Leicester School of Pharmacy

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  • ItemOpen Access
    Latest advances in glucose-responsive microneedle-based systems for transdermal insulin delivery
    (Elsevier, 2024-02-20) Martinez-Navarrete, Miquel; Pérez-López, Alexandre; Guillot García, Antonio José; Cordeiro, Ana Sara; Melero, Ana; Aparicio-Blanco, Juan
    The development of a self-regulated minimally invasive system for insulin delivery can be considered as the holy grail in the field of diabetes mellitus. A delivery system capable of releasing insulin in response to blood glucose levels would significantly improve the quality of life of diabetic patients, eliminating the need for frequent finger-prick tests and providing better glycaemic control with lower risk of hypoglycaemia. In this context, the latest advances in glucose-responsive microneedle-based transdermal insulin delivery are here compiled with a thorough analysis of the delivery mechanisms and challenges lying ahead in their clinical translation. Two main groups of microneedle-based systems have been developed so far: glucose oxidase-containing and phenylboronic acid-containing systems. Both strategies in combination have also been tested and two other novel strategies are under development, namely electronic closed-loop and glucose transporter-based systems. Results from preclinical studies conducted using these different types of glucose-triggered release systems are comprehensively discussed. Altogether, this analysis from both a mechanistic and translational perspective will provide rationale and/or guidance for future trends in the research hotspot of glucose-responsive microneedle-based insulin delivery systems.
  • ItemMetadata only
    Development of hybrid 3D-printed structure with aligned drug-loaded fibres using in-situ custom designed templates
    (Elsevier, 2023-09-07) Muldoon, Kirsty; Feng, Yu; Dooher, Thomas; O'Connor, Caolan; Wang, Baolin; Wang, Hui-Min David; Ahmad, Zeeshan; McLaughlin, James; Chang, Ming-Wei
    Fibre alignment technology is crucial in various emerging applications, such as drug delivery systems, tissue engineering, and scaffold fabrication. However, conventional methods have limitations when it comes to incorporating aligned fibres into 3D printed structures in situ. This research demonstrates the use of custom-designed templates made with conductive ink to control the alignment of drug-loaded polymer fibres on a 3D printed microscale structure. Three different geometries were designed, and the effects of the template on fibre diameter and pattern were investigated. The hybrid structure demonstrated successful control of aligned fibres on printed structures using grounded conductive ink geometric electrodes, as confirmed by SEM. All three custom-designed templates presented unique geometric alignments and fibre diameters of around 1 μm. Additionally, the different collector shapes had an impact on the distribution of fibre diameters. FTIR and EDX analyses concluded that the drug was effectively encapsulated throughout the fibres. In-situ deposition of fibres onto the 3D printed structure enhanced the mechanical properties, and water contact angle results showed that the hybrid structure transitioned to a hydrophilic state with the addition of fibres. A drug delivery study confirmed that the hybrid structure functions as a steady release system, following a Korsmeyer-Peppas kinetic release model. TGA results indicated that the samples are thermally stable, and DSC analysis concluded that the samples were homogeneously produced. The results obtained from the hybrid structures provide a novel mechanism for integrating aligned fibres and 3D printed structures for development in fields such as biomedical engineering, regenerative medicine, and advanced manufacturing.
  • ItemOpen Access
    Understanding the lived-experience and support-needs of people living with antimicrobial resistance in the UK through interpretative phenomenological analysis
    (Nature, 2024-02-10) Hamilton, Ryan A; Lond, Benjamin; Wilde, Lucina; Williamson, Iain
    In the UK nearly 54,000 infections were caused by serious resistant bacteria in 2022 but there is a lack of evidence regarding the long-term impact on patients’ lives nor what support they need. This research aimed to answer the question: “What are the key elements of experience and support needs of people living with AMR in the UK?”. In-depth semi-structured interviews were undertaken with nine people who had been living with resistant infections or colonisation for 12-months or longer. Interpretive Phenomenological Analysis was used to study the accounts and illustrate individuals’ experiences and support-needs. Participants experienced marginalisation and isolation but also empowerment; described across three major themes: (1) I live in fear and stigma: The long-term impact of AMR; (2) I am battling on my own: A journey toward self-advocacy; and (3) I like to share my story: The role of AMR communities. All participants perceived a lack of knowledge, information, and support from clinicians; difficulties accessing reliable and understandable information; and lack of understanding from family and friends. Charities and online groups provided support with coping with their situation and improving mental health and wellbeing. Understandable and relatable information regarding the science of AMR, transmission, prevention, and living with AMR needs to be provided by clinicians and healthcare services around the time of diagnosis to readily available after diagnosis.
  • ItemOpen Access
    Mitochondrial dysfunction in NPC1-deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol-binding proteins TSPO and StARD1
    (Wiley, 2024-02-01) Sillence, Dan; Wheeler, Simon; Bhardwaj, Meenakshi; Kenyon, Victor; Ferraz, Maria J.; Aerts, Johannes M. F. G.
    Niemann-Pick type C disease (NPCD) is a rare neurodegenerative disorder most commonly caused by mutations in the lysosomal protein Niemann-Pick C1 (NPC1), which is implicated in cholesterol export. Mitochondrial insufficiency forms a significant feature of the pathology of this disease, yet studies attempting to address this are rare. The working hypothesis is that mitochondria become overloaded with cholesterol which renders them dysfunctional. We examined two potential protein targets-translocator protein (TSPO) and steroidogenic acute regulatory protein D1 (StARD1)-which are implicated in cholesterol transport to mitochondria, in addition to glucocerbrosidase 2 (GBA2), the target of miglustat, which is currently the only approved treatment for NPCD. However, inhibiting these proteins did not correct the mitochondrial defect in NPC1-deficient cells.
  • ItemMetadata only
    A review of the analytical techniques for the detection of anabolic–androgenic steroids within biological matrices
    (Wiley, 2023-10-03) Harries, Richard L.; De Paoli, Giorgia; Hall, Sarah; Nisbet, Lorna A.
    Anabolic–androgenic steroids (AASs) and other image and performance enhancing drugs (IPEDs) are controlled by governments and sport institutions such as the World Anti‐doping Agency (WADA). Although elite athletes and professional bodybuilders are the most visible AAS abusers, the introduction of the internet has increased the accessibility of AASs, with use being observed among recreational gym goers at increasing prevalence. Despite reported increase in use, routine analysis for these substances is uncommon, with many forensic laboratories opting to outsource AAS analysis. This review collates information regarding the extraction and analysis of AASs from various biological matrices with the considered purpose of providing a reference for the development of AAS methods to allow for routine detection by forensic laboratories.
  • ItemOpen Access
    Placements as Communities of Practice (CoP): Insights from a student and a lecturer’s exploration of CoP in a placement module in higher education
    (Student Engagement in Higher Education Journal, 2023-01-26) Oliveira, Gisela; Daya, Abdullah
    Placements are becoming an integral part of undergraduates’ experiences of higher education. They are offered in various subject areas, including education, and can be taken by students as different types of work-based experiences, such as placements. The literature supports this focus on placement experiences through the publication of long lists of benefits for students, universities and employers. However, there is also evidence of limitations in placement experiences that hinder this generalised view of placements as beneficial. Therefore, this article offers a reflective account by a lecturer and a student of their experience of using the framework of Communities of Practice (CoP) and socio-cultural concepts in a placement module in higher education. Through this reflective account, the article argues that CoP, as a framework for social learning rooted in participation, can support students to engage with the setting, people and knowledge in the placement when integrated into a module. The article also suggests the need to consider additional features of the placement experience, such as structure and pedagogical approaches, thus offering valuable insights to other placement modules in the UK and beyond.
  • ItemEmbargo
    Engineering of tetanus toxoid-loaded polymeric microneedle patches
    (Springer, 2022-11-17) Arshad, Muhammad Sohail; Gulfam, Shafaq; Zafar, Saman; Jalil, Najmusama Abdul; Ahmad, Nadia; Qutachi, Omar; Chang, Ming-Wei; Singh, Neenu; Ahmad, Zeeshan
    This study is aimed to fabricate tetanus toxoid laden microneedle patches by using a polymeric blend comprising of polyvinyl pyrrolidone and sodium carboxymethyl cellulose as base materials and sorbitol as a plasticizer. The tetanus toxoid was mixed with polymeric blend and patches were prepared by using vacuum micromolding technique. Microneedle patches were evaluated for physical attributes such as uniformity of thickness, folding endurance, and swelling profile. Morphological features were assessed by optical and scanning electron microscopy. In vitro performance of fabricated patches was studied by using bicinchoninic acid assay (BCA). Insertion ability of microstructures was studied in vitro on model skin parafilm and in vivo in albino rat. In vivo immunogenic activity of the formulation was assessed by recording immunoglobulin G (IgG) levels, interferon gamma (IFN-γ) levels, and T-cell (CD4+ and CD8+) count following the application of dosage forms. Prepared patches, displaying sharp-tipped and smooth-surfaced microstructures, remained intact after 350 ± 36 foldings. Optimized microneedle patch formulation showed ~ 74% swelling and ~ 85.6% vaccine release within an hour. The microneedles successfully pierced parafilm. Histological examination of microneedle-treated rat skin confirmed disruption of epidermis without damaging the underneath vasculature. A significant increase in IgG levels (~ 21%), IFN-γ levels (~ 30%), CD4+ (~ 41.5%), and CD8+ (~ 48.5%) cell count was observed in tetanus vaccine-loaded microneedle patches treated albino rats with respect to control (untreated) group at 42nd day of immunization. In conclusion, tetanus toxoid-loaded microneedle patches can be considered as an efficient choice for transdermal delivery of vaccine without inducing pain commonly experienced with hypodermic needles.
  • ItemOpen Access
    Technical note: A preliminary assessment of UV-C imaging using the Full Spectrum Imaging System (FSIS-II) for the detection of latent fingermarks
    (Forensic Science International, 2024-01-20) Stoddart, Will; Georgiou, Kyprianos; Deacon, Paul; Nichols-Drew, Leisa; Farrugia, Kevin J.
    The Full Spectrum Imaging System (FSIS-II) was assessed for the detection of latent fingermarks on a variety of substrates, specifically focusing on UV-C imaging for untreated marks and those that have been treated with cyanoacrylate (CA). The use of UV-C was effective at the detection of latent fingermarks on a variety of substrates and UV-C imaging may be effective when UV-A does not provide any fingermark detections on thermal paper. A Phase 2 and a small Phase 3 trials on aluminium cans were carried out with a detection sequence of UV-C imaging, CA fuming, UV-C imaging, UV-A imaging and BY40. For Phase 2 laboratory trials, the use of initial UV-C reflection was effective at removing the background and was a useful tool for initial screening. The use of UV-C was superior to UV-A after CA fuming and provided the highest overall number of high-quality marks. For phase 3 trials, the results showed that BY40 fluorescence was marginally more effective than UV-C imaging of CA-treated marks. This preliminary study shows that the FSIS-II and UV-C imaging can complement other methods for the detection of latent fingermarks.
  • ItemOpen Access
    CYP1-Activation and Anticancer Properties of Synthetic Methoxylated Resveratrol Analogues
    (MDPI, 2024-01-15) Ruparelia, K. C.; Zeka, K.; Beresford, Kenneth J. M.; Wilsher, Nicola E.; Potter, Gerard A.; Androutsopoulos, V. P.; Brucoli, Federico; Arroo, R. R. J.
    Naturally occurring stilbenoids, such as the (E)-stilbenoid resveratrol and the (Z)-stilbenoid combretastatin A4, have been considered as promising lead compounds for the development of anticancer drugs. The antitumour properties of stilbenoids are known to be modulated by cytochrome P450 enzymes CYP1A1 and CYP1B1, which contribute to extrahepatic phase I xenobiotic and drug metabolism. Thirty-four methyl ether analogues of resveratrol were synthesised, and their anticancer properties were assessed, using the MTT cell proliferation assay on a panel of human breast cell lines. Breast tumour cell lines that express CYP1 were significantly more strongly affected by the resveratrol analogues than the cell lines that did not have CYP1 activity. Metabolism studies using isolated CYP1 enzymes provided further evidence that (E)-stilbenoids can be substrates for these enzymes. Structures of metabolic products were confirmed by comparison with synthetic standards and LC-MS co-elution studies. The most promising stilbenoid was (E)-4,3′,4′,5′-tetramethoxystilbene (DMU212). The compound itself showed low to moderate cytotoxicity, but upon CYP1-catalysed dealkylation, some highly cytotoxic metabolites were formed. Thus, DMU212 selectively affects proliferation of cells that express CYP1 enzymes.
  • ItemOpen Access
    The Interconnectedness of Mental Health and Sustainable Development: Illness or Prevention model
    (Unique Conferences Canada Publication. Toronto, Canada, 2023-10-19) Illingworth, Paul
    Wait until people are ill, then treat. Or prevent ill health before it happens. These are two ends of a spectrum, those working health care have argued about for years. This is a fundamental challenge for global health. The illness then treat approach has dominated, certainly Western health care. It is the approach most often championed by the World Health Organisation (WHO), United Nations (UN), associated organisations and Governments. But is it what we should be continuing to do? Is it the global universal health model it has been made out to be? This paper explores whether the illness model is sustainable (and affordable) for health care. We have all probably heard the phrase 'prevention is better than cure', the phrase attributed to the philosopher Erasmus in the 16th Century. It is often cited as a central principle of modern health care. If that is the case, why is western health care, disease/illness driven? Why have hospitals, their specialisms and spiralling costs been the focus and prevention the poor relation? Can global health care remain sustainable and affordable? Given the massively rising costs of medical care and medicines. Given the evidence that major events such as Covid-19 had a massive impact on the global economy. Given Climate Change is and will continue to significantly cause further disease, illness and ill health. Is it now time (or even too late) to make a change? A change that means we are less dependent on expensive treatments and an illness model. This paper looks at this through a mental health perspective.
  • ItemOpen Access
    Admixing Antimicrobials to PMMA Bone Cement in the Treatment of Bone and Joint Infections: The Development of Best Practice Recommendations
    (European Bone & Joint Infection Society, 2023-10-12) Azamgarhi, Tariq; Karunaharan, Natasha; Hamilton, Ryan A.; Scobie, Antonia; Mepham, Stephen; Dunsmure, Louise; Warren, Simon
    Aim Commercially available bone cement products with pre-mixed antimicrobials are available but do not cover all the organisms encountered (e.g. multi-drug resistant Gram-negatives and CoNS,VRE, fungi and NTM). Therefore, the manual mixing of additional antimicrobials when preparing the bone cement intraoperatively may be required to deliver localised high-concentrations of antimicrobial to treat resistant-organisms. These extemporaneous preparations have not been rigorously evaluated in experimental studies or clinical trials and do not follow strict regulatory approval processes. This project aims to establish best practice recommendations for safely compounding extemporaneously prepared antimicrobial-loaded polymethylmethacrylate (PMMA) bone cement in the theatre environment. From this, drug monographs for clinically useful antimicrobials will be prepared to guide practice. Methods A systematic search was undertaken using EMBASE and PUBMED for all clinically relevant human and in-vitro experimental studies evaluating the addition of antimicrobials to PMMA bone cement in orthopaedic surgery (1975 through to March 2023). Data were extracted regarding clinical situations, formulation (including the antimicrobial choice and the amount to add), base cement, and preferred manual mixing technique. Clinical outcomes analysed included reoperation rates and systemic toxicity. Experimental outcomes of interest included antimicrobial elution and its effect on mechanical properties. Depending on the study type, PMMA intervention, surgery type and outcome, the studies were split according to primaries and revision. Results We identified 1145 studies, of which 415 were excluded as out of scope. Seven hundred thirty studies were included; 377 relevant clinical studies, 197 in vitro studies and 156 reviews. Of the clinical studies, 6 RCTs, 116 non-comparative studies, 30 comparative cohort studies, 50 in-vivo elution studies, 79 case series and 96 case reports. Most clinical studies were uncontrolled and used various time points to evaluate outcomes. Most studies incorporated vancomycin and aminoglycosides into PMMA. Full-text reviews of clinical studies are required to assess the consistency of PMMA intervention within the study, follow-up period; antimicrobials admixed, the formulation used, antibiotic loading , total mass, and mixing technique . Conclusion The literature reviewed do not adequately support recommendations on adding antimicrobials to PMMA or the amount to load. Ongoing review aims to establish pragmatic recommendations for clinicians and the development of individual drug monographs.
  • ItemOpen Access
    Carbapenem Reduction Strategy at a District General Hospital in England (UK)
    (Microbiology Society, 2023-11-14) Hamilton, Ryan A.; El-Zimaity, Dina; Fosbrook, Julie; Lee, Amy; Lilley, Ross; Cruikshank, Jemma; Molloy, Kathleen
    Background Carbapenem antibiotics should be reserved for specialist use and to manage severe resistant Gram-negative infections, however injudicious use is linked to the selection of multi- and extensively-drug resistant organisms. Since 2016, Kettering General Hospital (KGH) has consistently been one of the biggest users of carbapenems (149.6 Define Daily Doses [DDDs]/1000 admissions, SD ± 22.1) compared to the average use in all England hospitals (mean 1.99 times more) and non-teaching hospitals (mean 2.48 times more). Here we report the results of an ongoing carbapenem reduction strategy. Methods The AMS team developed a carbapenem reduction strategy in January 2021. The plan focused on optimising the carbapenem authorisation processes, reviewing sepsis guidelines and implementation, increasing use of antimicrobial guidelines, education and awareness, and continual review of patients on meropenem. Prescribing data (DDDs/1000 admissions including day case) were obtained through RxInfo Define and analysed in Microsoft Excel. Results Over 2021-22, mean carbapenem use was reduced by 27.5% (to 108.9 ± 15.2 DDDs/1000 admissions) compared to the pre-pandemic baseline and reduced by 42.9% compared to the 2020-21 mean (190.8 ± 62.5 DDDs/1000 admissions) when pandemic surges inflated antimicrobial prescribing. This reduction was sustained at 92.7 DDDs/1000 admissions over 2022-23 with reduced month-on-month variation (SD ± 13.0). Most actions completed were low-hanging-fruit within direct scope of the AMS team. Further reductions need to be delivered through engaging senior clinicians and managers across the organisation, improving carbapenem prescribing reports to clinicians, removing carbapenems from all guidelines, and improving AMS education to all staff groups.
  • ItemOpen Access
    A Matter of Time: A Survey to Explore the Perceived Time Released Following a Timely Appropriate Intravenous to Oral Switch
    (Microbiology Society, 2023-11-14) Jenkins, Abi; Hamilton, Ryan A.; Gilani, Syed; Ashton, Corrine; Rushton, Charlotte; Hussain, Sadiya; Williams, Nathan; Razaq, Shahzad; Jamieson, Conor
    Introduction: Optimising timely appropriate intravenous to oral switch (TAIVOS) delivers clinical and operational benefits, as intravenous administration is associated with risk and delays to discharge. One underappreciated issue is the nursing workforce impact due to the increased time required to prepare and administer intravenous compared to oral medicines, at 20 minutes more per dose. Improving awareness of the workforce benefits of TAIVOS could be an additional driver to improving rates of TAIVOS. Awareness of these benefits amongst medical and nursing staff is not known therefore we aimed to gauge degree of awareness through a survey Method: A Microsoft Forms survey was developed by a multidisciplinary working group and distributed to patient facing professionals in acute trusts across the Midlands via QR code, hyperlink, and paper copies. Respondents were asked to estimate the amount of time that could be saved by switching a patient from a three times daily intravenous antibiotic to an oral equivalent. Results: 508 responses were received, 489 from nurses and 19 from doctors. The median time considered by nurses to be released following TAIVOS was 30 minutes (IQR 20-30 minutes), whereas doctors perceived this to be 60 minutes (IQR 20-60 minutes). The scenario provided to the respondent would have equated to a time saving of around 60 minutes. Conclusion: There is considerable underestimation of the time required to prepare and administer intravenous medicines, particularly with nursing staff. Further work is required to increase awareness of the benefit of TAIVOS for workforce capacity across the Midlands and beyond.
  • ItemOpen Access
    Don’t be unAWaRe – Supply of selected ‘watch’ antibiotic pre-packs in Midlands hospitals
    (Microbiology Society, 2023-11-14) Jenkins, Abi; Brush, Andrew; Hamilton, Ryan A; Gilani, Syed; Ashton, Corrine; Badyal, Karamjit; Begum, Gulshada; Clarkson, Annette; Hussain, Sadiya; Kang, Parmjit; Kay, Rachel; Lehal, Kayleigh; Shah, Kameron
    The UK 5-year national action plan on antimicrobial resistance aims to reduce broad spectrum (WHO Watch and Reserve categories) antimicrobial use in English hospitals by 10% by March 2024. Pre-packs are products prepared with template labels to allow legal supply directly from clinical areas – bypassing pharmacy. Pre-packs are typically used to expedite discharge out of hours and on high turnover wards. However, this often circumvents pharmacists’ medicines and AMS checks – and the contribution of prepacks to overall antimicrobial supply is poorly explored. We aimed to quantify consumption of the three most common ‘watch’ antibiotic pre-packs at Midlands NHS hospitals. Midland antimicrobial pharmacists representing 23 Trusts were invited to contribute. Twelve Trusts provided consumption data for oral formulations of co-amoxiclav, clarithromycin and ciprofloxacin in defined daily doses (DDD) for the period 01/12/2022 to 31/05/2023. Data were collated and analysed in Microsoft Excel. Prepack use from participating Trusts accounted for 198521 of 738492 DDDs (26.9%) for co-amoxiclav, 21118 of 256298 DDDs (8.2%) for clarithromycin and 23479 of 184064 (12.8%) for ciprofloxacin. Trust median proportions were similar at 25%, 6.6% and 11% respectively but with considerable variation (respective IQRs 15.5-32.6, 5.6-9.5, 6.2-16.5). High variation likely reflects operational differences between organisations. Interventions into pre-pack use may support hospitals meeting the 10% reduction in broad-spectrum antibiotics. Research is needed to fully understand whether prepacks are used appropriately in terms of choice, and whether they contribute to extended durations of therapy.
  • ItemOpen Access
    Don’t be unAWaRe – issues of selected ‘watch’ antibiotics on FP10 prescriptions from Midlands hospitals
    (Microbiology Society, 2023-11-14) Jenkins, Abi; Brush, Andrew; Hamilton, Ryan A; Gilani, Syed; Ashton, Corrine; Badyal, Karamjit; Begum, Gulshada; Clarkson, Annette; Hussain, Sadiya; Kang, Parmjit; Kay, Rachel; Lehal, Kayleigh; Shah, Kameron
    The World Health Organization emphasises key antibiotics to safeguard through its ‘AWaRe’ classifications. NHS England has adapted these and requires a 10% reduction in use of ‘watch’ and ‘reserve’ agents in English hospitals by March 2024. Antibiotics may be prescribed in hospital using FP10 (green) prescriptions for convenient community dispensing. However, this bypasses review by hospital pharmacists who typically benefit from better access to relevant clinical information and prescribers than community colleagues. The extent to which this happens is unclear, so this project aimed to quantify FP10 issues for the three most common oral ‘watch’ antibiotics at all Midland NHS hospitals. Consumption data in defined daily doses (DDD) for co-amoxiclav, clarithromycin and ciprofloxacin for the period 01/12/2022 to 31/05/2023 was available on Rx-Info’s ‘Define’ platform. Permission to use this was sought from Midlands antimicrobial pharmacists representing 23 Trusts. Eleven consented and data was extracted for analysis in Microsoft Excel. FP10 issues from eleven participating Trusts accounted for 33548 of 674969 DDDs (5%) for co-amoxiclav, 21924 of 224937 DDDs (9.7%) for clarithromycin and 8862 of 157000 DDDs (5.6%) or ciprofloxacin. Trust median proportions deviated slightly at 1.9%, 5.2% and 3% respectively with considerable variation evident (respective IQRs 1.5-11, 3.2-13.7, 1.1-13). Regionally, FP10s represent a substantial portion of the total oral consumption of these agents. High variation likely reflects operational differences in medication supply mechanisms. As FP10s bypass many secondary-care antimicrobial stewardship approaches optimisation could be significant in delivery of NHS standard contract obligations and in slowing development of antimicrobial resistance.
  • ItemMetadata only
    Assessing Dose‑Exposure–Response Relationships of Miltefosine in Adults and Children using Physiologically‑Based Pharmacokinetic Modeling Approach
    (Springer Nature, 2023-10-10) Madu, Shadrack J.; Wang, Ke; Chirumamilla, Siri Kalyan; Turner, David B.; Steel, Patrick G.; Li, M.
    Objectives: Miltefosine is the frst and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with diferences in exposure patterns and cure rates among diferent population groups e.g. ethnicity and age (i.e., children v adults) in clinical trials. In this work, mechanistic population physiologically-based pharmacokinetic (PBPK) models have been developed to study the dose-exposure–response relationship of miltefosine in in silico clinical trials and evaluate the diferences in population groups, particularly children and adults. Methods: The Simcyp population pharmacokinetics platform was employed to predict miltefosine exposure in plasma and peripheral blood mononuclear cells (PBMCs) in a virtual population under diferent dosing regimens. The cure rate of a simulation was based on the percentage of number of the individual virtual subjects with AUCd0-28>535 µg⋅day/mL in the virtual population. Results: It is shown that both adult and paediatric PBPK models of miltefosine can be developed to predict the PK data of the clinical trials accurately. There was no signifcant diference in the predicted dose-exposure–response of the miltefosine treatment for diferent simulated ethnicities under the same dose regime and the dose-selection strategies determined the clinical outcome of the miltefosine treatment. A lower cure rate of the miltefosine treatment in paediatrics was predicted because a lower exposure of miltefosine was simulated in virtual paediatric in comparison with adult virtual populations when they received the same dose of the treatment. Conclusions: The mechanistic PBPK model suggested that the higher fraction of unbound miltefosine in plasma was responsible for a higher probability of failure in paediatrics because of the diference in the distribution of plasma proteins between adults and paediatrics. The developed PBPK models could be used to determine an optimal miltefosine dose regime in future clinical trials.
  • ItemEmbargo
    Thermal degradation of (2R, 3R)-dihydromyricetin in neutral aqueous solution at 100 ℃
    (Elsevier, 2023-09-26) Zhang, Haolin; Lin, Shiye; Xie, Ruiwei; Zhong, Weizhi; Wang, Hui; Farag, Mohamed A.; Hussain, H,; Arroo, R. R. J.; Chen, Xiaojia; Xiao. Jianbo
    In the field of thermal degradation of flavonoids, most current studies have been mainly focused on the flavonols. However, the thermal degradation of dihydroflavonols in aqueous solution have been limited studied compared to flavonols. Different from the C2-C3 double bonds of flavonols, the single C2-C3 bonds of dihydroflavonols may cause different degradation mechanisms. Dihydromyricetin (DMY) is a typical dihydroflavonol with six hydroxyl groups, and possesses various health effects. We explored the thermal degradation of DMY in neutral aqueous solution (pH 7) at 100 ℃. Ultra-performance liquid chromatography combined with photodiode array and electrospray ionization quadrupole-time-of-flight tandem mass spectrometric detection (UPLC-PDA ESI-QTOF–MS/MS) provided suitable platform for exploring DMY degradation pathways, and negative ion mode was applied. Thermal treatment led to a decline in DMY level with time, accompanied by the appearance of various degradation products of DMY. Degradation mechanisms of DMY included isomerization, oxidation, hydroxylation, dimerization and ring cleavage. The pyrogallol-type ring B of DMY might be initially oxidized into ortho-quinone, which could further attack another DMY to form dimers. Besides, hydroxylation is likely to occur at C-2, C-3 of DMY or DMY dimers, and then further to yield ring-cleavage products via breakage of the O1-C2 bond, C2-C3 bond, or C3-C4 bond. The 3-hydroxy-5-(3,3,5,7-tetrahydroxy-4-oxochroman-2-yl) cyclohexa-3,5-diene-1, 2-dione (m/z 333.0244) and unknown compounds m/z 435.0925 were annotated as key intermediates in DMY degradation. Four phenolic acids, including 3,4,5-trihydroxybenzoic acid (m/z 169.0136, RT 1.4 min), 2,4,6-trihydroxyphenylglyoxylic acid (m/z 197.0084, RT 1.7 min), 2-oxo-2-(2,4,6-trihydroxyphenyl) acetaldehyde (m/z 181.0132, RT 2.4 min), and 2,4,6-trihydroxybenzoic acid (m/z 169.0139, RT 2.5 min) were identified as the major end products of DMY degradation. In addition, 5-((3,5dihydroxyphenoxy) methyl)-3-hydroxycyclohexa-3,5-diene-1,2-dione (m/z 261.0399, RT 11.7 min) and unidentified compound with m/z 329.0507 (RT 1.0 min) were also suggested to be end products of DMY degradation. These results provided novel insights on DMY stability and degradation products. Moreover, the heating treatment on DMY aqueous solution was found to gradually reduce the antioxidant activities of DMY, and even destroy the beneficial effect of DMY on the gut microbiota composition.
  • ItemMetadata only
    Developing Artemisia annua L. for the production of artemisinin to treat multi-drug resistant malaria
    (2023-09-19) Arroo, R. R. J.
    Sweet wormwood (Artemisia annua L.) is the commercial source of the sesquiterpene compound artemisinin – the key ingredient for several first-line antimalarial drugs. Currently artemisinin-based combination therapy (ACT) is recommended for the treatment of P. falciparum malaria. Fast acting artemisinin-based compounds are combined with a drug from a different class. The benefits of ACTs are their high efficacy, fast action and the reduced likelihood of resistance developing. A. annua also produces several polymethoxyflavones which are currently not in clinical use, but show some interesting pharmacological properties. The plants are grown as a medicinal crop, and the leaves are harvested for artemisinin extraction. Several attempts have been made to create varieties of A. annua that yield increased amounts of artemisinin; the efforts range from classical breeding to biotechnological approaches to use of genetic modification of crops. In a parallel development, key genes of the artemisinin biosynthetic pathways have been expressed in yeast, though full biosynthesis of the compound through yeast fermentation has not yet been achieved. At present, plant crops remain the only commercial source of artemisinin. In addition to its immediate pharmaceutical applications, over-the-counter available herbal preparations of Artemisia annua are widely promoted on-line as health supplements to fight inflammation or, even more controversially, as prophylactic against malaria for travellers to tropical countries.
  • ItemOpen Access
    Advances in the natural α‐glucosidase inhibitors
    (Wiley, 2023-09-12) Şöhretoğlu, Didem; Renda, Gülin; Arroo, R. R. J.; Xiao, Jianbo; Sari, Suat
    α‐Glucosidase (AG) inhibitors, one of the classes of oral antidiabetics used to treat type 2 diabetes mellitus, delay digestion and absorption of glucose, which in turn, has a lowering effect on postprandial blood glucose and insulin levels. Natural products are a great source for the development of new AG inhibitory drug candidates. We aim to summarize advances in natural AG inhibitors according to their secondary metabolite groups in the last decade. Their mechanisms of action and structure–activity relationships will especially be discussed.