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The rapid development and worldwide distribution of COVID-19 vaccines is a remarkable achievement of biomedical research and logistical implementation. However, these developments are associated with the risk of a surge of substandard and falsified (SF) vaccines, as illustrated by the 184 incidents with SF and diverted COVID-19 vaccines which have been reported during the pandemic in 48 countries, with a paucity of methods for their detection in supply chains. In this context, matrix-assisted laser desorption ionisation-time of flight (MALDI-ToF) mass spectrometry (MS) is globally available for fast and accurate analysis of bacteria in patient samples, offering a potentially accessible solution to identify SF vaccines. We analysed the COVISHIELD™ COVID-19 vaccine; falsified versions of which were found in India, Myanmar and Uganda. We demonstrate for the first time that analysis of spectra from the vaccine vial label and its adhesive could be used as a novel approach to detect falsified vaccines. Vials tested by this approach could be retained in the supply chain since it is non-invasive. We also assessed whether MALDI-ToF MS could be used to distinguish the COVISHIELD™ vaccine from surrogates of falsified vaccines and the effect of temperature on vaccine stability. Both polysorbate 80 and L-histidine excipients of the genuine vaccine could be detected by the presence of a unique combination of MALDI-ToF MS peaks which allowed us to distinguish between the genuine vaccines and falsified vaccine surrogates. Furthermore, even if a falsified product contained polysorbate 80 at the same concentration as used in the genuine vaccine, the characteristic spectral profile of polysorbate 80 used in genuine products is a reliable internal marker for vaccine authenticity. Our findings demonstrate that MALDI-ToF MS analysis of extracts from vial labels and the vaccine excipients themselves can be used independently to detect falsified vaccines. This approach has the potential to be integrated into the national regulatory standards and WHO's Prevent, Detect, and Respond strategy as a novel effective tool for detecting falsified vaccines., Competing Interests: Competing interests: SRC, KDP & SG are employees of the Serum Institute of India Pvt. Ltd, RS is an employee of Agilent Technologies LDA UK and J-PC is an employee of bioMérieux. No other authors have competing interests., (© 2025. The Author(s).)

The global population is increasingly reliant on vaccines to maintain population health with billions of doses used annually in immunisation programmes. Substandard and falsified vaccines are becoming more prevalent, caused by both the degradation of authentic vaccines but also deliberately falsified vaccine products. These threaten public health, and the increase in vaccine falsification is now a major concern. There is currently no coordinated global infrastructure or screening methods to monitor vaccine supply chains. In this study, we developed and validated a matrix-assisted laser desorption/ionisation-mass spectrometry (MALDI-MS) workflow that used open-source machine learning and statistical analysis to distinguish authentic and falsified vaccines. We validated the method on two different MALDI-MS instruments used worldwide for clinical applications. Our results show that multivariate data modelling and diagnostic mass spectra can be used to distinguish authentic and falsified vaccines providing proof-of-concept that MALDI-MS can be used as a screening tool to monitor vaccine supply chains., (© 2024. The Author(s).)

Background: There is limited evidence to support definite clinical outcomes of direct oral anticoagulant (DOAC) therapy in chronic kidney disease (CKD). By identifying the important variables associated with clinical outcomes following DOAC administration in patients in different stages of CKD, this study aims to assess this evidence gap., Methods: An anonymised dataset comprising 97,413 patients receiving DOAC therapy in a tertiary health setting was systematically extracted from the multidimensional electronic health records and prepared for analysis. Machine learning classifiers were applied to the prepared dataset to select the important features which informed covariate selection in multivariate logistic regression analysis., Results: For both CKD and non-CKD DOAC users, features such as length of stay, treatment days, and age were ranked highest for relevance to adverse outcomes like death and stroke. Patients with Stage 3a CKD had significantly higher odds of ischaemic stroke (OR 2.45, 95% Cl: 2.10-2.86; p = 0.001) and lower odds of all-cause mortality (OR 0.87, 95% Cl: 0.79-0.95; p = 0.001) on apixaban therapy. In patients with CKD (Stage 5) receiving apixaban, the odds of death were significantly lowered (OR 0.28, 95% Cl: 0.14-0.58; p = 0.001), while the effect on ischaemic stroke was insignificant., Conclusions: A positive effect of DOAC therapy was observed in advanced CKD. Key factors influencing clinical outcomes following DOAC administration in patients in different stages of CKD were identified. These are crucial for designing more advanced studies to explore safer and more effective DOAC therapy for the population., (© 2024. The Author(s).)

Substandard (including degraded) and falsified (SF) vaccines are a relatively neglected issue with serious global implications for public health. This has been highlighted during the rapid and widespread rollout of COVID-19 vaccines. There has been increasing interest in devices to screen for SF non-vaccine medicines including tablets and capsules to empower inspectors and standardise surveillance. However, there has been very limited published research focussed on repurposing or developing new devices for screening for SF vaccines. To our knowledge, rapid diagnostic tests (RDTs) have not been used for this purpose but have important potential for detecting falsified vaccines. We performed a proof-in-principle study to investigate their diagnostic accuracy using a diverse range of RDT-vaccine/falsified vaccine surrogate pairs. In an initial assessment, we demonstrated the utility of four RDTs in detecting seven vaccines. Subsequently, the four RDTs were evaluated by three blinded assessors with seven vaccines and four falsified vaccines surrogates. The results provide preliminary data that RDTs could be used by multiple international organisations, national medicines regulators and vaccine manufacturers/distributors to screen for falsified vaccines in supply chains, aligned with the WHO global 'Prevent, Detect and Respond' strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Through predictable pharmacokinetics-including a convenient fixed-dose regimen, direct oral anticoagulants (DOACs) are preferred over previous treatments in anticoagulation for various indications. However, the association between higher body weight and the risk of adverse consequences is not well studied among DOAC users. We aim to explore the association of body weight and adverse clinical outcomes in DOAC users., Methods: A total of 97,413 anonymised DOAC users in a tertiary care setting were identified following structured queries on the electronic health records (EHRs) to extract the feature-rich anonymised dataset. The prepared dataset was analysed, and the features identified with machine learning (ML) informed the adjustments of covariates in the multivariate regression analysis to examine the association. Kaplan-Meier analysis was performed to evaluate the mortality benefits of DOACs., Results: Among DOAC users, the odds of adverse clinical outcomes, such as clinically relevant non-major bleeding (CRNMB), ischaemic stroke, all-cause mortality, and prolonged hospital stay, were lower in patients with overweight, obesity, or morbid obesity than in patients with normal body weight. The odds of ischaemic stroke (OR 0.42, 95% CI: 0.36-0.88, p = 0.001) and all-cause mortality (OR 0.87, 95% CI: 0.81-0.95, p = 0.001) were lower in patients with morbid obesity than in patients with normal body weight. In the Kaplan-Meier analysis, apixaban was associated with a significantly lower rate of mortality overall and in obesity and overweight subgroups than other DOACs (p < 0.001). However, rivaroxaban performed better than apixaban in the morbid obesity subgroup (p < 0.001)., Conclusion: This study shows the positive effects of DOAC therapy on clinical outcomes, particularly in patients with high body weight. However, this still needs validation by further studies particularly among patients with morbid obesity., (© 2023. The Author(s).)

Introduction: Sustaining a healthy weight is a challenge and obesity, with associated risk of co-morbidities, is a major public health concern. Bariatric surgery has shown a great promise for many where pharmacological and lifestyle interventions failed to work. However, challenges and limitations associated with bariatric surgery has pushed the demand for less invasive, reversible (anatomically) interventions, such as intragastric balloons (IGBs)., Areas Covered: This review critically appraises IGBs used in the past, present, and those in clinical trials, discussing the device designs, limitations, placement and removal techniques, patient eligibility, efficacy, and safety issues., Expert Opinion: Several intragastric balloons were developed over the years that brought excitement to patients and healthcare professionals alike. Albeit good efficacy, there had been several safety issues reported with IGBs such as spontaneous deflation, intestinal occlusion, gut perforation, and mucosal ulcerations. This led to evolution of IGBs design; device material, filling mechanism, fluid type, inflation volume, and further innovations to ease ingestion and removal of device. There are some IGB devices under development aimed to swallow like a conventional pill and excrete naturally through defecation, however, how successful they will be in clinical practice in terms of their efficacy and tolerability remains to be seen in the future.

Preventing, detecting, and responding to substandard and falsified vaccines is of critical importance for ensuring the safety, efficacy, and public trust in vaccines. This is of heightened importance in context of public health crisis, such as the COVID-19 pandemic, in which extreme world-wide shortages of vaccines provided a fertile ground for exploitation by falsifiers. Here, a proof-of-concept study explored the feasibility of using a handheld Spatially Offset Raman Spectroscopy (SORS) device to authenticate COVID-19 vaccines through rapid analysis of unopened vaccine vials. The results show that SORS can verify the chemical identity of dominant excipients non-invasively through vaccine vial walls. The ability of SORS to identify potentially falsified COVID-19 vaccines was demonstrated by measurement of surrogates for falsified vaccines contained in vaccine vials. In all cases studied, the SORS technique was able to differentiate between surrogate samples from the genuine COVISHIELD™ vaccine. The genuine vaccines tested included samples from six batches across two manufacturing sites to account for any potential variations between batches or manufacturing sites. Batch and manufacturing site variations were insignificant. In conjunction with existing security features, for example on labels and packaging, SORS provided an intrinsic molecular fingerprint of the dominant excipients of the vaccines. The technique could be extended to other COVID-19 and non-COVID-19 vaccines, as well as other liquid medicines. As handheld and portable SORS devices are commercially available and widely used for other purposes, such as airport security, they are rapidly deployable non-invasive screening tools for vaccine authentication., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pavel Matousek reports financial support was provided by Agilent Technologies. Pavel Matousek has patent #US20100053606 licensed to Agilent Technologies. Pavel Matousek also declares consultancy for Agilent Technologies, of which Robert Stokes is an employee., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The clinical outcomes of direct oral anticoagulant (DOAC) dosage regimens in morbid obesity are uncertain due to limited clinical evidence. This study seeks to bridge this evidence gap by identifying the factors associated with clinical outcomes following the dosing of DOACs in morbidly obese patients., Method: A data-driven observational study was carried out using supervised machine learning (ML) models with a dataset extracted from electronic health records and preprocessed. Following 70%:30% partitioning of the overall dataset via stratified sampling, the selected ML classifiers (e.g., random forest, decision trees, bootstrap aggregation) were applied to the training dataset (70%). The outcomes of the models were evaluated against the test dataset (30%). Multivariate regression analysis explored the association between DOAC regimens and clinical outcomes., Results: A sample of 4,275 morbidly obese patients was extracted and analysed. The decision trees, random forest, and bootstrap aggregation classifiers achieved acceptable (excellent) values of precision, recall, and F1 scores in terms of their contribution to clinical outcomes. The length of stay, treatment days, and age were ranked highest for relevance to mortality and stroke. Among DOAC regimens, apixaban 2.5 mg twice daily ranked highest for its association with mortality, increasing the mortality risk by 43% (odds ratio [OR] 1.430, 95% confidence interval [CI] 1.181-1.732, p = 0.001). On the other hand, apixaban 5 mg twice daily reduced the odds of mortality by 25% (OR 0.751, 95% CI 0.632-0.905, p = 0.003) but increased the odds of stroke events. No clinically relevant non-major bleeding events occurred in this group., Conclusion: Data-driven approaches can identify key factors associated with clinical outcomes following the dosing of DOACs in morbidly obese patients. This will help design further studies to explore well tolerated and effective DOAC doses for morbidly obese patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This article aims to highlight the dosing issues of direct oral anticoagulants (DOACs) in patients with renal impairment and/or obesity in an attempt to develop solutions employing advanced data-driven techniques. DOACs have become widely accepted by clinicians worldwide because of their superior clinical profiles, more predictable pharmacokinetics, and hence more convenient dosing relative to other anticoagulants. However, the optimal dosing of DOACs in extreme bodyweight  patients and patients with renal impairment is difficult to achieve using the conventional dosing approach. The standard dosing approach (fixed-dose) is based on limited data from clinical studies. The existing formulae (models) for determining the appropriate doses for these patient groups leads to suboptimal dosing. This problem of mis-dosing is worsened by the lack of standardized laboratory parameters for monitoring the exposure to DOACs in renal failure and extreme bodyweight patients. Model-informed precision dosing (MIPD) encompasses a range of techniques like machine learning and pharmacometrics modelling, which could uncover key variables and relationships as well as shed more light on the pharmacokinetics and pharmacodynamics of DOACs in patients with extreme bodyweight or renal impairment. Ultimately, this individualized approach-if implemented in clinical practice-could optimise dosing for the DOACs for better safety and efficacy., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The mechanism of action of excipients eliciting sex differences in drug bioavailability is poorly understood. In this study, the excipients Cremophor RH 40 (PEG 40 hydrogenated castor oil), Poloxamer 188 (2-methyloxirane) and Tween 80 (polyoxyethylene (80) sorbitan monooleate) were screened at 0.07 - 5% concentrations for their effect on ranitidine bioavailability in male and female Wistar rats. We show that all excipient concentrations significantly increased ranitidine bioavailability in male, but not female, rats. The effect of these excipients on the intestinal efflux transporters P-glycoprotein (P-gp), breast cancer resistant protein (BCRP) and multi-drug resistant protein 2 (MRP2) were also monitored. Measured by ELISA assay, in male rats, peak reductions in intestinal P-gp protein expression occurred in the presence of 1% Cremophor RH 40 and Poloxamer 188 and 0.5% Tween 80. In contrast, no distinct changes were observed in female intestinal P-gp expression. Unlike P-gp, all excipients had a positive effect on MRP2 protein expression - albeit only in males - in a concentration-dependent manner. The excipients did not modulate intestinal BCRP protein expression in either sex. Endogenous hormones and a nuclear receptor (testosterone, oestradiol and pregnane X receptor; PXR) that are purported to regulate intestinal efflux membrane transporter expression were also quantified. In the presence of all excipients, testosterone levels significantly elevated in males, although PXR levels reduced at similar rates in both sexes. No significant effects were identified in oestradiol levels in male and female rats. It is clear that excipients are not inert and their pathway for modulating drug response is multi-dimensional and specific between sexes. This study showed that excipients increased drug bioavailability of a P-gp drug substrate due to its reductive effect on intestinal P-gp expression; we propose that this link may be due to the excipients modulating fundamental testosterone levels. Understanding the implication of excipients on intestinal physiology and hormone levels can therefore improve pharmaceutical design, clinical efficacy and instigate next generation personalised, sex-specific formulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Covid immunization commenced on 2nd Feb 2021 in Pakistan and as of 7th Sep 2021, over 84 million vaccine doses were administered in Pakistan, of which 72% procured by the government, 22% received through Covax and 6% were donated. The vaccines rolled out nationally included: Sinopharm, Sinovac and CanSinoBIO (China), AstraZeneca (UK), Moderna and Pfizer (USA), Sputnik (Russia), and PakVac (China/Pakistan). About half of the eligible population in Pakistan (63 m) had received at least one dose of Covid vaccine as of Sep 2021. Pakistan National Pharmacovigilance Centre (PNPC) in coordination with WHO, MHRA and Uppsala Monitoring Centre (UMC) established pharmacovigilance centers across Pakistan. The Covid vaccine AEFIs in Pakistan were mainly reported via NIMS (National Immunization Management System), COVIM (Covid-19 Vaccine Inventory Management System), 1166 freephone helpline and MedSafety. There have been 39,291 ADRs reported as of 30th Sept 2021, where most reported after the first dose ( n  = 27,108) and within 24-72 h of immunization ( n  = 27,591). Fever or shivering accounted for most AEFI (35%) followed by injection-site pain or redness (28%), headache (26%), nausea/vomiting (4%), and diarrhoea (3%). 24 serious AEFIs were also reported and investigated in detail by the National AEFI review committee. The rate of AEFIs reports ranged from 0.27 to 0.79 per 1000 for various Covid vaccines in Pakistan that was significantly lower than the rates in UK (∼4 per 1000), primarily atrributed to underreporting of cases in Pakistan. Finally, Covid vaccines were well tolerated and no significant cause for concern was flagged up in Pakistan's Covid vaccine surveillance system concluding overall benefits outweighed risks., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. No funding was received to prepare this manuscript. AR was the Director for the Pakistan National Pharmacovigilance Centre, Drug Regulatory Authority of Pakistan (DRAP) at the time of writing this analysis., (© 2022 The Authors. Published by Elsevier Inc.)

This study aimed to assess the vaccination status and factors contributing to vaccine hesitancy among pregnant women in the largest province of Pakistan. A multicentric, prospective, survey-based study using an interviewer-administered tool was conducted among pregnant women attending antenatal clinics between 1 December 2021 through 30 January 2022 across seven hospitals in Pakistan. The healthcare professionals providing care at the participating hospitals administered the survey. Four hundred and five pregnant women fully consented and completed the study. The majority of the study participants (70.6%, n = 286) were aged between 25 and 34 and had a previous successful pregnancy history. More than half of the study participants (56.0%, n = 227) did not receive COVID-19 vaccination at the time of data collection despite their family members (93.9%, n = 372) had already received at least one dose of COVID-19 vaccine. Among those who received COVID-19 vaccination (n = 173), vaccine efficacy, protection for the foetus, and risk of COVID-19-associated hospitalisation were the main driving factors for vaccine hesitancy. The majority of the unvaccinated women (77.8%, n = 182) had no intention of receiving the vaccine. However, more than two-thirds (85.7%, n = 342) consulted the doctor about COVID-19 vaccines, and most were recommended to receive COVID-19 vaccines by the doctors (80.7%, n = 280). Women were significantly more likely to be vaccinated if they had employment (odds ratio [OR] 4.47, 95% confidence interval [CI]: 2.31-8.64) compared with their counterparts who were homemakers, consulted their doctors (OR 0.12, 95% CI: 0.04-0.35), and if they did not have pregnancy-related issues (OR 6.02, 95% CI: 2.36-15.33). In this study, vaccine hesitancy was prevalent, and vaccine uptake was low among pregnant women. Education and employment did impact COVID vaccination uptake, emphasising the need for more targeted efforts to enhance the trust in vaccines.

Universal Health Coverage (UHC), initiative from the World Health Organization (WHO), is a means to provide the human right to health by providing essential health services to everyone, enabling disease prevention, treatment, rehabilitation, and palliative care. In line with the WHO recommendations, the UHC was first introduced in Pakistan in Khyber Pakhtunkhwa (KP) province under the name 'Sehat Sahulat Programme' (SSP), literally 'Health Facility Program' in 2015. The provincial Government in Punjab approved a similar initiative in Punjab, the largest province (by population) of the country, and the program was later rolled out in Islamabad Capital Territory (ICT), Azad and Jammu Kashmir (AJK), Gilgit Baltistan (GB), Sindh, and Baluchistan provinces leaping into the nation-wide coverage. This article provides a current overview of the UHC initiative in Pakistan, analyses its progress in appraising key milestones, and makes recommendations to achieve a robust universal health coverage across Pakistan.

Aldén et al. (2022) recently reported the intracellular reverse transcription of Pfizer BioNTech COVID-19 mRNA Vaccine BNT162b2 in vitro in a human liver cell line (Huh7) [...].

Purpose: The advent of clinically adapted machine learning algorithms can solve numerous problems ranging from disease diagnosis and prognosis to therapy recommendations. This systematic review examines the performance of machine learning (ML) algorithms and evaluates the progress made to date towards their implementation in clinical practice., Methods: Systematic searching of databases (PubMed, MEDLINE, Scopus, Google Scholar, Cochrane Library and WHO Covid-19 database) to identify original articles published between January 2011 and October 2021. Studies reporting ML techniques in clinical practice involving humans and ML algorithms with a performance metric were considered., Results: Of 873 unique articles identified, 36 studies were eligible for inclusion. The XGBoost (extreme gradient boosting) algorithm showed the highest potential for clinical applications (n = 7 studies); this was followed jointly by random forest algorithm, logistic regression, and the support vector machine, respectively (n = 5 studies). Prediction of outcomes (n = 33), in particular Inflammatory diseases (n = 7) received the most attention followed by cancer and neuropsychiatric disorders (n = 5 for each) and Covid-19 (n = 4). Thirty-three out of the thirty-six included studies passed more than 50% of the selected quality assessment criteria in the TRIPOD checklist. In contrast, none of the studies could achieve an ideal overall bias rating of 'low' based on the PROBAST checklist. In contrast, only three studies showed evidence of the deployment of ML algorithm(s) in clinical practice., Conclusions: ML is potentially a reliable tool for clinical decision support. Although advocated widely in clinical practice, work is still in progress to validate clinically adapted ML algorithms. Improving quality standards, transparency, and interpretability of ML models will further lower the barriers to acceptability., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Lactoferrin (Lf) is one of the key immunomodulatory substances found naturally in various body fluids, such as saliva, tears, and breast milk, and forms a vital part of the innate defense against invading pathogens. Various studies have demonstrated antibacterial, antifungal, and antiviral properties of Lf and its protective role against respiratory tract infections (RTIs). The present meta-analysis aims to elucidate the association of Lf administration in reducing the risk of RTIs by systematically reviewing the data from randomized controlled trials (RCTs)., Methods: We systematically searched PubMed, Cochrane Library, Medline & CINAHL, Turning Research into Practice (TRIP), ProQuest Theses & Dissertations Databases, and China National Knowledge Infrastructure (CNKI) from inception till March 15, 2021. The primary outcome measure was a reduction in respiratory illness; decrease in frequency, symptoms, and duration. Random-effects model was used to estimate the odds ratio (OR) and 95% confidence interval (CI). We used Cochrane's RoB-2 to appraise the risk of bias of included RCTs., Results: A total of nine RCTs were eligible for this review, of which six were included in the meta-analysis. Overall, two studies demonstrated a high risk of bias. The meta-analysis revealed a significantly reduced odds of developing respiratory infections with the use of Lf relative to the control (pooled odds ratio = 0.57; 95% confidence interval 0.44 to 0.74, n = 1,194), with sufficient evidence against the hypothesis of 'no significant difference' at the current sample size., Conclusions: The administration of Lf shows promising efficacy in reducing the risk of RTIs. Current evidence also favours Lf fortification of infant formula. Lf may also have a beneficial role in managing symptoms and recovery of patients suffering from RTIs and may have potential for use as an adjunct in COVID-19, however this warrants further evidence from a large well-designed RCT., Competing Interests: Declaration of competing interest HAM is on a scientific advisory board for a lactoferrin supplement product but does not have any financial or other affiliation with the company and has neither received any funding or financial reimbursements. HAM is committed to promote the science behind Lf and its immunomodulatory role in the prevention and management of infections., (Copyright © 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Objective: The effect of ivermectin on mortality in patients with novel coronavirus disease 2019 (COVID-19) has been investigated in many studies. We aimed to perform a meta-analysis of randomized controlled trials to investigate the overall effect of ivermectin on the risk of mortality in patients with COVID-19., Methods: We systematically searched PubMed, Cochrane Central Register of Controlled Trials, Google Scholar, and preprint repository databases (up to February 28, 2021). Random-effects and inverse variance heterogeneity meta-analysis were used to pool the odds ratio of individual trials. The risk of bias was appraised using Version 2 of the Cochrane risk-of-bias tool for randomized trials., Results: Six randomized controlled trials were included in this analysis with a total of 658 patients who were randomized to receive ivermectin and 597 patients randomized in the control group who did not receive ivermectin. Of six trials, four had an overall high risk of bias. The estimated effect of ivermectin indicated mortality benefits (pooled odds ratio = 0.21; 95% confidence interval 0.11-0.42, n = 1255), with some evidence against the hypothesis of 'no significant difference' at the current sample size., Conclusion: We observed a preliminary beneficial effect on mortality associated with ivermectin use in patients with COVID-19 that warrants further clinical evidence in appropriately designed large-scale randomized controlled trials., (© 2021. Maj Institute of Pharmacology Polish Academy of Sciences.)

Direct-acting oral anticoagulants (DOACs) are replacing conventional VKA (vitamin K antagonist, i.e., warfarin) for various indications where a therapeutic anticoagulant effect is desired. We evaluated the prescribing patterns of the DOACs and warfarin, cost implications of the increasing DOACs prescribing, and deduce the reporting of serious and fatal events, during 2009-2019 in primary care England. Prescriptions and fatal or serious adverse events reporting data, between 2009 and 2019 were analysed, using linear regression to examine the trends in prescriptions, costs, and serious and fatal events reporting. We also compared the prescribing trends of four direct-acting oral anticoagulants and warfarin, normalised to per 1000 clinical commissioning group (CCG) patient population for the year 2019 to better understand the regional differences in DOACs prescribing. The overall use of any DOACs (as a proportion of total anticoagulants) increased from 16% in 2015 to 62% in 2019 with an average increase of 87% (95% CI 83.1, 90.5) per year. The reporting of serious and fatal events associated with DOACs decreased by 6% (95% CI 12.5, - 0.1) per year. Apixaban is by far the most prescribed with an average drug cost increasing to 156% (95% CI 140, 172) per year. In England, the lowest anticoagulant prescribing region was Greater London whereas the highest prescribing regions were Yorkshire and Humber for DOACs and the East Midlands for warfarin. Interestingly, Lancashire, Merseyside, and Cheshire showed a higher usage for warfarin over DOACs. The differing prescription patterns could be a result of changes in national guidelines and increasing population. Nevertheless, DOACs appear to make an increasing contribution to total anticoagulant prescription items and costs., (© 2021. The Author(s).)

Professor Henry Higgins in My Fair Lady said, 'Why can't a woman be more like a man?' Perhaps unintended, such narration extends to the reality of current drug development. A clear sex-gap exists in pharmaceutical research spanning from preclinical studies, clinical trials to post-marketing surveillance with a bias towards males. Consequently, women experience adverse drug reactions from approved drug products more often than men. Distinct differences in pharmaceutical response across drug classes and the lack of understanding of disease pathophysiology also exists between the sexes, often leading to suboptimal drug therapy in women. This review explores the influence of sex as a biological variable in drug delivery, pharmacokinetic response and overall efficacy in the context of pharmaceutical research and practice in the clinic. Prospective recommendations are provided to guide researchers towards the consideration of sex differences in methodologies and analyses. The promotion of disaggregating data according to sex to strengthen scientific rigour, encouraging innovation through the personalisation of medicines and adopting machine learning algorithms is vital for optimised drug development in the sexes and population health equity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Introduction : The first confirmed COVID-19 case in UK dates to 11 January 2020, exhibiting its first peak during April 2020. The country has since been hit by another wave in the winter 2020, almost at the first anniversary of the pandemic. Areas covered: An in-depth analysis of the COVID-19 positive cases in the UK throughout the year, hospitalizations, patients in critical care, and COVID-19 associated deaths. Expert opinion : The COVID-19 associated hospital admission accounts to 15% of total COVID-19 positive cases in November 2020. The percentage of total COVID-19 positive patients in the country died from the disease was under 4% in November 2020. Total deaths in England (all-cause) from June to October 2020 were similar to the historic averages. Age was the single most determinator of COVID-19 associated mortality, 50 years or older accounted for 98% of total COVID deaths. Age distribution of COVID-19 associated deaths in 2020 was similar to all-cause mortality age distribution in 2019. There was no significant improvement in the survival rate of COVID-19 patients receiving critical care. This prompts an urgent need to invest in novel antiviral therapeutics to save the most vulnerable in the society.

Objectives : The question remained if mortality benefits with dexamethasone seen in patients with coronavirus disease 2019 (COVID-19) also extend to other systemic corticosteroids such as methylprednisolone. This article presents a meta-analysis of randomized controlled trials (RCTs) to ascertain if methylprednisolone can be recommended for use in patients with COVID-19 to prevent deaths. Methods : Systematic literature search was performed in PubMed, Scopus, Cochrane Central Register of Controlled Trials, and preprint servers until 13 April 2021. The outcome of interest was all-cause mortality. The random-effects model for the meta-analysis was utilized to estimate the pooled odds ratio (OR) at 95% confidence intervals (CI). Results : Five RCTs were included in the meta-analysis. The pooled OR for all-cause mortality was 0.64 (95% CI: 0.29 - 1.43, n = 652) comparing methylprednisolone with the control, indicating no mortality benefits. A similar finding was noted with a sub-group analysis including four trials that used low-dose methylprednisolone. However, the only trial that administered high dose methylprednisolone indicated a statistically significant mortality benefit (OR 0.08, 95% CI: 0.02-0.42). Conclusions : In determining equipotent doses for an acute short-course pulse therapy of corticosteroids, the biological half-life of steroids should also be accounted for besides the potency factor. A short duration (3-5 days) pulse therapy of high-dose methylprednisolone can be a promising alternative to the low-dose dexamethasone therapy in severely ill patients with COVID-19 to prevent deaths.

The social restrictions amid coronavirus disease 2019 (COVID-19) pandemic have posed a serious threat to mental health and have implications in the use of medications for mental health including antidepressants (ADs). This study investigated the trends in prescriptions and costs of various ADs in England during COVID-19 pandemic. National prescribing rates and net ingredient costs (NIC) of all ADs prescriptions during 2016 to 2020 were analyed. The total number of ADs prescriptions dispensed during COVID-19 pandemic (January to December 2020) were 78 million, 4 million more than in 2019 that costed NHS England £ 139 million more than in 2019. Sertraline, an SSRI antidepressant drug, alone accounted for an extra £113 million during 2020 than in 2019. The peak dispensing for ADs was observed in March 2020 while the total costs for AD drugs peaked in April 2020. The rising prescription costs for ADs during COVID-19 pandemic is a potential cause of concern, in particular the increasing use in adolescents and younger adults needs attention, who are at a higher risk of life-threatening adverse drug reactions.

Introduction: Diabetes mellitus is one of the most prevalent comorbidities identified in patients with coronavirus disease 2019 (COVID-19). This article aims to discuss the pharmacotherapeutic considerations for the management of diabetes in hospitalized patients with COVID-19., Areas Covered: We discussed various aspects of pharmacotherapeutic management in hospitalized patients with COVID-19: (i) susceptibility and severity of COVID-19 among individuals with diabetes, (ii) glycemic goals for hospitalized patients with COVID-19 and concurrent diabetes, (iii) pharmacological treatment considerations for hospitalized patients with COVID-19 and concurrent diabetes., Expert Opinion: The glycemic goals in patients with COVID-19 and concurrent type 1 (T1DM) or type 2 diabetes (T2DM) are to avoid disruption of stable metabolic state, maintain optimal glycemic control, and prevent adverse glycemic events. Patients with T1DM require insulin therapy at all times to prevent ketosis. The management strategies for patients with T2DM include temporary discontinuation of certain oral antidiabetic agents and consideration for insulin therapy. Patients with T2DM who are relatively stable and able to eat regularly may continue with oral antidiabetic agents if glycemic control is satisfactory. Hyperglycemia may develop in patients with systemic corticosteroid treatment and should be managed upon accordingly.

Introduction: The use of renin-angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), was alleged to cause a more severe course of novel coronavirus disease 2019 (COVID-19)., Methods: We systematically reviewed the published studies to assess the association of RAS inhibitors with mortality as well as disease severity in COVID-19 patients. A systematic literature search was performed to retrieve relevant original studies investigating mortality and severity (severe/critical disease) in COVID-19 patients with and without exposure to RAS inhibitors., Results: A total of 59 original studies were included for qualitative synthesis. Twenty-four studies that reported adjusted effect sizes (24 studies reported mortality outcomes and 16 studies reported disease severity outcomes), conducted in RAS inhibitor-exposed and unexposed groups, were pooled in random-effects models to estimate overall risk. Quality assessment of studies revealed that most of the studies included were of fair quality. The use of an ACEI/ARB in COVID-19 patients was significantly associated with lower odds (odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.56-0.95; n = 18,749) or hazard (hazard ratio [HR] = 0.75, 95% CI 0.60-0.95; n = 26,598) of mortality compared with non-use of ACEI/ARB. However, the use of an ACEI/ARB was non-significantly associated with lower odds (OR = 0.91, 95% CI 0.75-1.10; n = 7446) or hazard (HR = 0.73, 95% CI 0.33-1.66; n = 6325) of developing severe/critical disease compared with non-use of an ACEI/ARB., Discussion: Since there was no increased risk of harm, the use of RAS inhibitors for hypertension and other established clinical indications can be maintained in COVID-19 patients.

Objectives: We critically evaluated the quality of evidence and quality of harm reporting in clinical trials that evaluated the effectiveness of hydroxychloroquine (HCQ) or chloroquine (CQ) for the treatment of coronavirus disease 2019 (COVID-19)., Study Design and Setting: Scientific databases were systematically searched to identify relevant trials of HCQ/CQ for the treatment of COVID-19 published up to 10 September 2020. The Cochrane risk-of-bias tools for randomized trials and non-randomized trials of interventions were used to assess risk of bias in the included studies. A 10-item Consolidated Standards of Reporting Trials (CONSORT) harm extension was used to assess quality of harm reporting in the included trials., Results: Sixteen trials, including fourteen randomized trials and two non-randomized trials, met the inclusion criteria. The results from the included trials were conflicting and lacked effect estimates adjusted for baseline disease severity or comorbidities in many cases, and most of the trials recruited a fairly small cohort of patients. None of the clinical trials met the CONSORT criteria in full for reporting harm data in clinical trials. None of the 16 trials had an overall 'low' risk of bias, while four of the trials had a 'high', 'critical', or 'serious' risk of bias. Biases observed in these trials arise from the randomization process, potential deviation from intended interventions, outcome measurements, selective reporting, confounding, participant selection, and/or classification of interventions., Conclusion: In general, the quality of currently available evidence for the effectiveness of CQ/HCQ in patients with COVID-19 is suboptimal. The importance of a properly designed and reported clinical trial cannot be overemphasized amid the COVID-19 pandemic, and its dismissal could lead to poorer clinical and policy decisions, resulting in wastage of already stretched invaluable health care resources., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: The acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis is one of the main causes of high mortality in patients with COVID-19 (novel coronavirus disease 2019). We systematically reviewed mortality in COVID-19 patients with ARDS and the potential role of systemic corticosteroids in COVID-19 patients., Methods: Electronic databases and country-specific healthcare databases were searched to identify relevant studies/reports. The quality assessment of individual studies was conducted using the Newcastle-Ottawa Scale. Country-specific proportion of individuals with COVID-19 who developed ARDS and reported death were combined in a random-effect meta-analysis to give a pooled mortality estimate of ARDS., Results: The overall pooled mortality estimate among 10,815 ARDS cases in COVID-19 patients was 39% (95% CI: 23-56%). The pooled mortality estimate for China was 69% (95% CI: 67-72%). In Europe, the highest mortality estimate among COVID-19 patients with ARDS was reported in Poland (73%; 95% CI: 58-86%) while Germany had the lowest mortality estimate (13%; 95% CI: 2-29%) among COVID-19 patients with ARDS. The median crude mortality rate of COVID-19 patients with reported corticosteroid use was 28.0% (lower quartile: 13.9%; upper quartile: 53.6%)., Conclusions: The high mortality in COVID-19 associated ARDS necessitates a prompt and aggressive treatment strategy which includes corticosteroids. Most of the studies included no information on the dosing regimen of corticosteroid therapy, however, low-dose corticosteroid therapy or pulse corticosteroid therapy appears to have a beneficial role in the management of severely ill COVID-19 patients.

The potential detrimental effects of steroids on the immune system to fight viral infections had always been a concern for patients on long term steroids in chronic conditions. A recent warning from WHO on systemic corticosteroid use amid COVID-19 raised suspicion among public and healthcare professionals regarding the safety of steroid use during the SARS-CoV-2 pandemic. The corticosteroids (inhaled and oral) are commonly prescribed in the management of asthma and COPD patients and any unsolicited changes in medications use may lead to potentially severe exacerbations and may risk patient lives. This article provides a critical review of clinical evidence and offers a detailed discussion on the safety and efficacy of corticosteroids in asthma and COPD patients, both with and without COVID-19., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The world is facing a medical crisis amid the CoViD-19 pandemic and the role of adequate hygiene and hand sanitisers is inevitable in controlling the spread of infection in public places and healthcare institutions. There has been a great surge in demand for hand sanitisation products leading to shortages in their supply. A consequent increase of substandard products in the market has raised safety concerns. This article, therefore, presents a critical review of hand sanitation approaches and products available on the market in light of the scientific evidence available to date. This review also provides a range of hand sanitisation product formulations, and manufacturing instructions to allow for extemporaneous preparations at the community and hospital pharmacies during this urgent crisis. In addition, this emergent situation is expected to continue, hence hand sanitisers will be in demand for an extended time, and the availability and purchase of substandard products on the market create an ongoing safety concern. Therefore, this article shall also provide various commercial organisations, interested in stepping forward the production and marketing of hand sanitisers, with a guide on the development of products of standardised ingredients and formulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The present study aimed to explore a new source of montmorillonite and to develop an extraction and purification protocol for its isolation from raw clay samples acquired from the Koh-e-Suleiman mountain range in Pakistan. The process involved the collection of raw clay from the source, identification and quantification of montmorillonite. Granulometric extraction and purification protocols increased the montmorillonite content from 21.8-25.1% in the raw clay to 90.1-93.9% after small-scale extraction and 85.33-89.33% on a larger scale. A techno-economic analysis highlighted the practicality and economic benefits of large-scale extraction for industrial applications. This study highlights the existence of a substantial new source of this valuable clay which is currently used across multiple industries including construction, pottery making, pharmaceuticals, cosmetics and engineering. It is intuitively expected that the large-scale extraction of the material will improve the economic condition of the region by providing employment opportunities to locals and may be a valuable resource for export.

Capsules are a widely used oral dosage form due to their simplicity and ease of manufacture. They are equally popular for both pharmaceutical and nutraceutical products and since they do not need extensive formulation development, it is a dosage form of choice for new drugs undergoing animal or clinical trials. In addition to the standard hard-gelatin or cellulose-based vegetarian capsules, functional capsules such as those with built-in gastroresistance would be of great value. In this work, commonly used enteric polymers were investigated for the production of hard-capsules. The polymers used in this study included cellulose derivatives (HPMC AS-LF and HP-55) and acrylic/methacrylic acid derivatives (EUDRAGIT L100 and S100). A range of concentrations of polymers and plasticisers were tested to optimise the formulation for the production of capsule shells with desirable physicochemical and gastroresistance characteristics. Drug release from optimised capsules produced from HPMC AS-LF, HP-55, EUDRAGIT L100 and S100 was shown to be comparable to drug release from corresponding polymer-coated tablets in both compendial and physiological bicarbonate buffer. In summary, herein we report a simple method for producing enteric capsule shells which do not need an additional coating step which, if validated at large scale, can significantly reduce the cost of manufacturing of conventional enteric coated dosage forms. These capsules are also likely to improve the inter-tablet variability in post-gastric drug release inherent in conventional dosage forms due to coating variability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A range of enteric polymers is used in pharmaceutical industry for developing gastro-resistant formulations. It is generally implied that these coatings are interchangeable due to similar dissolution pH thresholds reported by suppliers. Despite rapid dissolution in compendial phosphate buffers, these products can take up to 2 h to disintegrate in-vivo in the human small intestine. The factors primarily responsible for such variability in dissolution of these polymeric coatings are the differences in ionisation of acidic functional groups on polymer chains and their interplay with ions and buffer species present in gastrointestinal fluids. In this study, we aim to develop a novel, simple and inexpensive technique that can be used under various in-vitro conditions to study the ionisation behaviour of commonly used polymers (EUDRAGIT-E100, L100, S100, HPMC AS-LF, AS-HF, HP-50, HP-55) and to estimate their pK a . Moreover, this method was successfully applied to study the ionisation behaviour of a range of natural polymers (Guar, Tara, locust bean, Konjac gums, gum Arabic, citrus pectin, chitosan and alginate) and their pK a was also estimated. The proposed method would allow a better understanding of the dissolution behaviour of these polymers within gastrointestinal tract and will aid rational design of modified release dosage forms., Competing Interests: None.

Subjects diagnosed with non-alcoholic fatty liver disease (NAFLD) or hepatic steatosis are usually obese or overweight. NAFLD has also been reported in many non-obese healthy subjects as an incidental finding during imaging. Subjects with early-stage NAFLD who are otherwise healthy are often left unmanaged in current clinical practice; it is not clear if an early intervention in those individuals would be of any benefit in preventing NAFLD progression to more serious conditions. Since many of these subjects are non-alcoholic and have a normal body mass index (BMI), an intensive lifestyle change program is not usually recommended. This report presents an otherwise healthy non-alcoholic subject with incidental NAFLD having a normal BMI and a waist circumference below 90 cm who successfully reversed his condition by undertaking a lifestyle intervention. The case report is expected to encourage large cohort studies to substantiate the benefits of dietary interventions in alleviating hepatic steatosis among non-obese individuals., Competing Interests: The author has declared a relationship with the subject of the clinical case presented in this article.

Physiological functions of the two extreme ends of the age spectrum, children (<18 y old) and older adults (aged 65 y and over), differ from healthy young adults. This consequently affects the pharmacokinetic profiles of administered drugs, which, in turn, impacts upon clinical practice and drug therapy. The gastrointestinal milieu acts as a distinct and vital organ regulating the dissolution, absorption and metabolism of orally ingested drugs. Age-mediated alteration in the physiology and function of the gut can reshape the pharmacokinetics of certain drugs. However, our understanding of this topic is limited. This article references the gut physiology of healthy adults to capture the available evidence in the literature on the extent and nature of the changes in childhood and older age. The gut, as an organ, is examined with regards to the effect of age on luminal fluid, microbiota, transit and motility, and the intestinal mucosa. Whilst drastic developmental changes were observed in certain aspects of the gastrointestinal environment, the examination reveals significant gaps in our knowledge in the physiology and function of the developing or ageing gut. The revelation of the unknown paves the way towards a better characterization of the human gastrointestinal tract for optimized drug therapy in children and older adults., (Copyright © 2016. Published by Elsevier B.V.)

"All animals are equal, but some are more equal than others" was the illustrious quote derived from British writer George Orwell's famed work, Animal Farm. Extending beyond the remit of political allegory, however, this statement would appear to hold true for the selection of appropriate animal models to simulate human physiology in preclinical studies. There remain definite gaps in our current knowledge with respect to animal physiology, notably those of intra- and inter-species differences in gastrointestinal (GI) function, which may affect oral drug delivery and absorption. Factors such as cost and availability have often influenced the choice of animal species without clear justification for their similarity to humans, and lack of standardization in techniques employed in past studies using various animals may also have contributed to the generation of contradictory results. As it stands, attempts to identify a single animal species as appropriately representative of human physiology and which may able to adequately simulate human in vivo conditions are limited. In this review, we have compiled and critically reviewed data from numerous studies of GI anatomy and physiology of various animal species commonly used in drug delivery modeling, commenting on the appropriateness of these animals for in vivo comparison and extrapolation to humans., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Objectives: To characterise the gastrointestinal (GI) environment in rat, rabbit and pig for the purpose of determining their utility as animal models for drug delivery in humans., Methods: GI fluid samples were characterised for osmolality, surface tension, pH and buffer capacity. The solubility of two model drugs, mesalazine (ionisable) and prednisolone (unionisable), were also measured and the results were correlated to the physicochemical fluid data., Key Findings: The solubility of the ionisable drug mesalazine was positively correlated to the GI pH in all three species and was significantly influenced by the pH difference. In contrast, the solubility of the unionisable compound prednisolone was not correlated significantly to the changes in pH, buffer capacity, osmolality or surface tension. In general, the solubility of prednisolone was constant irrespective of the location of the sample in the gut from rabbit and pig; however, an unusual trend was observed for the solubility of prednisolone in rats., Conclusions: The results suggest that solubility of ionisable drugs or pH-responsive formulations is significantly influenced by the differences in pH along the GI tract and inter-species differences. It was also found that the data on the GI solubility of prednisolone (a neutral compound) in rats might overestimate its true value in humans., (© 2015 Royal Pharmaceutical Society.)

The aminosalicylate mesalazine (mesalamine) forms the mainstay of treatment in ulcerative colitis (UC), a disease for which many commercial modified-release products have been developed with the aim of providing targeted gastrointestinal release. The release profiles of five of these commercial formulations were evaluated in bicarbonate buffer using a novel dissolution model that mimics the dynamic conditions of the gastrointestinal tract. Monolithic and multi-particulate mesalazine formulations with pH-dependent and/or independent release mechanisms were evaluated (Asacol(®) 800, Octasa(®), Mezavant(®) XL, Salofalk(®), Pentasa(®)), and each of the products displayed a distinctive dissolution profile. The dissolution results for Mezavant(®) XL (Lialda(®)) (lag time 290 min) demonstrated good correlation with previously reported in vivo disintegration times assessed by gamma-scintigraphy in humans. Octasa(®) showed a similar lag time to Mezavant(®) XL. Drug release from Asacol(®) 800 (Asacol(®) HD) showed a wide standard deviation, reflecting the great variability in vivo. Salofalk(®) displayed both delayed release and extended release characteristics. Pentasa(®) released more than 50% of its drug load in the stomach compartment of the model, which is attributed to the absence of a gastro-resistant coating in this product. The new dissolution method provided a realistic and discriminative in vitro assessment of mesalazine release from different formulations. These results demonstrate that this strategy can be used to predict intestinal release behaviour, and potentially aid the rational design of products developed to target different sites of the gut., (Copyright © 2015. Published by Elsevier B.V.)

The establishment of physiologically relevant in vitro-in vivo correlations (IV-IVCs) is key for any biorelevant dissolution test. Historically, bicarbonate buffers have produced better correlations than compendial phosphate buffered media, though such tests are usually performed at a constant pH experiment, overlooking the notion that the pH of the luminal fluids is variable and fluctuating. In this work, we have devised a dynamic dissolution test method employing a physiological bicarbonate buffer under pH conditions of the proximal gut in order to assess the dissolution behaviour of various enteric polymer-coated (gastro-resistant) prednisolone tablets. The pH of the media is modulated and controlled by an Auto pH System™ which exploits the physiological equilibria between [H2CO3] and [HCO3(-)], to match it to the aboral change in pH with transit of the dosage form through the proximal small intestine (from pH 5.6 up to 6.8). The lag time values for an accelerated release and standard EUDRAGIT(®) L30D-55 coated formulation (25 min and 60 min, respectively) were close to the previously reported initial tablet disintegration time data obtained in-vivo by γ-scintigraphy (28 min and 66 min, respectively). Dissolution of alternative delayed release coated products was also better discriminated in the dynamic buffer system. These data confirm the dynamic dissolution system provides a robust and reliable platform to predict the in vivo fate of oral products in a laboratory setting., (Copyright © 2014. Published by Elsevier B.V.)

Age-mediated changes in gut physiology are considerations central to the elucidation of drug performance from oral formulations. Using rats of different age groups we measured the pH, buffer capacity, fluid volume, osmolality, and surface tension of gastrointestinal (GI) fluids, and therein explored the impact of these variables on prednisolone and mesalazine solubility in luminal fluids. We also studied the distribution of gut associated lymphoid tissue (GALT) and mucus layer thickness across the GI tract in rats of different age groups. At a mucosal level, there was an increase in GALT from young to adult rat. Gastrointestinal pH and buffer capacity remained mostly unchanged with age, except some pH differences in stomach and distal small intestine and a higher buffer capacity in the large intestinal fluids of young rats. Osmolality and surface tension also remained unaffected with the exception of a lower osmolality in elderly stomach and a lower surface tension in the small intestine of young rats. The difference in luminal environment on ageing influenced the solubility of studied drugs, for instance prednisolone solubility was shown to be higher in adult rats (mid small intestine and caecum) and solubility of mesalazine was significantly higher in the elderly distal small intestine., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Despite rapid dissolution in compendial phosphate buffers, gastro resistant (enteric coated) products can take up to 2 h to disintegrate in the human small intestine, which clearly highlights the inadequacy of the in vitro test method to predict in vivo behaviour of these formulations. The aim of this study was to establish the utility of a novel pH 5.6 bicarbonate buffer, stabilized by an Auto pH™ System, as a better surrogate of the conditions of the proximal small intestine to investigate the dissolution behaviour of standard and accelerated release enteric double coating formulations. Prednisolone tablets were coated with 3 or 5 mg/cm(2) of partially neutralized EUDRAGIT(®) L 30 D-55, HP-55 or HPMC adjusted to pH 6 or 8. An outer layer of EUDRAGIT(®) L 30 D-55 was applied at 5mg/cm(2). For comparison purposes, a standard single layer of EUDRAGIT(®) L 30 D-55 was applied to the tablets. Dissolution was carried out using USP II apparatus in 0.1 M HCl for 2 h, followed by pH 5.6 bicarbonate buffer. EUDRAGIT(®) L 30 D-55 single-coated tablets showed a slow drug release with a lag time of 75 min in buffer, whereas release from the EUDRAGIT(®) L 30 D-55 double-coated tablets was accelerated. These in vitro lag times closely match the in vivo disintegration times for these coated tablets reported previously. Drug release was further accelerated from modified double coatings, particularly in the case of coatings with a thinner inner layer of HP-55 or HPMC (pH 8 and KH2PO4). This study confirms that the pH 5.6 bicarbonate buffer system offers significant advantages during the development of dosage forms designed to release the drug in the upper small intestine., (Copyright © 2014. Published by Elsevier B.V.)

Novel and highly tuneable pulsatile drug delivery systems have been prepared through the electrospinning of a blend of poly(ethylene oxide) (PEO), sodium alginate (SA), and sodium ibuprofen (SI). The resultant fibres contain crystallites of SI embedded in a PEO-SA matrix, and rather than being obtained as flat mats on the collector plate form novel three dimensional structures extending upwards the needle. Fibres were prepared with a range of loadings of SI and SA. It was found that at pH 6.8 (reminiscent of the intestinal tract) the fibres dissolve very rapidly, freeing all the embedded drug within ca. 20 minutes. However, at pH 3 (representative of the stomach pH in the fed state or in older patients) an unusual two stage release mechanism is seen. This comprises a rapid burst release, followed by a period where no further drug is released for ca. 120-150 minutes, and then a final stage of release freeing the remainder of the drug into solution. The amount of release in the initial stage, and the length of time between the first and final drug release stages, can be controlled by adjusting the SI and SA contents of the fibres respectively. This results in highly tunable pulsatile release materials.

The aim of this study was to investigate the stability of four corticosteroids in the presence of human colonic bacteria to understand better their luminal behaviour when delivered orally in the treatment of inflammatory bowel disease. The stability of prednisolone, budesonide, beclometasone (17, 21) dipropionate (BDP) and its active metabolite, beclometasone-17-monopropionate (17-BMP), were investigated at three different concentrations following incubation in a mixed faecal inoculum (simulated human colonic fluid) under anaerobic conditions. Prednisolone, at all three concentrations, was completely degraded within 3 h. The degradation of budesonide progressed at a slower rate, with complete degradation occurring within 7h; the degradation of the S epimer of budesonide was faster than the R epimer. BDP degraded completely within 2 h while its active metabolite 17-BMP was comparatively stable. In contrast to the results in the faecal inoculum, all molecules were stable in the simulated colonic fluid in the absence of human faeces (control). This study demonstrates that prednisolone, BDP and budesonide are completely metabolized in simulated human colonic fluid and confirms the role of colonic bacteria in the metabolism of corticosteroids., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Putative colonic release formulations of calcium (Ca)-alginate coated with chitosan containing two different actives, prednisolone and inulin, were prepared in three different sizes, beads (D50 = 2104 μm) and microparticles (D50 = 354 and 136 μm). The formulations were tested in standard phosphate buffer and biorelevant Krebs bicarbonate buffer at pH 7.4, and were further evaluated in the presence of the bacterium E. coli. Product yield and encapsulation were higher with prednisolone than with inulin. In Krebs bicarbonate buffer, a clear relationship between particle size and prednisolone release was observed. In contrast, release of inulin was independent of the particle size. In phosphate buffer, the particles eroded quickly, whereas in Krebs buffer, the particles swelled slowly. The difference in behavior can be attributed to the formation of calcium phosphate in the phosphate buffer medium, which in turn weakens the Ca-alginate matrix core. In the presence of E. coli, the formulations were fermented and the release of prednisolone was accelerated. In conclusion, the buffer media affects formulation behavior and drug release, with the bicarbonate media providing a better simulation of in vivo behavior. Moreover, the susceptibility of the formulations to bacterial action indicates their suitability as carriers for colonic drug delivery., (Copyright © 2013 Wiley Periodicals, Inc.)

We all respond differently to drugs. Personalised medicine aims to improve efficacy and reduce side effects, and efforts are being made to understand the physiological differences that underlie responses to drugs. Genetics, diet and disease state can be key; however, gender also plays an important role in pharmacokinetics, pharmacodynamics and drug toxicity. Differences in metabolism and clearance of drugs as a consequence of distinct hepatic and renal processes in males and females are now much better understood but little is known about gender differences in the gastrointestinal tract. As the recipient of all orally administered medications, differences at this level can have a major impact on drug delivery and bioavailability; yet these continue to be ignored and insufficiently studied in the context of drug disposition. The aim of this review is to highlight the known gender differences in gut physiology. Clinical case studies are presented, where possible, to illustrate the influence of these differences on drug disposition and gaps in current knowledge are highlighted to encourage further research in this area., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The use of compendial pH 6.8 phosphate buffer to assess dissolution of enteric coated products gives rise to poor in vitro-in vivo correlations because of the inadequacy of the buffer to resemble small intestinal fluids. A more representative and physiological medium, pH 6.8 bicarbonate buffer, was developed to evaluate the dissolution behaviour of enteric coatings. The bicarbonate system was evolved from pH7.4 Hanks balanced salt solution to produce a pH 6.8 bicarbonate buffer (modified Hanks buffer, mHanks), which resembles the ionic composition and buffer capacity of intestinal milieu. Prednisolone tablets were coated with a range of enteric polymers: hypromellose phthalate (HP-50 and HP-55), cellulose acetate phthalate (CAP), hypromellose acetate succinate (HPMCAS-LF and HPMCAS-MF), methacrylic acid copolymers (EUDRAGIT® L100-55, EUDRAGIT® L30D-55 and EUDRAGIT® L100) and polyvinyl acetate phthalate (PVAP). Dissolution of coated tablets was carried out using USP-II apparatus in 0.1M HCl for 2h followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, the various enteric polymer coated products displayed rapid and comparable dissolution profiles. In pH 6.8 mHanks buffer, drug release was delayed and marked differences were observed between the various coated tablets, which is comparable to the delayed disintegration times reported in the literature for enteric coated products in the human small intestine. In summary, the use of pH 6.8 physiological bicarbonate buffer (mHanks) provides more realistic and discriminative in vitro release assessment of enteric coated formulations compared to compendial phosphate buffer., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6) was recorded in the rabbits. The small intestinal pH was found in the range of 6.4-7.4 in the guinea pigs and rabbits, whereas lower pH (6.1-6.7) was recorded in the pig, which may have consequences for ionisable or pH responsive systems when tested in pig. A relatively lower pH than in the small intestine was found in the caecum (6.0-6.4) and colon (6.1-6.6) of the guinea pig, rabbit and the pig. The water content in the gastrointestinal tract of guinea pig, rabbit and pig was 51g, 153g and 1546g, respectively. When normalized to the body weight, the guinea pig, had larger amounts of water compared to the rabbit and the pig (guinea pig>rabbit>pig); in contrast, a reverse order was found when normalized to per unit length of the gut (guinea pig