Toxicity Potential of Nutraceuticals.

During the past few decades and especially during and after the COVID-19 pandemic, the use of nutraceuticals has become increasingly popular in both humans and animals due to their easy access, cost-effectiveness, and tolerability with a wide margin of safety. While some nutraceuticals are safe, others have an inherent toxic potential. For a large number of nutraceuticals, no toxicity/safety data are available due to a lack of pharmacological/toxicological studies. The safety of some nutraceuticals can be compromised via contamination with toxic plants, metals, mycotoxins, pesticides, fertilizers, drugs of abuse, etc. Knowledge of pharmacokinetic/toxicokinetic studies and biomarkers of exposure, effect, and susceptibility appears to play a pivotal role in the safety and toxicity assessment of nutraceuticals. Interaction studies are essential to determine efficacy, safety, and toxicity when nutraceuticals and therapeutic drugs are used concomitantly or when polypharmacy is involved. This chapter describes various aspects of nutraceuticals, particularly their toxic potential, and the factors that influence their safety.

Direct analysis in real time mass spectrometry (DART-MS/MS) for rapid urine opioid detection in a clinical setting.

BACKGROUND AND AIMS: Current laboratory methods for opioid detection involve an initial screening with immunoassays which offers efficient but non-specific results and a subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirmation which offers accurate results but requires extensive sample preparation and turnaround time. Direct Analysis in Real Time (DART) tandem mass spectrometry is evaluated as an alternative approach for accurate opioid detection with efficient sample preparation and turnaround time. MATERIALS AND METHODS: DART-MS/MS was optimized by testing the method with varying temperatures, operation modes, extraction methods, hydrolysis times, and vortex times. The method was evaluated for 12 opioids by testing the analytical measurement range, percent carryover, precision studies, stability, and method-to-method comparison with LC-MS/MS. RESULTS: DART-MS/MS shows high sensitivity and specificity for the detection of 6-acetylmorphine, codeine, hydromorphone, oxymorphone, hydrocodone, naloxone, buprenorphine, norfentanyl, and fentanyl in urine samples. However, its performance was suboptimal for norbuprenorphine, morphine and oxycodone. CONCLUSION: In this proof-of-concept study, DART-MS/MS is evaluated for its rapid quantitative definitive testing of opioids drugs in urine. Further research is needed to expand its application to other areas of drug testing.

Eco-friendly chitosan microspheres as a novel one-step sorbent for the rapid purification and determination of pesticides and veterinary drug multi-residues in aquatic products with HPLC-MS/MS.

A modified QuEChERS method was developed to determine multi-class pesticide and veterinary residues in aquatic products. Chitosan microspheres were conveniently synthesized and utilized as the cleanup adsorbent in the QuEChERS procedure, showcasing rapid filtration one-step pretreatment ability for the determination of drug multi-residues in aquatic products. Compared to conventional synthetic sorbents, chitosan microspheres not only have good purification performance, but also have renewable and degradable properties. This novel sorbent worked well in the simultaneous determination of 95 pesticides and veterinary drug residues in aquatic products after being combined with an improved one-step vortex oscillating cleanup method. We achieved recoveries ranging from 64.0% to 115.9% for target drugs in shrimp and fish matrix. The limits of detection and quantification were 0.5-1.0 and 1.0-2.0 µg kg-1, respectively. Notably, hydrocortisone was detected with considerable frequency and concentration in the tested samples, underscoring the necessity for stringent monitoring of this compound in aquatic products.

A scalable approach to assess the safety of recently marketed systemic treatments for atopic dermatitis in clinical practice.

Targeted systemic immune-modulating drugs (IMDs) to treat atopic dermatitis (AD) were highly efficacious in randomized trials. Trials with limited number of subjects leave questions about their safety. We describe a data and analytics structure for the production of timely, high-quality evidence on the comparative safety of recently approved IMDs in patients with AD in clinical practice. We established a series of sequential propensity score (PS)-balanced cohorts that grow in size with each annual data refresh. Nine health outcomes of interest plus conjunctivitis as a positive tracer outcome were identified. The initial treatment comparison was dupilumab, an interleukin-4/13 inhibitor, or tralokinumab, an interleukin-13 inhibitor, versus abrocitinib/upadacitinib, both JAK inhibitors. The first analysis cycle (December 2021-February 2023) compared 269 patients initiating JAK inhibitors and 2,650 initiating IL-4/IL-13 inhibitors. Patient characteristics were well balanced after PS-matching. Outpatient infections within 180 days occurred in 18% of JAK-1 inhibitor initiators versus 12% of dupilumab/ tralokinumab initiators (RR=1.50; 0.96 to 2.33) whereas acne risks were 7% vs. 3%, respectively (RR=2.29, 0.96 to 5.46). This sequential monitoring system will produce essential knowledge on the safety of IMDs to treat AD based on its growing study size of patients observed in clinical practice.

How post overdose response efforts can address social determinants of health among people who use drugs: perspectives from the New York State Department of Health (NYSDOH) Post Overdose Response Team (PORT).

Individuals who have survived an overdose often have myriad needs that extend far beyond their drug use. The social determinants of health (SDOH) framework has been underutilized throughout the opioid overdose crisis, despite widespread acknowledgment that SDOH are contributors to the majority of health outcomes. Post Overdose Response Teams (PORTs) engage with individuals who have experienced 1 or more nonfatal overdoses and bear witness to the many ways in which overdose survivors experience instability with healthcare, housing, employment, and family structure. Employing a harm reduction model, PORTs are well-positioned to reach people who use drugs (PWUD) and to address gaps in basic needs on an individualized basis, including providing social support and a sense of personal connection during a period of heightened vulnerability. The New York State Department of Health (NYSDOH) PORT program is a harm reduction initiative that utilizes law enforcement data and several public databases to obtain accurate referral information and has been active since 2019 in NYC. This PORT program offers various services from overdose prevention education and resources, referrals to health and treatment services, and support services to overdose survivors and individuals within their social network. This perspective paper provides an in-depth overview of the program and shares quantitative and qualitative findings from the pilot phase and Year 1 of the program collected via client referral data, interviews, and case note reviews. It also examines the barriers and successes the program encountered during the pilot phase and Year 1. The team's approach to addressing complex needs is centered around human connection and working toward addressing SDOH one individualized solution at a time. Application of the NYSDOH PORT model as outlined has the potential to create significant positive impacts on the lives of PWUD, while potentially becoming a new avenue to reduce SDOH-related issues among PWUD.

Identification of honokiol-based scaffold to design tankyrase 1/2 inhibitors by in silico and in vitro studies.

Recently, we identified magnolol bioinspired derivatives as new Tankyrase 1/2 (TNKS1/2) inhibitors by our Inverse Virtual Screening protocol. Based on these findings, in the present contribution, we enlarged our investigation of neolignans to the natural product honokiol (1) and a group of its analogues (2-8). By integrating in silico analysis and Surface Plasmon Resonance experiments, we demonstrated the binding of 1 (honokiol), 2, 6 and 7 towards TNKS2. Furthermore, we also proved the binding specificity of 1 and 7 against TNKS2, while 2 and 6 were found to be also TNSK1 binders, along with 4. Promising antiproliferative activity in A549 cancer cell line were observed for 1 and 6, with honokiol (1) presenting a higher potency than the well-known TNKS2 inhibitor XAV939. Collectively, these outcomes suggest that the honokiol-based scaffold can be employed to design novel anti-cancer therapeutic agents.

Important Drugs and Its Patterns during the Late Goryeo Dynasty -Obtain and distribution of Bupleuri Radix and Ginger.

This article deals with drugs obtain and distribution during the Goryeo Dynasty. In particular, I analyzed the case of 'Bupleuri Radix', which corresponds to 'dot-ui minali' as Idu, an archaic Korean notation, and Ginger, which was intentionally introduced and cultivated in Goryeo. Drugs of the Goryeo Dynasty can be classified into 5 types. Drugs that use the Chinese character name as the name of Goryeo were type A, drugs that correspond 1:1 with the archaic Korean notation to the Chinese character name were type B, and drugs that have the Chinese character name translated directly into the Korean name were type C. And although it were originally the foreign drugs, the drugs cultivated in Goryeo were Type D, and the drugs imported from foreign countries were Type E. Among these, types B and D are particularly interesting. Bupleuri Radix and Ginger discussed in this article were representative examples of type B and D respectively. Looking overall, type B had the highest proportion, followed by type A. Type E was the next most common. On the other hand, type C and D were relatively small. However, regardless of the high or low proportion, these types coexisted and constituted the therapeutic drugs of the Goryeo Dynasty. In conclusion, during the Goryeo Dynasty, interest and use of local drugs, namely Hyangjae, greatly expanded.

Self-medication among Basic Science Medical Students of a Tertiary Care Centre: A Descriptive Cross-sectional Study.

INTRODUCTION: Self-medication is using drugs to treat self-diagnosed signs or symptoms of oneself or others. Being closer to pharmacology and pathology, medical students have been more prone to it. The study aimed to determine the prevalence of self-medication among basic sciences medical students in a tertiary care centre in Kathmandu. METHODS: A descriptive cross-sectional study was conducted among basic science students from 15 February 2023 to 14 March 2023 after obtaining ethical approval from the Institutional Review Committee (Reference number: 04122022/04). A convenience sampling method was used. Data were collected online and analysed. Point estimate at 95% confidence interval was calculated. RESULTS: Among 322 basic science medical students the prevalence of self-medication was 218 (67.70%) (64.81-70.59 at 95% Confidence Interval). Fever was the most common condition treated by self-medication 106 (48.62%) and paracetamol was the most common medication 93 (42.66%). Of those who engaged in self-medication, 97 (44.50%) did so to save time. Moreover, within this group, 67 (30.73%) experienced adverse drug reactions, leading 37 (16.97%) of these students to visit a private doctor. Additionally, 138 (63.30%) refrained from prescribing medication to their family and friends. CONCLUSIONS: Self-medication among basic science medical students was found to be lower in comparison to other studies done in similar settings.

Novel methylenetetrahydrofolate reductase (MTHFR) mutation presenting with neonatal encephalopathy, hair loss and marfanoid features.

We present a case of a male term neonate with lethargy, hypotonia, hypoventilation and severe encephalopathy. The infant had a history of two siblings who died in the neonatal period from unclear causes. The infant exhibited skin and hair abnormalities, including desquamation of the extremities, angular stomatitis, cheilitis, neonatal acne and thin, sparse hair. Additionally, the infant had a tall stature; long, slender fingers and toes; and facial dysmorphism characterised by a long, narrow face with increased interpalpebral distance. The condition deteriorated rapidly, and unfortunately, death occurred before a definitive diagnosis could be established. Tandem mass spectrometry suggested low methionine and clinical exome sequencing identified a nonsense mutation in the MTHFR gene.

Utilising integrated bio-behavioural surveillance (IBBS) to investigate declining hepatitis C antibody prevalence among people who inject drugs in the Australian Needle and Syringe Program Survey.

BACKGROUND: Prevalence of hepatitis C virus (HCV) antibody (Ab) on dried blood spot (DBS) samples in the Australian Needle and Syringe Program Survey (ANSPS) decreased nationally from 57 % in 2015 to 32 % in 2022. We aimed to investigate potential explanations for this decline. METHODS: Changes in DBS HCV Ab prevalence were investigated by redefining positive cases as those with those with either a positive HCV Ab test result or a self-reported history of ever having HCV treatment (modified prevalence), examining HCV Ab prevalence by birth and age cohorts, and assessing trends in key risk behaviours. RESULTS: Overall prevalence of DBS HCV Ab declined rapidly and significantly from 57 % in 2015 to 32 % in 2022 (p < 0.001) however modified HCV Ab prevalence remained stable over time (85 % and 88 % in 2015 and 2022, respectively, p = 0.357). The proportion of participants with negative HCV Ab and self-reported HCV infection increased from 20 % in 1995 to 40 % in 2022 (p < 0.001) and the proportion with negative HCV Ab and lifetime HCV treatment increased from 3 % in 1999 to 67 % in 2022 (p < 0.001). We also observed a decreasing trend in DBS HCV Ab prevalence in all birth and age cohorts with a noticeable acceleration in the decline commensurate with the advent of HCV DAA treatment. A long-term decreasing trend was also observed for key risk behaviours (p < 0.001) however the short-term trend was not significant for recent receptive syringe sharing. CONCLUSION: The temporal decline in HCV Ab prevalence appears related to reduced sensitivity of DBS HCV Ab detection with viral clearance following treatment. Since 2016, HCV treatment uptake has increased markedly including among people who inject drugs. In this context, continuing to monitor HCV Ab prevalence by DBS testing is problematic, with a shift to surveillance of active infection the most relevant to guide policy and practice in this setting.

Safety observation of antiarrhythmic drug use in a patient with sinus bradycardia following atrial fibrillation radiofrequency ablation combined with cardiac neural ablation: a case report.

This study assessed the safety of Antiarrhythmic Drug (AAD) administration in a patient experiencing sinus bradycardia following radiofrequency ablation for Atrial Fibrillation (AF), followed by cardiac ganglion ablation. Post-AF radiofrequency ablation, the employment of AADs is a prevalent clinical practice; however, these drugs may exacerbate bradycardia, leading to increased patient discomfort and treatment complexity. The decision to employ AADs in patients with sinus bradycardia post-AF ablation poses a significant clinical challenge. This investigation aimed to ascertain the safety of AADs in such patients. The study encompassed a single case, wherein a patient with pre- and post-procedure sinus bradycardia was treated with AADs following AF radiofrequency ablation and cardiac ganglion ablation, with a subsequent safety assessment. The findings indicate that AADs can be safely administered to patients with sinus bradycardia after these procedures, offering valuable insights for clinical decision-making. This case report underscores the intricacies of post-AF ablation management in patients with sinus bradycardia and advocates for personalized therapeutic strategies. The results enhance the clinical knowledge regarding the safety of AADs in this patient subset and may guide future treatment protocols. Nonetheless, the study's conclusions are drawn from a single case, and further research with larger cohorts is essential to substantiate these findings and elucidate the long-term safety and efficacy of this therapeutic approach.

A novel C-4-modified isotetrone acts as a potent bio-enhancer to augment the activities of anti-tuberculosis drugs against Mycobacterium tuberculosis.

Mycobacterium tuberculosis is a deadly pathogen that claims millions of lives every year. Current research focuses on finding new anti-tuberculosis drugs that are safe and effective, with lesser side effects and toxicity. One important approach is to identify bio-enhancers that can improve the effectiveness of anti-tuberculosis drugs, resulting in reduced doses and shortened treatment times. The present study investigates the use of C-4 modified isotetrones as bio-enhancers. A series of studies suggest an isotetrone, labeled as C11, inhibits growth, improves MIC, MBC and enhances the killing of M. tuberculosis H37Rv strain when used in combination with the first line and injectable anti-TB drugs in a dose-dependent manner. The combination of C11 and rifampicin also reduces the generation of spontaneous mutants against rifampicin and reaches a mutation prevention concentration (MPC) with moderate rifampicin concentrations. The identified compounds are effective against the MDR strain of M. tuberculosis and non-cytotoxic in HepG2 cells. We find that C11 induces the generation of reactive oxygen species (ROS) inside macrophages and within bacteria, resulting in better efficacy.

Neuropathic pain in spondyloarthritis: Decoding its prevalence, risk factors, and impact on disease activity.

OBJECTIVES: This study aimed to evaluate the prevalence and characteristics of neuropathic pain in patients with various subtypes of spondyloarthritis (SpA), including axial SpA (axSpA), psoriatic arthritis (PsA), and undifferentiated peripheral SpA (p-SpA). Additionally, the study sought to identify potential risk factors associated with the presence or severity of neuropathic pain and to investigate its impact on clinical disease activity assessment. METHODS: We conducted a cross-sectional study at two tertiary rheumatology centers, enrolling patients diagnosed with SpA. Data on demographic and clinical characteristics, comorbidities, and current therapies were collected. Neuropathic pain was assessed using the PainDETECT Questionnaire (PD-Q) and the Neuropathic Pain Symptom Inventory (NPSI). Statistical analyses included descriptive statistics, t-tests, and Pearson's correlations to evaluate the relationships between neuropathic pain scores and clinical disease activity indices. RESULTS: The study included 177 patients. Of these, 22.2% had a PD-Q score ≥19, showing a high likelihood of neuropathic pain, while 64.9% scored ≤12, suggesting the absence of significant neuropathic components. The mean PD-Q score was 11.5 ± 10.1. Subgroup analyses showed that females had significantly higher scores for paroxysmal and evoked pain (p < 0.05), and obese patients had significantly higher scores across all NPSI subscores (p < 0.05). Moderate positive correlations were found between neuropathic pain scores and clinical disease activity indices, such as DAPSA (r = 0.46, p < 0.0001) and ASDAS-CRP (r = 0.42, p < 0.01). CONCLUSIONS: Neuropathic pain is prevalent among patients with SpA and is significantly associated with disease activity assessments and management. This study highlights the importance of integrating neuropathic pain evaluation into the clinical assessment of SpA to tailor treatment approaches effectively and improve patient outcomes.

Comprehensive eco-geno-toxicity and environmental risk of common antiviral drugs in aquatic environments post-pandemic.

The eco-geno-toxicological impacts of the most widely used antiviral drugs against SARS-CoV2 - ribavirin, ritonavir, nirmatrelvir and tenofovir - were investigated in freshwater organisms. Ribavirin and tenofovir exhibited the highest acute toxicity in the rotifer Brachionus calyciflorus at concentrations of a few mg/L while ritonavir and nirmatrelvir showed similar effects at tens of mg/L; acute toxicity of ribavirin was also observed in the crustacean Ceriodaphnia dubia at similar concentrations. In contrast, the crustacean Thamnocephalus platyurus showed the lowest sensitivity to the antiviral drugs tested with no sublethal effects. Chronic toxicity tests revelead that these antivirals induced effects in consumers at concentrations of environmental concern (ng-µg/L). Ribavirin showed the highest toxicity to the alga Raphidocelis subcapitata, while ritonavir showed the highest toxicity to B. calyciflorus and C. dubia. DNA damage and oxidative stress were observed in C. dubia at 0.001 µg/L and 0.1 µg/L when exposed to ritonavir and nirmatrelvir respectively, and at 1 µg/L when exposed to ribavirin and tenofovir. Toxic and genotoxic environmental risks were assessed with risk quotients for ritonavir, tenofovir and ribavirin exceeding the threshold of 1, indicating significant environmental concern.

Cocaine and other illicit drugs in the marine environment: Potential effects and future directions.

Cocaine and its primary metabolite, benzoylecgonine, have been recently detected in sharks, indicating a growing concern over marine drug pollution. The presence of this drug in marine fauna poses risks such as physiological stress, impaired growth, reproduction, and altered behaviors, potentially leading to biodiversity loss and disrupted ecological interactions. Biomagnification may further affect higher trophic levels, including humans. Addressing this issue requires continuous monitoring, studies on physiological effects, understanding contamination routes, and improving wastewater treatment. Additionally, stricter regulations on pharmaceutical disposal are necessary to mitigate the impacts of such pollutants on marine ecosystems and human health.

Continuous atmospheric pressure interfaced ion trap mass spectrometry with thermal desorption for detection of nonvolatile drugs.

The escalating need for prompt and highly sensitive on-site detection of trace-level drugs is fueling the advancement of miniature, high-performance mass spectrometers and analytical methodologies. In this study, a miniature continuous atmospheric pressure interfaced ion trap mass spectrometer integrated with thermal desorption acetone-assisted photoionization (TD-CAPI-ITMS) was developed for highly sensitive detection of nonvolatile drugs in saliva and blood. By strategically extending the sampling time of the TD-CAPI-ITMS to cover the entire desorption process, a remarkable two-order-of-magnitude enhancement in the signal intensity of individual drugs was observed. Moreover, the simultaneous detection of drug mixtures with widely varying boiling points and saturation vapor pressures was accomplished. Optimization of the parameters yielded a limit of detection (LOD) for ketamine and 5F-EMB-PICA of 1 pg/µL accompanied by a robust stability, as evidenced by a relative standard deviation (RSD) of 5.30 %. Combined with straightforward liquid-liquid extraction, the sensitivity of drugs in saliva as low as 10 pg/µL was achieved, which met the requirements of Chinese national standard GA1333-2017. Owing to its exceptional sensitivity, the matrix effect present in blood samples was significantly alleviated through dilution, allowing for accurate monitoring of antibiotic concentrations. The results underscore the substantial potential of the TD-CAPI-ITMS for lab-free applications in drug-related forensic analysis, therapeutic drug monitoring, and pharmacokinetic studies.

A Review on Recent Trends in Photo-Drug Efficiency of Advanced Biomaterials in Photodynamic Therapy of Cancer.

Photodynamic Therapy (PDT) has emerged as a highly efficient and non-invasive cancer treatment, which is crucial considering the significant global mortality rates associated with cancer. The effectiveness of PDT primarily relies on the quality of the photosensitizers employed. When exposed to appropriate light irradiation, these photosensitizers absorb energy and transition to an excited state, eventually transferring energy to nearby molecules and generating Reactive Oxygen Species (ROS), including singlet oxygen [1O2]. The ability to absorb light in visible and nearinfrared wavelengths makes porphyrins and derivatives useful photosensitizers for PDT. Chemically, Porphyrins, composed of tetra-pyrrole structures connected by four methylene groups, represent the typical photosensitizers. The limited water solubility and bio-stability of porphyrin photosensitizers and their non-specific tumor-targeting properties hinder PDT effectiveness and clinical applications. Therefore, a wide range of modification and functionalization techniques have been used to maximize PDT efficiency and develop multidimensional porphyrin-based functional materials. Recent progress in porphyrin-based functional materials has been investigated in this review paper, focusing on two main aspects including the development of porphyrinic amphiphiles that improve water solubility and biocompatibility, and the design of porphyrin-based polymers, including block copolymers with covalent bonds and supramolecular polymers with noncovalent bonds, which provide versatile platforms for PDT applications. The development of porphyrin-based functional materials will allow researchers to significantly expand PDT applications for cancer therapy by opening up new opportunities. With these innovations, porphyrins will overcome their limitations and push PDT to the forefront of cancer treatment options.

The therapeutic effect of DX2 inhibition in nicotine-induced lung cancer progression.

Alternative splicing products of AIMP2 and AIMP2-DX2 (DX2) have been reported to be associated with human lung cancer. In fact, DX2 expression is elevated in human lung cancers, and DX2 transgenic mice also develop lung cancer, in particular small cell lung cancer (SCLC). However, the mechanism by which DX2 is induced during cancer progression has not been clearly elucidated. Here, we show that DX2 is induced by nicotine, the main component of smoking-related chemicals, which can stabilize the human epidermal growth factor receptor 2 (HER2) protein and transcriptionally increase sonic hedgehog (Shh). Indeed, nicotine showed tumorigenicity via DX2 by promoting spheroid formation and in vivo lung and kidney cancer progression. Moreover, the elimination of DX2 using small interfering RNA (siRNA) or an optimized inhibitor (SNU-14) blocked the induction of HER2 and Shh and completely suppressed tumor sphere formation in response to nicotine. These results indicate that DX2 is critical for lung cancer progression, and a specific DX2 inhibitor would be useful for the treatment of human cancers, including SCLC and non-SCLC (NSCLC).

Functional cure of chronic hepatitis B-hope or hype?

Chronic hepatitis B constitutes a substantial disease burden worldwide. The steps advocated by the World Health Organization in 2016 to eradicate hepatitis B by 2030 has failed to achieve significant progress, especially with respect to immunization coverage and linkage to care. The lack of governmental and public awareness regarding the long-term implications of hepatitis B burden cause underfunding of developmental projects. The presently approved treatment modalities have limited efficacy in complete viral eradication, hence the need for newer molecules to achieve functional cure (sustained undetectable hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA in peripheral blood after a finite period of therapy). However, preliminary results from trials of novel therapies show their inadequacy to achieve this end by themselves but better performance with a low baseline serum HBsAg with nucleos(t)ide analogues (NA) treatment which need to be combined with/without pegylated interferon as an immunomodulator. Such therapy is limited by cost and adverse events and need to show incremental benefit over the standard of care (long-term NA therapy) with respect to efficacy and drug toxicities, making the development process tenuous. Thus, while such therapies continue to be tested, strategies should still focus on prevention of transmission by non-pharmaceutical measures, vaccination and increasing linkage to care.