi strategy synergistic therapy. This review summarizes the research progress of hydrogels for the treatment of urothelial carcinoma, hoping to provide a reference for the future research of safe, reliable, effective, and advanced hydrogels with little side effects. [ABSTRACT FROM AUTHOR]

ABSTRACT Herein, pyrazinamide (L1) was used as a powerful ligand to promote a CuSO4‐catalyzed reaction between aryl halides and imidazole (HID) under mild conditions, generating various N‐arylation products in good to excellent yields. The findings indicate that CuSO4 was reduced and coordinated with L1 to form [CuIL1], which activated ArX to produce [ArCuIL1X] through oxidative addition. This intermediate subsequently underwent reductive elimination to form N‐arylation products, with [ArCuILID] being generated from a reaction between [ArCuIL1X] and HID. This method was successfully extended to the synthesis of 2‐phenylindole and pyrrolo[1,2‐a]quinoxaline under mild conditions. The method significantly enhances the efficiency and cost effectiveness of C‐N coupling reaction. [ABSTRACT FROM AUTHOR]

Recent considerations of natural sources as potential anticancer agents have arisen due to the origins of numerous drugs commonly used in chemotherapy. Plant‐based drugs, in particular, have attracted attention for offering the advantage of low adverse effects. Among these, the black mulberry plant (Morus nigra L.) stands out as a natural source of polyphenols, widely used to treat metabolic dysfunctions and confer benefits on human health. This study explores the potential of this plant as an anticancer agent, examining its effectiveness based on the type of application of the plant extracts or isolated substances, extraction methods, and its potential biological effects on cancer cells. Consequently, this study contributes to a better understanding of the distribution of phytochemicals in M. nigra and their applications in the context of cancer field. Among the compounds found in black mulberry are flavonoids, chlorogenic acid, cryptochlorogenic acid, and protocatechuic acid, along with cyanidin‐3‐O‐glucoside as the main anthocyanin on the fruit. The phytochemicals derived from M. nigra exhibit antinociceptive and antimicrobial activities, while also showing protective effects, such as antioxidant properties that underline their potential as anticancer agents. The black mulberry's roots, stem bark, pulp, and leaves are particularly rich sources of anti‐inflammatory compounds. Ethanol and methanol extraction methods appear to be the most effective in cancer management, offering compounds that facilitate the integration of apoptosis induction, cell growth inhibition, and cytotoxicity modulation. These results collectively represent the salient biological attributes that positioned black mulberry as a promising anticancer agent. Therefore, these findings highlight the multifaceted potential of M. nigra as an anticancer agent, making a compelling case for further research to advance prospects in the medical field. [ABSTRACT FROM AUTHOR]

Literature reported drug poisoning as a major cause for visiting emergency departments, with various rates of occurrences across countries, regions, socioeconomic status, and cultures. Therefore, this study was conducted in Qassim to describe the sociodemographic patterns of acute drug poisoning as well as the most common drugs involved. A retrospective method of data collection was used employing medical record review for drug poisoning cases that occurred in the Qassim region during the 8 years from January 2008 to December 2015. Data was collected using a standardized, validated data collection sheet. The study failed to reveal any pattern (either decreasing or increasing) in the number of poisoning cases over time. Most cases (56.2%) of drug poisoning were accidental, caused by analgesics (35%), affected children younger than 5 years of age (41.4%), and occurred via ingestion (99.2%). It can be concluded that as most poisoning cases affected children, this highlights the importance of increasing awareness and educating families about the safe handling and storage of drugs out of reach of children. [ABSTRACT FROM AUTHOR]

Cloud point (CP) of aqueous solution of metformin hydrochloride (MNH) and triton X-100 (TX-100) was examined in presence of several alcohols (MeOH, EtOH, 1-PrOH, 2-PrOH, and 1-BuOH). The main focal point of this study was to evaluate the cloud development for the combination of TX-100 and MNH, as well as to indicate the mode of how various alcohols influence both the physicochemical parameters and interaction forces of that mixture. The cloud point (CP) measurement technique was chosen because of its broad applicability in both the medical and industrial sectors. As alcohol contents increased, higher CP values of TX-100 and MNH mixture were observed except in aq. 1-BuOH (CP is decreased). In the aqueous alcoholic medium (above 3000 mmol·kg−1), the phase separation of TX-100 (92.7 mmol·kg−1) and MNH (2 mmol·kg−1) mixture showed the subsequent trend: CP (H2O + 2-PrOH) ˃ CP (H2O + MeOH) > CP (H2O + EtOH) ˃ CP (H2O + 1-PrOH). It was observed that the depth to which alcohol molecules penetrate micelles is influenced by the length of the alcohol chain. Longer hydrophobic alcohol molecules have the ability to impair more ethylene oxide–water (EO-water) interactions by penetrating deeper into the micelle's palisade layer. As a result, there is more occurrence of dehydration, which promotes the production of micellar particles as well as lowers the cloud point substantially. The calculated Δ G c 0 values of the TX-100 + MNH mixture in alcohols media are appeared as positive in every scenario examined, proving that the clouding procedure is not spontaneous. The positive Δ G c 0 results might be attributed to the surfactant's surface layer in forming H-bond via the water molecules. A decrease in the positive Δ G c 0 values is evidenced by a rise in alcohol concentrations. Consequently, there is less non-spontaneity at higher alcohol concentrations. The + Δ H c 0 (endothermic) and + Δ S c 0 magnitudes are detected in aq. MeOH, EtOH, and 2-PrOH solutions. However, Δ H c 0 and Δ S c 0 magnitudes are found as positive (endothermic) and negative (exothermic) at lower and higher contents of 1-PrOH solution while the opposite trend in the Δ H c 0 and Δ S c 0 was detected in aq. 1-BuOH solution. Possible interactions among TX-100 and metformin hydrochloride in aqueous 1-BuOH media [ABSTRACT FROM AUTHOR]

This review examines the impact of combining acupuncture with drug therapy on abnormal glucose metabolism and investigates their underlying mechanisms. Conditions like diabetes pose significant health risks due to irregular glucose metabolism. Traditional drug treatments often encounter challenges related to side effects and drug resistance. Acupuncture, as a non-pharmacological intervention, is thought to enhance glucose metabolism and mitigate medication side effects. We selected the relevant studies of acupuncture or electroacupuncture combined with drugs in the treatment of abnormal glucose metabolism in the past five years, and the results indicate that the combination of acupuncture or electroacupuncture and drug therapy markedly enhances glucose metabolism and mitigates medication-related side effects such as gastrointestinal discomfort and hypoglycemia. Overall, this review underscores the synergistic benefits of acupuncture and drug therapy in improving treatment efficacy and reducing adverse effects, offering promising new approaches for managing abnormal glucose metabolism. Our review provides evidence for the potential benefits of combining acupuncture with drug therapy for abnormal glucose metabolism, which could lead to improved treatment outcomes and reduced side effects for patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Apoptosis is an evolutionarily conserved cell death pathway that plays a crucial role in maintaining tissue homeostasis, orchestrating organismal development, and eliminating damaged cells. Dysregulation of apoptosis can contribute to the pathogenesis of malignant tumors and neurodegenerative diseases. Anticancer drugs typically possess the capacity to induce apoptosis in tumor cells. The Bcl-2 protein family, consisting of 27 members in humans, serves as the key regulator of mitochondrial function. This family can be divided into two functional groups: anti-apoptotic proteins (e.g., Bcl-2, Bcl-xl, Mcl-1) and pro-apoptotic proteins (e.g., Bad, Bax). Mcl-1 exerts its function by binding pro-apoptotic Bcl-2 proteins thereby preventing apoptosis induction. Overexpression of Mcl-1 not only correlates closely with tumorigenesis but also associates significantly with resistance towards targeted therapy and conventional chemotherapy. Effective induction of apoptosis can be achieved through inhibition or interference with Mcl-1. Thus, this mini review discusses existing Mcl-1 inhibitors. [ABSTRACT FROM AUTHOR]

AbstractVascular calcification is a common complication of chronic kidney disease (CKD). The molecular mechanisms underlying this condition and the efficacy of potential treatments remain unclear. Bioinformatic methods were employed to analyze gene ontology (GO) annotations and pathway enrichments. Subsequently, an analysis of potential therapeutic agents for vascular calcification in CKD was performed. A total of 76 common genes, 181 enriched GO annotations—comprising 153 biological processes, 10 cellular components, and 18 molecular functions—41 KEGG pathways, 13 REACTOME pathways, and 3 BIOCARTA pathways were identified. Five key genes (PSMC5, TNFSF11, TNFRSF11A, TNFRSF12A, and ICAM1) were isolated. Most notably, the top five potential therapeutic drugs—ENAVATUZUMAB, DENOSUMAB, ALICAFORSEN, BI-505, and ENLIMOMAB PEGOL—were identified for vascular calcification in CKD. However, further molecular biological experiments are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Cyclosporine A (CsA) is used as a steroid-sparing or alternative immunosuppressing agent in cats with various immune-mediated diseases such as immune-mediated hemolytic anemia. Daily treatment dosages of 5–20  mg/ kg have been described. Interindividual variations in CsA blood levels are known to occur. To determine when steady-state conditions are reached and thus the earliest advisable time for monitoring CsA blood levels during the course of treatment, a prospective experimental study was conducted in six healthy adult Domestic Shorthair cats. Materials and methods: Cats were treated with an oral dosage of 7  mg/kg CsA q 12  h for 10  days. On days 1, 2, 3, 5, 7, and 10 after the start of CsA administration (i.e., after 1, 3, 5, 9, 13, and 19 CsA administrations), EDTA blood was collected to measure the CsA level 12  h after the CsA administration (trough values) using high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). Results: Statistical analysis revealed a significant increase in mean CsA blood levels up to day 5 (2,050  ±  964.2  ng/mL [mean  ±  SD], 832–3,203  ng/mL [minimum–maximum]; repeated-measures ANOVA: p  =  0.0021), while values on days 5 and 7 did not differ significantly from CsA concentrations on day 10. CsA concentrations showed markedly interindividual variability. Conclusion: Cyclosporine A blood levels reached a steady state on day 5 of high dosages of CsA q 12  h (i.e., after nine CsA administrations), indicating that this time point is suitable for monitoring blood levels in clinical patients. Results confirmed the well-known remarkable interindividual variability of CsA, indicating the need for treatment monitoring. The assessed treatment regime resulted in significantly higher mean CsA trough levels than the target range for immunosuppressive therapy (200–600  ng/mL). [ABSTRACT FROM AUTHOR]

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Drug infusion therapy after surgery for urothelial carcinoma is an effective measure to reduce cancer recurrence rate. Hydrogels are drug carriers with good biocompatibility and high drug loading capacity, which can optimize the pharmacokinetics of drugs in the urinary system to improve the therapeutic effect. Compared with the traditional free drug in situ perfusion, the hydrogel drug loading system can still maintain effective drug concentration in the face of continuous urinary flushing due to its good mucosal adhesion effect. The significantly prolonged drug retention time can not only improve the therapeutic effect of drugs, but also reduce the discomfort and risk of urinary tract infections caused by frequent drug infusion, and improve patient compliance. In addition, the combination of hydrogel with nanoparticles and magnetic materials can also improve the mucosal permeability and targeting effect of the hydrogel drug loading system, so as to overcome the mucus layer of urinary epithelium and the physiological barrier of tumor and minimize the impact on normal tissue and cell functions. At present, the research of hydrogels for urothelial cancer treatment involves chemotherapy, immunotherapy, gene therapy, inhibition of metabolism and multi strategy synergistic therapy. This review summarizes the research progress of hydrogels for the treatment of urothelial carcinoma, hoping to provide a reference for the future research of safe, reliable, effective, and advanced hydrogels with little side effects. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionsCurrently, there are great hopes for psychedelic substances in treating psychiatric conditions and improving well-being. These substances are illegal in many countries, and we lack knowledge of how conflicting discourses shape psychedelic use in naturalistic settings. This study explores how psilocybin use is made meaningful by participants and staff at a retreat including psychedelic ceremonies aimed at personal growth.Ethnographic fieldwork was conducted at a psychedelic retreat with participants from Sweden. The material was organized using Zinberg’s model of drug, set, and setting. Theoretical work related to comparisons was utilized to elucidate how psilocybin use was distinguished from other illicit drug use.The participants’ desires to be fundamentally transformed, combined with the staff’s staging of the setting as a haven primed the participants to approach psilocybin as an inherently benevolent substance. Positive experiences during the ceremonies were attributed to the substance, and negative experiences to personal shortcomings.The staff and participants combined different discourses to define the meaning of psilocybin, all of which condemned using it for purely recreational purposes. The psilocybin use at the retreat was considered an improvement and wholly unrelated to illegal drug use, dissociating this practice from such use to establish legitimate transgression. [ABSTRACT FROM AUTHOR]

Background: Inconsistent study results and contradictory recommendations from health authorities regarding the use of apixaban in patients on hemodialysis have generated considerable uncertainty among clinicians, making investigations of appropriate dosing an unmet need. Methods: We analyzed pre-dialysis apixaban drug levels from a tertiary care dialysis unit, comparing 2.5 mg once versus twice daily dosing. We applied mixed-effects models including dialysis modality, adjusted standard Kt/V, ultrafiltration, and dialyzer characteristics. We included an exploratory analysis of bleeding events and compared the drug levels of our dialysis patients to those from non-CKD reference populations taking the standard dose of 5 mg twice daily. Results: We analyzed 143 drug levels from 24 patients. Mean (SD) age at first drug level measurement was 64.7 (15.9) years (50 % female), median (IQR) follow-up was 12.5 (5.5 – 21) months. For the apixaban 2.5 mg once and twice daily groups, median (IQR) drug levels were 54.4 (< 40 – 72.1) and 71.3 (48.8 – 104.1) ng/mL respectively (P < 0.001). Levels were below the detection limit in 30 % (with 2.5 mg once daily) and 14 % (with 2.5 mg twice daily) respectively. Only dosing group (twice versus once daily) was independently associated with higher drug levels (P = 0.002). Follow-up did not suggest accumulation. The 95th percentile of drug levels did not exceed those of non-CKD populations taking 5 mg twice daily. Median (IQR) drug levels before a bleeding (8 episodes) were higher than those without a subsequent bleeding: 111.6 (83.1 – 129.3) versus 54.8 (< 40 – 77.1) ng/mL (P < 0.001). Concomitant antiplatelet therapy was used in 86% of those with bleeding events versus 6% without bleeding events (P < 0.001). Conclusions: Drug monitoring may be a contributory tool to increase patient safety. Despite non-existing target ranges, drug levels on both edges of the spectrum (e.g. below detectability or beyond the 95th percentiles of reference populations) may improve decision-making in highly individualized risk-benefit analyses. [ABSTRACT FROM AUTHOR]

Objectives: Dental caries, a prevalent infectious disease affecting teeth, ranks highest among 328 diseases, according to a 2017 Lancet study. In demineralized human dentin, matrix metalloproteinase‐3 (MMP3) functions as a proteoglycanase, contributing to the degradation of proteoglycan components. This process exposes collagen fibrils, thereby facilitating the demineralization of the dentin matrix. Inhibiting MMP3 shows potential for preventing dental caries. Methods: The binding affinity of 20 cinnamic acid derivatives, namely cynarin, chlorogenic acid, rosmarinic acid, cinnamyl caffeate, phenethyl caffeate, N‐p‐coumaroyltyramine, caffeic acid 3‐glucoside, caffeic acid phenethyl ester, roscovitine, benzyl caffeate, o‐coumaric acid, artepillin C, caffeic acid, methyl caffeate, 2‐methylcinnamic acid, ferulic acid, drupanin, p‐coumaric acid, cinnamic acid, and sinapinic acid, to the MMP3 catalytic cleft, was assessed utilizing AutoDock 4.0. Molecular dynamics simulation was then employed to analyze the stability of backbone atoms in free MMP3, MMP3‐positive control inhibitor, and MMP3 complexed with the top‐ranked cinnamic acid over a 100 ns computer simulation. Results: Four cinnamic acids demonstrated ΔGbinding scores below −10 kcal/mol, with cynarin emerging as the most potent MMP3 inhibitor, featuring a ΔGbinding score and inhibition constant value of −15.57 kcal/mol and 3.83 pM, respectively. The MMP3–cynarin complex exhibited stability after a 50 ns computer simulation, showing a root‐mean‐square deviation of 8 Å. Conclusions: The inhibition of MMP3 by cynarin, chlorogenic acid, rosmarinic acid, and cinnamyl caffeate holds promise as a potential preventive strategy for dental caries. [ABSTRACT FROM AUTHOR]

The development of innovative antibiotic medications is particularly crucial since the increased bacterial resistance to antibiotics poses a serious danger to human health. Here, an adamantine moiety-containing family of Schiff base tetracycline derivatives was created and the structural characterization of the compounds was carried out via spectral methods (FTIR and 1H NMR), after which the physical properties of the synthesis compounds and the biological activity were tested in vitro. The Schiff bases derived from tetracycline show significantly higher activity against Gram-positive bacteria as compared to tetracycline. Further study on these derived compounds will help in marketing new derivatives of tetracycline that will have more broad-spectrum activity than tetracycline. [ABSTRACT FROM AUTHOR]

• Combination therapy is efficacious in treating women with OAB. • Rapid effect and persistent clinical improvement were evident from week 2. • There were fewer side effects over time. We hypothesized that combination therapy would provide a synergistic effect to improve treatment outcomes for overactive bladder (OAB), thus enhancing the motivation for continuous exercise, and that it would be associated with fewer adverse events than monotherapy. Therefore, we investigated whether biofeedback-assisted pelvic floor muscle training (PFMT), drug therapy, or a combination of both would be more effective in improving the symptoms of OAB. This randomized controlled trial included women diagnosed with OAB. Group 1 received biofeedback-assisted pelvic muscle floor training (PFMT) for 12 weeks; group 2 took 5 mg of solifenacin/day for 12 weeks; and group 3 received 5 mg of solifenacin/day in combination with biofeedback-assisted PFMT during the first 4 weeks and biofeedback-assisted PFMT for another 8 weeks. All participants had 5 follow-up visits. The primary outcomes were objective improvement of OAB symptoms and quality of life. The secondary outcomes were treatment-related adverse events, subjective improvement of OAB symptoms, and electromyographic activity of pelvic floor muscle (PFM) contraction. All participants reported significant improvement of OAB symptoms and quality of life. Participants in group 2 experienced more pronounced adverse events than those in group 3. Intervention duration was positively associated with subjective improvement in OAB symptoms in groups 2 and 3. Drug-related adverse events, including dry mouth, myalgia, and restlessness, had a negative impact on the subjective improvement of OAB symptoms in group 2. In group 1, exercise adherence was positively correlated with subjective improvement of OAB symptoms, whereas in group 3, PFM contraction and biofeedback effect were positively correlated with symptom improvement. Combination therapy is efficacious in treating women with OAB. [ABSTRACT FROM AUTHOR]

[Display omitted] Here, we report the preparation of a novel Janus nanoparticle with opposite Ir and mesoporous silica nanoparticles through a partial surface masking with toposelective modification method. This nanomaterial was employed to construct an enzyme-powered nanomachine with self-propulsion properties for on-command delivery. The cargo-loaded nanoparticle was provided with a pH-sensitive gate and unit control at the mesoporous face by first attaching boronic acid residues and further immobilization of glucose oxidase through reversible boronic acid esters with the carbohydrate residues of the glycoenzyme. Addition of glucose leads to the enzymatic production of H 2 O 2 and gluconic acid, being the first compound catalytically decomposed at the Ir nanoparticle face producing O 2 and causing the nanomachine propulsion. Gluconic acid leads to a pH reduction at the nanomachine microenvironment causing the disruption of the gating mechanism with the subsequent cargo release. This work demonstrates that enzyme-mediated self-propulsion improved release efficiency being this nanomotor successfully employed for the smart release of Doxorubicin in HeLa cancer cells. [ABSTRACT FROM AUTHOR]

Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown. Design: Retrospective cohort study. Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations. Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens. Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p < 0.001) regimens. The survival benefit of ASP/GEM-based regimens over other ASP-based regimens was substantial across risk-stratified and advanced-stage subgroups. The survival benefits of a combination of RT, ASP, and GEM were consistent after adjustment for confounding factors by IPTW. Conclusion: These results suggest that combining ASP/GEM with RT for ENKTCL is an efficacious and feasible therapeutic option and provides a rationale and strategy for developing combination therapies. [ABSTRACT FROM AUTHOR]

Background: Effective medication management, disposal, and donation are vital for public health and environmental sustainability. Improper handling of medications can lead to drug misuse, accidental poisoning, and environmental damage. This study examines current practices and challenges in Saudi Arabia, identifying opportunities for improvement. Method: A cross-sectional survey conducted in October and November 2023 targeted the general population in Saudi Arabia. This study employed convenience sampling to explore medication usage, storage, disposal practices, and awareness of donation procedures. Data were analyzed through both descriptive and inferential statistical methods. Results: This study involved 430 respondents. Of these, 73.0% held a university degree, yet 66.3% were unaware of drug donation programs, and 84.2% lacked knowledge about proper medication disposal. Despite this, 71.4% believed that drug donation programs positively impact healthcare, and 87.9% saw them as reducing drug waste and environmental pollution. However, 48.1% expressed concerns about the potential misuse of donated medicines. Awareness and knowledge were significantly higher among participants aged 30 and above. Conclusions: The findings highlight the need for enhanced public awareness, clear medication disposal guidelines, and ethically governed donation practices in Saudi Arabia. These measures can improve healthcare outcomes, protect the environment, and support global health and sustainability goals. [ABSTRACT FROM AUTHOR]

Presently, there are many drugs for the treatment of atherosclerosis (AS), among which lipid-lowering, anti-inflammatory, and antiproliferative drugs have been the most studied. These drugs have been shown to have inhibitory effects on the development of AS. Nanoparticles are suitable for AS treatment research due to their fine-tunable and modifiable properties. Compared with drug monotherapy, experimental results have proven that the effects of nanoparticle-encapsulated drugs are significantly enhanced. In addition to nanoparticles containing a single drug, there have been many studies on collaborative drug treatment, collaborative physical treatment (ultrasound, near-infrared lasers, and external magnetic field), and the integration of diagnosis and treatment. This review provides an introduction to the therapeutic effects of nanoparticles loaded with drugs to treat AS and summarizes their advantages, including increased targeting ability, sustained drug release, improved bioavailability, reduced toxicity, and inhibition of plaque and vascular stenosis. [ABSTRACT FROM AUTHOR]

Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug extensively used by people living with HIV. The TDF molecule is hydrolysed in vivo and liberates tenofovir, the active part of the molecule. Tenofovir is a very stable drug and the discharge of its residues into the environment can potentially lead to risk for aquatic species. This study evaluated the TDF biodegradation and removal by cultures of Microcystis novacekii with the bacteria Pseudomonas pseudoalcaligenes. Concentrations of TDF of 12.5, 25.0, and 50.0 mg/L were used in this study. The process occurred in two stages. In the first 72 h, TDF was de-esterified, forming the tenofovir monoester intermediate by abiotic and enzymatic processes associated in an extracellular medium. In a second step, the monoester was removed from the culture medium by intracellular processes. The tenofovir or other by-products of TDF were not observed in the test conditions. At the end of the experiment, 88.7 to 94.1% of TDF and its monoester derivative were removed from the culture medium over 16 days. This process showed higher efficiency of TDF removal at the concentration of 25 mg/L. Tenofovir isoproxil monoester has partial antiviral activity and has shown to be persistent, maintaining a residual concentration after 16 days in the culture medium, therefore indicating the need to continue research on methods for total removal of this product from the aquatic environment. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae, which is among the top three pathogens on WHO's priority list, is one of the gram-negative bacteria that doctors and researchers around the world have fought for decades. Capsular polysaccharide (CPS) protein is extensively recognized as an important K. pneumoniae virulence factor. Thus, CPS has become the most characterized target for the discovery of novel drug candidates. The ineffectiveness of currently existing antibiotics urges the search for potent antimicrobial compounds. Flavonoids are a group of plant metabolites that have antibacterial potential and can enhance the present medications to elicit improved results against diverse diseases without adverse reactions. Henceforth, the present study aims to illustrate the inhibitory potential of flavonoids with varying pharmacological properties, targeting the CPS protein of K. pneumoniae by in silico approaches. The flavonoid compounds (n = 169) were retrieved from the PubChem database and screened using the structure-based virtual screening approach. Compounds with the highest binding score were estimated through their pharmacokinetic effects by ADMET descriptors. Finally, four potential inhibitors with PubChem CID: (4301534, 5213, 5481948, and 637080) were selected after molecular docking and drug-likeness analysis. All four lead compounds were employed for the MDS analysis of a 100 ns time period. Various studies were undertaken to assess the stability of the protein–ligand complexes. The binding free energy was computed using MM-PBSA, and the outcomes indicated that the molecules are having stable interactions with the binding site of the target protein. The results revealed that all four compounds can be employed as potential therapeutics against K. pneumoniae. [ABSTRACT FROM AUTHOR]

The unique non‐coding RNA molecule known as circular RNA (circRNA) is distinguished from conventional linear RNA by having a longer half‐life, greater degree of conservation and inherent solidity. Extensive research has demonstrated the profound impact of circRNA expression on cellular drug sensitivity and therapeutic efficacy. There is an immediate need for the creation of efficient computational techniques to anticipate the potential correlations between circRNA and drug sensitivity, as classical biological research approaches are time‐consuming and costly. In this work, we introduce a novel deep learning model called SNMGCDA, which aims to forecast the relationships between circRNA and drug sensitivity. SNMGCDA incorporates a diverse range of similarity networks, enabling the derivation of feature vectors for circRNAs and drugs using three distinct calculation methods. First, we utilize a sparse autoencoder for the extraction of drug characteristics. Subsequently, the application of non‐negative matrix factorization (NMF) enables the identification of relationships between circRNAs and drugs based on their shared features. Additionally, the multi‐head graph attention network is employed to capture the characteristics of circRNAs. After acquiring the characteristics from these three separate components, we combine them to form a unified and inclusive feature vector for each cluster of circRNA and drug. Finally, the relevant feature vectors and labels are inputted into a multilayer perceptron (MLP) to make predictions. The outcomes of the experiment, obtained through 5‐fold cross‐validation (5‐fold CV) and 10‐fold cross‐validation (10‐fold CV), demonstrate SNMGCDA outperforms five other state‐of‐art methods in terms of performance. Additionally, the majority of case studies have predominantly confirmed newly discovered correlations by SNMGCDA, thereby emphasizing its reliability in predicting potential relationships between circRNAs and drugs. [ABSTRACT FROM AUTHOR]