Enantiomeric Analysis of Chiral Drugs Using Mass Spectrometric Methods: A Comprehensive Review.

Chirality plays a crucial role in the drug development process, influencing fundamental chemical and biochemical processes and significantly affecting our daily lives. This review provides a comprehensive examination of mass spectrometric (MS) methods for the enantiomeric analysis of chiral drugs. It thoroughly investigates MS-hyphenated techniques, emphasizing their critical role in achieving enantioselective analysis. Furthermore, it delves into the intricate chiral recognition mechanisms inherent in MS, elucidating the fundamental principles that govern successful chiral separations. By critically assessing the obstacles and potential benefits associated with each MS-based method, this review offers valuable insights for researchers navigating the complexities of chiral analysis. Both qualitative and quantitative approaches are explored, presenting a comparative analysis of their strengths and limitations. This review is aimed at significantly enhancing the understanding of chiral MS methods, serving as a crucial resource for researchers and practitioners engaged in enantioselective studies.

Stereoselective analysis of chiral pesticides: a review.

Chiral organic pollutants, including pesticides, herbicides, medicines, flame retardants, and polycyclic musk, represent a significant threat to both the environment and human health. The presence of asymmetric centers in the structure of chiral pesticides introduces stereoisomers with distinct distributions, fates, biomagnification capacities, and cytotoxicities. In aquatic environments, pesticides, as persistent/pseudo-persistent compounds, have been detected in substantial quantities, posing severe risks to non-target species and, ultimately, public health through water supply and food exposures. In response to this environmental challenge, stereoselective analytical methods have gained prominence for the identification of pesticide/drug enantiomers in recent years. This review examines the environmental impact of chiral pesticides, emphasizing the distinct biological activities and distribution patterns of their stereoisomers. By highlighting the advancements in liquid chromatography for enantiomeric analysis, the review aims to underscore the urgent need for a comprehensive understanding of these pollutants to facilitate informed remediation strategies and ensure the safer dispersal of chiral organic pollutants in the environment, thereby addressing the potential risks they pose to ecosystems and human health. Future research should focus on developing sustainable and efficient methodologies for the precise analysis of stereoisomers in complex matrices, particularly in sewage water, emphasizing the importance of sewage processing plants in ensuring water quality.

Assessment and application of Marfey's reagent and analogs in enantioseparation: a decade's perspective.

Of the various methods available for high-performance liquid chromatography separation of enantiomers (of e.g. amino acids and amino group containing compounds) by the pre-column derivatization approach, use of Marfey's reagent has been most successful with continued application since its introduction in 1984. The reagent is prepared from difluoro dinitro benzene by nucleophilic substitution of one of its F atoms by l-alanine amide. There is flexibility to prepare several chiral variants (by substituting the F atom with different chiral auxiliaries) and to tailor the hydrophobicity and resolution, ultimately, of the diastereomeric derivatives. The present paper assesses and reviews applications of Marfey's reagent and its chiral variants (i.e. other FDNP reagents) for enantioseparation of certain amino group containing drugs/amino acids, and to provide some case studies on enantiomeric separations that are important for the pharmaceutical industry. Various explanations for separation mechanism and elution order using FDNP reagents are included and the question of the configuration of the corresponding enantiomer using an indirect approach has also been addressed.

Liquid chromatographic methods for separation, determination, and bioassay of enantiomers of etodolac: A review.

The control of enantiomeric purity and determination of individual enantiomeric drug molecules remains the subject of importance for clinical, analytical, and regulatory purposes and to facilitate an accurate evaluation of the risks posed by them to human health. A large number of pharmaceuticals are marketed and administered as racemates. Etodolac is among such nonsteroidal anti-inflammatory drugs. Overall literature reports on its enantioseparation are scanty. Liquid chromatography (LC) methods of enantioseparation of (±)-etodolac, including certain unconventional ones, are well covered and discussed in this paper. Methods of direct approach without using chiral columns or chiral thin-layer chromatography plate and of indirect approach using certain chiral derivatizing agents such as (S)-naproxen and (S)-levofloxacin are described. Most interesting aspects include establishment of structure and molecular asymmetry of chemically different types of diastereomeric derivatives using liquid chromatography with mass spectrometry (LC-MS), 1 H NMR spectroscopy and by drawing conformations in three dimensional views by using certain software. The methods provide chirality recognition even in the absence of pure enantiomers. Besides, recovery of pure enantiomers by detagging or via solubility difference of chiral inducing reagent and the analyte, without racemization at any stage, has been achieved. The limits of detection and quantification are much lower than the industry benchmarks.

Enantioselective LC analysis and determination of selective serotonin reuptake inhibitors.

LC separation of biologically and pharmaceutically important enantiomers (from racemic or non-racemic mixtures) remains a subject of importance. The present review article deals with the liquid chromatographic enantioseparation of chiral selective serotonin reuptake inhibitors (SSRIs), namely citalopram, paroxetine, sertraline and fluoxetine. It is now known that the enantiomers of numerous psychotropic drugs exhibit distinct pharmacodynamics, pharmacokinetic patterns and receptor binding properties, and psychiatric patients are frequently taking more than one medication. Therefore, monitoring of the levels of these analytes in biological fluids is important to determine the levels of enantiomer concentrations; the present paper may be helpful in understanding the present state of available methods (along with a critical discussion of applicability of the methods) and in developing the new ones for this purpose. Different approaches using LC discussed herein may be applied for determining the enantiomeric composition (and enantiomeric purity) of SSRIs and numerous other racemic drugs, of current/future pharmaceutical importance and utility, using simple separation methods, instrumentation, inexpensive reagents and potentially significant analytical approaches. The contents cover the essential data to understand the various separation techniques and associated issues, if any, with documented examples.

Radioactive elements in wastewater and potable water: Sources, effects, and methods of analysis and removal.

Radioactive effluents, originating from nuclear power plants, medical-nuclear applications, and various extraction industries worldwide, present a significant and dangerous contamination challenge. The concentrations of radioactive substances in wastewater, surface water, and potable water vary widely depending on the source and location. For example, cesium-137 levels in wastewater from nuclear facilities can range from 0.1 to 10 Bq/L, while tritium concentrations in surface water near nuclear plants can reach up to 100 Bq/L. Regulatory guidelines, like the maximum contaminant level of 0.185 Bq/L for combined radium-226 and radium-228 in drinking water, are critical for ensuring safety and environmental protection. Specifically, in Fukushima, Japan, cesium-137 levels in surface water range from 0.1 to 10 Bq/L due to the nuclear accident. In contrast, regions with natural uranium deposits, like parts of the United States, have reported radium-226 concentrations in potable water up to 1 Bq/L. These variations highlight the necessity for focused monitoring and evaluation to protect water quality and community health. Among various methods, Gamma spectrometry and inductively coupled plasma mass spectrometry are precise for radionuclide quantification, scintillation detectors, and ion exchange, and adsorption techniques efficiently remove radioactive substances from water. This critical review examines the sources, adverse effects, and analysis and remediation strategies for various radioactive elements in wastewater. By thoroughly evaluating the origins and potential dangers associated with radioactive effluents, this report emphasizes the urgent need for rigorous monitoring and effective treatment practices to maintain the integrity of water resources and ecosystems. PRACTITIONER POINTS: Comprehensive analysis of the radioactive elements frequently found in wastewater and drinking water. Assess the negative effects of radioactive elements in water systems. Examine the treatment methods used to eliminate radioactive pollutants from water sources. Outline effective methods and tactics for addressing and controlling radioactive contamination occurrences. Analyze the latest advancements in technology, regulatory enhancements, and optimal methods to guarantee the safety of drinking water and the sustainable handling of radioactive substances in wastewater.

Meta-analysis: The efficacy of therapeutic drug monitoring of anti-TNF-therapy in inflammatory bowel disease.

BACKGROUND AND AIMS: This systematic review and meta-analysis aimed to determine whether the use of therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients on anti-tumour necrosis factor (anti-TNF) therapy results in improved rates of clinical and endoscopic remission, surgery, corticosteroid-free remission and hospitalisation. METHODS: MEDLINE, EMBASE, EMBASE classic, PubMed, Cochrane central databases register of controlled trials and Cochrane Specialised Trials Register were searched between 01 Janurary 1946 and 08 April 2022. Randomised controlled trials (RCTs) and prospective and retrospective observational studies were included, comparing TDM to standard of care (SOC) or reactive vs proactive TDM. Results were reported as pooled relative risks (RR) with 95% confidence intervals (95% CI). RESULTS: Twenty-six studies, including 9 RCTs, were included. Compared to SOC, proactive TDM was associated with a significantly decreased risk of treatment failure (RR 0.64, 95% CI 0.48-0.85 p<0.01), and a non-significant decrease in need for surgery (RR 0.51, 95% CI 0.25-1.02) and hospitalisation (RR 0.64, 95% CI 0.40-1.00). Furthermore compared to SOC, Proactive TDM was associated with higher rates of endoscopic remission (RR 1.19, 95% CI 0.93-1.53) and clinical remission (RR 1.07, 95% CI 0.97-1.18). Compared to reactive TDM, proactive TDM was associated with significant decreased risk of treatment failure (RR 0.46, 95% CI 0.21 = 0.98, p = 0.04) and significant reduction in hospitalisation (RR 0.33, 95% CI 0.21-0.54, p < 0.01). CONCLUSIONS: Compared to SOC, proactive TDM was associated with significant benefit in reducing treatment failure. Compared to reactive TDM, proactive TDM led to a significant reduction in hospitalisation and treatment failure. More studies with larger RCTs and standardised assays are needed to substantiate these results and validate the cost-effectiveness of TDM.

Chirality of antidepressive drugs: an overview of stereoselectivity.

Stereochemistry plays an important role in drug design because the enantiomers of a drug frequently vary in their biological action and pharmacokinetic profiles. Racemates of a drug with either an inactive or an unsafe enantiomer can lead to detrimental effects. The manufacturing industry may still produce racemates, but such decisions must pass through rigorous analyses of the pharmacological and pharmacokinetic characteristics of the particular enantiomer related to the racemates. The pharmacokinetics of antidepressants or antidepressive agents is stereoselective and predominantly favors one enantiomer. The use of pure enantiomers offers (i) better specificity than the racemates in terms of certain pharmacological actions, (ii) enhanced clinical indications, and (iii) optimized pharmacokinetics. Therefore, controlling the stereoselectivity in the pharmacokinetics of antidepressive drugs is of critical importance in dealing with depression and psychiatric conditions. The objective of this review is to highlight the importance of the stereochemistry of antidepressants in the context of the design and development of new chirally pure pharmaceuticals, the potential complications caused by using racemates, and the benefits of using pure enantiomers.

Women in gastroenterology: the UK trainee experience.

Introduction: Compared with other medical specialties, there are lower numbers of female trainees and lower rates of flexible working in gastroenterology. This study aims to examine the experience of male and female trainees to understand specialty demographics and the experience of training. Methods: Gastroenterology training data were obtained from the British Society of Gastroenterology (BSG) trainee surveys from 2014, 2018 and 2020, and from the Royal College of Physicians Medical Workforce unit between 2011 and 2019. Data on endoscopy measures from 2011 to 2021 were obtained from the Joint Advisory Group (JAG) on gastrointestinal endoscopy, including the JAG Endoscopy training system and the National Endoscopy Database. Data were segregated and compared by gender. Results: The percentage of female gastroenterology trainees remains at around 40%, largely unchanged over the previous decade. From the BSG trainee survey, 29.5% of women have flexible working patterns compared with 2.6% of men (p<0.001), which is lower than other medical specialties. Less than half of female trainees felt confident about their job prospects once they qualify. A greater proportion of male than female trainees achieved provisional colonoscopy certification during training (55% vs 45%, p=0.005) and female trainees took longer to certify than male trainees (63 months vs 56 months, p=0.004). The total length of training time from primary medical qualification to consultancy was the same for men and women. Conclusion: Changes must be addressed from a national and institutional level to address equitable access to national training programmes and equality of outcome for male and female trainees.

Simultaneous spectrophotometric determination of drug components from their dosage formulations.

Spectrophotometry is a quick and reliable method for determining the composition of a variety of complex drug mixtures. Several mathematical models are available for the resolution of complex multicomponent UV spectra. UV spectrophotometric methods have the inherent capacity to resolve the interlaced spectra of complex mixtures quickly and appropriately, particularly for quantitative determination of components of mixture where several costly tools are not available. These methods also have the benefit of lower operational costs as they are operated using lesser amounts of analytical grade solvents and generate less waste. In this review, we discussed the theoretical background of different UV spectrometric methods for quantitative analysis of drug mixtures. The main focus of this review is to describe and report applications of extended Beer's law-based multicomponent analysis and to highlight the recent developments in the simultaneous determination of drug components from their complex mixtures.

COVID-19 seroprevalence after the first UK wave of the pandemic and its association with the physical and mental wellbeing of secondary care healthcare workers.

Objectives: To determine the seroprevalence of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibody status amongst healthcare workers (HCWs) working through the first wave of the Coronavirus (COVID-19) pandemic in 2020. To examine the association of seroprevalence and self-reported COVID-19 symptoms with occupation, sex, and ethnicity; and how these factors were associated with physical and mental wellbeing. Design: Single-centre cohort study. Setting: Large public hospital in the United Kingdom. Intervention: All HCWs who had been tested for anti-SARS-CoV-2 immunoglobulin (Ig) G nucleocapsid antibody in summer 2020 were asked to complete an electronic survey focusing on their physical and mental health in Winter 2020-21. This survey was comprised of the Short Form 12v2, Physical Component Summary (PCS), Mental Component Summary (MCS), and Generalised Anxiety Disorder 7-item (GAD-7) questionnaires. Results: 7604/9781 (77.7%) HCWs were antibody tested, of which 1082 completed the full survey. Antibody testing was conducted between 17/06/20-30/07/20, during which time our seroprevalence rate was 28% (299/1082). Of those self-reporting COVID-19 symptoms, 51% (201/395) were antibody positive. Antibody-positive participants had lower PCS scores (p = 0.016), indicating poorer physical health. Lower PCS scores were also found in those deemed high risk for COVID-19 by their GP (p = 0.001), and those aged >44 years (p = 0.009). Antibody-negative participants had lower MCS scores (p = 0.044), indicating poorer mental health. Those who self-reported COVID-19 symptoms had lower PCS scores (p=<0.001) than those with no symptoms. Lower MCS scores were found in women (p = 0.001), Caucasians (p = 0.018), non-clinicians (p = 0.001), and those aged <44 years (p = 0.009). Significantly higher GAD-7 anxiety scores were evident in staff aged <44 years (p = 0.023), and those with self-reported COVID symptoms (p = 0.031). Doctors had lower GAD-7 anxiety scores (p = 0.009). Conclusion: Self-reported symptoms did not correlate with seroprevalence; data surrounding this can be useful for future workforce planning. Interventions are needed to reduce the mental and physical burden of the pandemic on HCWs. Further work is needed to identify which particular HCWs may require further support, to ensure well-being and effective patient care. Trial registration: Sponsor Protocol number - 2020COV112, Clinicaltrials.gov number -NCT04527432.

The UPTAKE study: implications for the future of COVID-19 vaccination trial recruitment in UK and beyond.

BACKGROUND: Developing a safe and effective vaccine will be the principal way of controlling the COVID-19 pandemic. However, current COVID-19 vaccination trials are not adequately representing a diverse participant population in terms of age, ethnicity and comorbidities. Achieving the representative recruitment targets that are adequately powered to the study remains one of the greatest challenges in clinical trial management. To ensure accuracy and generalisability of the safety and efficacy conclusions generated by clinical trials, it is crucial to recruit patient cohorts as representative as possible of the future target population. Missing these targets can lead to reduced validity of the study results and can often slow down drug development leading to costly delays. OBJECTIVE: This study explores the key factors related to perceptions and participation in vaccination trials. METHODS: This study involved an anonymous cross-sectional online survey circulated across the UK. Statistical analysis was done in six phases. Multi-nominal logistic models examined demographic and geographic factors that may impact vaccine uptake. RESULTS: The survey had 4884 participants of which 9.44% were Black Asian Minority Ethnic (BAME). Overall, 2020 (41.4%) respondents were interested in participating in vaccine trials; 27.6% of the respondents were not interested and 31.1% were unsure. The most interested groups were male (OR = 1.29), graduates (OR = 1.28), the 40-49 and 50-59 age groups (OR = 1.88 and OR = 1.46 respectively) and those with no health issues (OR = 1.06). The least interested groups were BAME (OR = 0.43), those from villages and small towns (OR = 0.66 and 0.54 respectively) and those aged 70 and above (OR = 1.11). CONCLUSIONS: In order to have a vaccination that is generalisable to the entire population, greater work needs to be done in engaging a diverse cohort of participants. Public health campaigns need to be targeted in improving trial recruitment rates for the elderly, BAME community and the less educated rural population.

The UPTAKE study: a cross-sectional survey examining the insights and beliefs of the UK population on COVID-19 vaccine uptake and hesitancy.

OBJECTIVE: A key challenge towards a successful COVID-19 vaccine uptake is vaccine hesitancy. We examine and provide novel insights on the key drivers and barriers towards COVID-19 vaccine uptake. DESIGN: This study involved an anonymous cross-sectional online survey circulated across the UK in September 2020. The survey was designed to include several sections to collect demographic data and responses on (1) extent of agreement regarding various statements about COVID-19 and vaccinations, (2) previous vaccination habits (eg, if they had previously declined vaccination) and (3) interest in participation in vaccine trials. Multinominal logistic models examined demographic factors that may impact vaccine uptake. We used principle component analysis and text mining to explore perception related to vaccine uptake. SETTING: The survey was circulated through various media, including posts on social media networks (Facebook, Twitter, LinkedIn and Instagram), national radio, news articles, Clinical Research Network website and newsletter, and through 150 West Midlands general practices via a text messaging service. PARTICIPANTS: There were a total of 4884 respondents of which 9.44% were black, Asian and minority ethnic (BAME) group. The majority were women (n=3416, 69.9%) and of white ethnicity (n=4127, 84.5%). RESULTS: Regarding respondents, overall, 3873 (79.3%) were interested in taking approved COVID-19 vaccines, while 677 (13.9%) were unsure, and 334 (6.8%) would not take a vaccine. Participants aged over 70 years old (OR=4.63) and the BAME community (OR=5.48) were more likely to take an approved vaccine. Smokers (OR=0.45) and respondents with no known illness (OR=0.70) were less likely to accept approved vaccines. The study identified 16 key reasons for not accepting approved vaccines, the most common (60%) being the possibility of the COVID-19 vaccine having side effects. CONCLUSIONS: This study provides an insight into focusing on specific populations to reduce vaccine hesitancy. This proves crucial in managing the COVID-19 pandemic.

Effects of sleep deprivation on cognitive and physical performance in university students.

Sleep deprivation is common among university students, and has been associated with poor academic performance and physical dysfunction. However, current literature has a narrow focus in regard to domains tested, this study aimed to investigate the effects of a night of sleep deprivation on cognitive and physical performance in students. A randomized controlled crossover study was carried out with 64 participants [58% male (n = 37); 22 ± 4 years old (mean ± SD)]. Participants were randomized into two conditions: normal sleep or one night sleep deprivation. Sleep deprivation was monitored using an online time-stamped questionnaire at 45 min intervals, completed in the participants' homes. The outcomes were cognitive: working memory (Simon game© derivative), executive function (Stroop test); and physical: reaction time (ruler drop testing), lung function (spirometry), rate of perceived exertion, heart rate, and blood pressure during submaximal cardiopulmonary exercise testing. Data were analysed using paired two-tailed T tests and MANOVA. Reaction time and systolic blood pressure post-exercise were significantly increased following sleep deprivation (mean ± SD change: reaction time: 0.15 ± 0.04 s, p = 0.003; systolic BP: 6 ± 17 mmHg, p = 0.012). No significant differences were found in other variables. Reaction time and vascular response to exercise were significantly affected by sleep deprivation in university students, whilst other cognitive and cardiopulmonary measures showed no significant changes. These findings indicate that acute sleep deprivation can have an impact on physical but not cognitive ability in young healthy university students. Further research is needed to identify mechanisms of change and the impact of longer term sleep deprivation in this population.