Updated perspectives on the contribution of the microbiome to the pathogenesis of mucositis using the MASCC/ISOO framework.

Advances in the treatment of cancer have significantly improved mortality rates; however, this has come at a cost, with many treatments still limited by their toxic side effects. Mucositis in both the mouth and gastrointestinal tract is common following many anti-cancer agents, manifesting as ulcerative lesions and associated symptoms throughout the alimentary tract. The pathogenesis of mucositis was first defined in 2004 by Sonis, and almost 20 years on, the model continues to be updated reflecting ongoing research initiatives and more sophisticated analytical techniques. The most recent update, published by the Multinational Association for Supportive Care in Cancer and the International Society for Oral Oncology (MASCC/ISOO), highlights the numerous co-occurring events that underpin mucositis development. Most notably, a role for the ecosystem of microorganisms that reside throughout the alimentary tract (the oral and gut microbiota) was explored, building on initial concepts proposed by Sonis. However, many questions remain regarding the true causal contribution of the microbiota and associated metabolome. This review aims to provide an overview of this rapidly evolving area, synthesizing current evidence on the microbiota's contribution to mucositis development and progression, highlighting (i) components of the 5-phase model where the microbiome may be involved, (ii) methodological challenges that have hindered advances in this area, and (iii) opportunities for intervention.

The atypical antipsychotics lurasidone and olanzapine exert contrasting effects on the gut microbiome and metabolic function of rats.

BACKGROUND AND PURPOSE: Antipsychotics such as olanzapine are associated with significant metabolic dysfunction, attributed to gut microbiome dysbiosis. A recent notion that most psychotropics are detrimental to the gut microbiome has arisen from consistent findings of metabolic adverse effects. However, unlike olanzapine, the metabolic effects of lurasidone are conflicting. Thus, this study investigates the contrasting effects of olanzapine and lurasidone on the gut microbiome to explore the hypothesis of 'gut neutrality' for lurasidone exposure. EXPERIMENTAL APPROACH: Using Sprague-Dawley rats, the effects of olanzapine and lurasidone on the gut microbiome were explored. Faecal and blood samples were collected weekly over a 21-day period to analyse changes to the gut microbiome and related metabolic markers. KEY RESULTS: Lurasidone triggered no significant weight gain or metabolic alterations, instead positively modulating the gut microbiome through increases in mean operational taxonomical units (OTUs) and alpha diversity. This novel finding suggests an underlying mechanism for lurasidone's metabolic inertia. In contrast, olanzapine triggered a statistically significant decrease in mean OTUs, substantial compositional variation and a depletion in short-chain fatty acid abundance. Microbiome depletion correlated with metabolic dysfunction, producing a 30% increase in weight gain, increased pro-inflammatory cytokine expression, and increased blood glycaemic and triglyceride levels. CONCLUSION AND IMPLICATIONS: Our results challenge the notion that all antipsychotics disrupt the gut microbiome similarly and highlights the potential benefits of gut-neutral antipsychotics, such as lurasidone, in managing metabolic side effects. Further research is warranted to validate these findings in humans to guide personalised pharmacological treatment regimens for schizophrenia.

Contrasting the pharmacokinetic performance and gut microbiota effects of an amorphous solid dispersion and lipid nanoemulsion for a poorly water-soluble anti-psychotic.

Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable âˆ¼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a 'gut neutral' effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota - an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.

Targeting the gut microbiome to control drug pharmacomicrobiomics: the next frontier in oral drug delivery.

INTRODUCTION: The trillions of microorganisms that comprise the gut microbiome form dynamic bidirectional interactions with orally administered drugs and host health. These relationships can alter all aspects of drug pharmacokinetics and pharmacodynamics (PK/PD); thus, there is a desire to control these interactions to maximize therapeutic efficacy. Attempts to modulate drug-gut microbiome interactions have spurred advancements within the field of 'pharmacomicrobiomics' and are poised to become the next frontier of oral drug delivery. AREAS COVERED: This review details the bidirectional interactions that exist between oral drugs and the gut microbiome, with clinically relevant case examples outlining a clear motive for controlling pharmacomicrobiomic interactions. Specific focus is attributed to novel and advanced strategies that have demonstrated success in mediating drug-gut microbiome interactions. EXPERT OPINION: Co-administration of gut-active supplements (e.g. pro- and pre-biotics), innovative drug delivery vehicles, and strategic polypharmacy serve as the most promising and clinically viable approaches for controlling pharmacomicrobiomic interactions. Targeting the gut microbiome through these strategies presents new opportunities for improving therapeutic efficacy by precisely mediating PK/PD, while mitigating metabolic disturbances caused by drug-induced gut dysbiosis. However, successfully translating preclinical potential into clinical outcomes relies on overcoming key challenges related to interindividual variability in microbiome composition and study design parameters.

Who would be a pharmacist? A national representative cross-sectional survey of pharmacists and students to explore personality traits and associations with job satisfaction and career outlook.

OBJECTIVES: Pharmacists' response to practice change tends to range from apprehension to excitement. It is unknown if these varying responses are related to differing personality traits. This study aimed to describe the personality traits of Australian pharmacists, pharmacist interns and pharmacy students and any potential associations with their career satisfaction and/or outlook. METHODS: Australian pharmacy students, pre-registration and registered pharmacists were eligible to participate in the cross-sectional online survey that consisted of participant demographics, personality traits (using a reliable validated instrument, the Big Five Inventory) and career outlook statements (three optimistic and three pessimistic statements). Data were analysed descriptively and using linear regression. KEY FINDINGS: The 546 respondents scored highly for agreeableness (4.0 ± 0.6) and conscientiousness (4.0 ± 0.6) and lowest in neuroticism (2.8 ± 0.8)). Pessimistic career outlook statements were predominantly neutral or disagreement, in contrast to the responses to the optimistic outlook statements that were predominantly neutral or agreement. Just over half (198 out of 368, 53%) of the registered pharmacists stated that they intended to practice in the profession for more than 10 years. For pharmacists, age had significant positive associations with the three optimistic career outlook statements and significant inverse relationships with three pessimistic career outlook statements. Neuroticism had significant inverse associations with optimistic statements and positive relationships with pessimistic statements. CONCLUSIONS: All demographics tested was overall optimistic about the pharmacy profession with pharmacists scoring highly in agreeableness, conscientiousness and openness.

The impact of common pharmaceutical excipients on the gut microbiota.

INTRODUCTION: Increasing attention is being afforded to understanding the bidirectional relationships that exist between oral medications and the gut microbiota, in an attempt to optimize pharmacokinetic performance and mitigate unwanted side effects. While a wealth of research has investigated the direct impact of active pharmaceutical ingredients (APIs) on the gut microbiota, the interactions between inactive pharmaceutical ingredients (i.e. excipients) and the gut microbiota are commonly overlooked, despite excipients typically representing over 90% of the final dosage form. AREAS COVERED: Known excipient-gut microbiota interactions for various classes of inactive pharmaceutical ingredients, including solubilizing agents, binders, fillers, sweeteners, and color additives, are reviewed in detail. EXPERT OPINION: Clear evidence indicates that orally administered pharmaceutical excipients directly interact with gut microbes and can either positively or negatively impact gut microbiota diversity and composition. However, these relationships and mechanisms are commonly overlooked during drug formulation, despite the potential for excipient-microbiota interactions to alter drug pharmacokinetics and interfere with host metabolic health. The insights derived from this review will inform pharmaceutical scientists with the necessary design considerations for mitigating potential adverse pharmacomicrobiomic interactions when formulating oral dosage forms, ultimately providing clear avenues for improving therapeutic safety and efficacy.

Self-emulsifying drug delivery systems (SEDDS) disrupt the gut microbiota and trigger an intestinal inflammatory response in rats.

Self-emulsifying drug delivery systems (i.e. SEDDS, SMEDDS and SNEDDS) are widely employed as solubility and bioavailability enhancing formulation strategies for poorly water-soluble drugs. Despite the capacity for SEDDS to effectively facilitate oral drug absorption, tolerability concerns exist due to the capacity for high concentrations of surfactants (typically present within SEDDS) to induce gastrointestinal toxicity and mucosal irritation. With new knowledge surrounding the role of the gut microbiota in modulating intestinal inflammation and mucosal injury, there is a clear need to determine the impact of SEDDS on the gut microbiota. The current study is the first of its kind to demonstrate the detrimental impact of SEDDS on the gut microbiota of Sprague-Dawley rats, following daily oral administration (100 mg/kg) for 21 days. SEDDS comprising a lipid phase (i.e. Type I, II and III formulations according to the Lipid Formulation Classification Scheme) induced significant changes to the composition and diversity of the gut microbiota, evidenced through a reduction in operational taxonomic units (OTUs) and alpha diversity (Shannon's index), along with statistically significant shifts in beta diversity (according to PERMANOVA of multi-dimensional Bray-Curtis plots). Key signatures of gut microbiota dysbiosis correlated with the increased expression of pro-inflammatory cytokines within the jejunum, while mucosal injury was characterised by significant reductions in plasma citrulline levels, a validated biomarker of enterocyte mass and mucosal barrier integrity. These findings have potential clinical ramifications for chronically administered drugs that are formulated with SEDDS and stresses the need for further studies that investigate dose-dependent effects of SEDDS on the gastrointestinal microenvironment in a clinical setting.

NE-OBT and TFWT activity concentrations in wild plants in the vicinity of the PHWR nuclear power plant and control regions of the tropical monsoonal climatic region of the Indian subcontinent.

The results of the first detailed study, involving a large number of samples, on water equivalent factor (WEQp), non-exchangeable organically bound tritium (NE-OBT) and tissue free water tritium (TFWT) activity concentrations in predominant plant species of the tropical monsoonal climatic region, are presented. A total of 369 samples from the vicinity of the PHWR nuclear power plant (NPP) at Kaiga, West Coast of India, and 47 samples of the control region (region not affected by local anthropogenic sources) were analysed. The WEQp varied in the range of 0.347-0.666 L kg-1 with an overall mean value of 0.540 ± 0.045 L kg-1. The NE-OBT activity concentration varied in the range of <9.8-60.9 Bq L-1 of combustion water (mean = 24.6 ± 11.5 Bq L-1) and that of TFWT in the range of 9.2-60.5 Bq L-1 (mean = 30.7 ± 10.9 Bq L-1) in the vicinity of the NPP. Rigorous statistical analysis of the data confirmed that (i) the activity concentrations of both forms of tritium decreased with the increase in the distance between the sampling location and NPP, and beyond 10 km, it was similar to that of the control region, (ii) the incorporation of tritium released from the NPP into wild plant leaves is not species-dependent, (iii) the NE-OBT activity concentration in the 5-10 km zone exhibited a dependence on the prevailing wind regime with respect to the NPP, but not in the 2.3-5 km zone which suggests that the transport of tritium, released into the atmosphere as the gaseous effluent, through diffusion is a dominating factor governing its activity concentration in the 2.3-5 km zone. The NE-OBT to TFWT specific activity concentration ratio (R-value) had a mean value of 0.82 ± 0.27 (range: 0.38-1.64) for samples collected from the vicinity of the NPP and 1.93 ± 0.50 (range: 1.35-3.19) for the control region. Recording higher NE-OBT activity concentration and R-value at the control region highlights the necessity of detailed studies to understand the mechanism of NE-OBT partitioning in the terrestrial environment.

Optimisation of a batch thermal combustion method using a tube furnace oxidation system (pyrolyser) and LSC for carbon-14 determination in environmental matrices.

Accelerator mass spectrometry and benzene synthesis coupled with liquid scintillation spectrometry are often used for accurate measurements of 14C activity in the environmental matrices. Thermal oxidation is one of the methods employed for 14C determination in environmental matrices. In this method, the sample is oxidised at high temperature (600-900 °C) to convert carbon species to CO2 and trapped in an amine-based absorber for determining the activity in a liquid scintillation counting (LSC) system. In this study, the performance of a commercially available tube furnace system (pyrolyser), for batch combustion of samples, was evaluated for the determination of 14C specific activity in terrestrial biota samples. Significant improvements over the manufacturer specified method, which is primarily designed for analysis of samples with activity well above the environmental background level, was implemented to achieve accurate determination of 14C specific activity at ambient background level. In the improved method, the CO2 produced from the combustion of the sample was isolated from the combustion products through cryogenic trapping and then absorbed in the absorber (Carbo-Sorb E) through a simple off-line transfer process. This allowed (i) optimisation of CO2 absorption by the absorber (2.2477 g of CO2/10 mL), (ii) achieving good accuracy and precision in the measurements, and a minimum detectable activity value of 13 Bq kg-1C for a counting time of 300 min (7 Bq kg-1C for 1000 min), (iii) avoiding uncertainty associated with the determination of recovery of 14C in the combustion and trapping process, and (iv) elimination of the need for an independent determination of carbon content (%) for expressing the results in terms of 14C specific activity. The method is capable of yielding accurate results with a deviation of <2.4% from the target value for IAEA C3 quality assurance reference material (with a relative standard deviation of 1.40%, and relative error of 0.34%). The combined uncertainty (1σ) associated with the measurements was computed to be 3.4%. Upon optimisation, the suitability of the method for the determination of 14C specific activity in typical terrestrial biota samples of clean air region (region not affected by local anthropogenic sources) and for the quantification of a small increase in the 14C activity above ambient levels in the vicinity of a nuclear power plant is demonstrated.

Experimental database on water equivalent factor (WEQp) and organically bound tritium activity for tropical monsoonal climate region of South West Coast of India.

Tritium in the form of tritiated water is easily incorporated into terrestrial biota as tissue free water tritium (TFWT). A part of TFWT is converted into organically bound tritium (OBT) through metabolic processes. For the computation of NE-OBT activity (expressed as Bq L-1 of combustion water) in terrestrial plants, knowledge on 'water equivalent factor (WEQp)', defined as the volume of water produced from the combustion of 1 kg of the dry sample, is essential. On a global scenario, experimental data are not available on this parameter. This paper presents (i) a method for determination of WEQp by combustion method using a tube furnace system, (ii) a large database (N = 294) on WEQp parameter for samples of tropical monsoonal climate region of the Indian subcontinent, and (iii) NE-OBT activity in terrestrial biota samples (N = 186) collected from the vicinity of a PHWR nuclear power plant of India. The data generated in this study on WEQp serves for the validation of the data compiled in IAEA (2009 and 2010), which are estimated based on the hydrogen content of protein, fat and carbohydrates, and the fractions of protein, fat and carbohydrates. The WEQp varied in the ranges of 0.492-0.678 L kg-1 (GM = 0.569 Bq L-1, GSD = 1.06), 0.520-0.630 L kg-1 (GM = 0.557 Bq L-1, GSD = 1.02) 0.473-0.633 L kg-1 (GM = 0.562 Bq L-1, GSD = 1.02) for non-leafy vegetables, leafy vegetables, and fruits, respectively. A comparison between the experimental WEQp data with those compiled in the IAEA report revealed that the maximum deviation between the two data sets is <10%. The NE-OBT activity in the food samples collected from 2.3 to 20 km zone around NPP had a geometric mean (GM) value of 25.4 Bq L-1 (GSD = 1.6, N = 186). Variations in NE-OBT activity with different seasons of the year are discussed.

A WALK-IN TYPE CALIBRATION CHAMBER FACILITY FOR 222Rn MEASURING DEVICES AND INTER-COMPARISON EXERCISES.

A walk-in type 222Rn calibration chamber of volume 22.7 m3, which has traceability to international standards, is established at the Centre for Advanced Research in Environmental Radioactivity, Mangalore University, India. It has a human-machine interface communication system, a programmable logic controller and sensor feedback circuit for controlling and data acquisition of relative humidity (RH) and temperature (T). An innovative method for the generation of desired 222Rn concentration (a few hundred Bq m-3 up to about 36 kBq m-3) using soil gas as a source was adopted. Leak rates of 222Rn from the chamber for the mixing fan ON and OFF conditions were determined to be 0.0011 and 0.00018 h-1 respectively. With the exhaust system fully turned on, the maximum clearance rate of the chamber was 0.58 ± 0.07 h-1. Excellent spatial uniformity in 222Rn concentration in the chamber was confirmed (with a mean value of relative standard deviation < 12%) through measurements at 23 locations using CR-39 film-based passive devices. Demonstration of calibration applications was performed using charcoal canister and PicoRad vials as the 222Rn adsorption devices. The study shows that gamma spectrometry is a convenient alternative approach to liquid scintillation analysis of PicoRad vials for 222Rn measurement.

A study of temporal variations of 7Be and 210Pb concentrations and their correlations with rainfall and other parameters in the South West Coast of India.

As a part of establishing a regional database on natural radioactivity, the atmospheric concentrations of 210Pb and 7Be were measured over a three and half year period (2014-2017) in Mangalore and Kaiga in the South West Coast of India. A total of 99 air samples, collected in the different months of the year, were analysed in this study. The mean activity concentrations of 7Be and 210Pb were found to be 5.5 ±â€¯3.1 mBq m-3 and 1.1 ±â€¯0.73 mBq m-3, respectively. Both the radionuclides exhibited strong seasonal variations, with maximum concentration of 7Be occurring in the summer and that of 210Pb in the winter season. The concentration of both the radionuclides was minimum in the rainy season. Higher 210Pb concentration during winter was attributed to the ingression of continental air masses due to the wind regime from the North East. The sunspot number index of the solar activity also plays an important role in the increase and decrease of 7Be concentration in the air. A clear trend of increased and lowered concentration of 7Be with lower and higher solar activity (low and high sunspot number), respectively, in accordance with the 11-year solar cycle, was observed in this study. The temporal variation of PM10 concentration was also studied and it showed maximum value in the winter and minimum in the rainy season with an average of 56.9 µg m-3. Statistically significant positive correlation was observed between the PM10 and 210Pb activity concentration, whereas a weak correlation was observed between PM10 and 7Be. This is due to the fact that 7Be is largely associated with sub-micrometer size particles, whereas PM10 is contributed by larger sizes. The dependence of the activity concentrations of 7Be and 210Pb with meteorological parameters such as rainfall, temperature, and humidity was studied through linear regression analysis. A significant correlation was observed between 7Be and 210Pb concentrations with rainfall intensity (with identical correlation coefficients), which suggested that the removal mechanisms of these two radionuclides were similar. 7Be showed a strong correlation with temperature, whereas 210Pb with humidity. A comparison of the data obtained in the present study for the South West Coast of India with the global literature values of 7Be and 210Pb in aerosols showed that the values did not reflect the well-known latitudinal dependence of the 7Be tropospheric fluxes. Overall, the study provides an improved understanding of the correlation and variability of 210Pb and 7Be concentrations in the atmosphere in the South West Coast of India.