A method of diamorphine (heroin) administration for harm reduction.

As societal attitudes toward narcotics have changed, harm reduction strategies have emerged which make it safer to inject intravenous drugs. Diamorphine (heroin) is commonly sold as its free base-better known as brown-which has extremely poor aqueous solubility. As such, it needs to be chemically modified (cooked) to enable administration. Needle exchange programmes commonly supply citric or ascorbic acids which facilitate intravenous administration by increasing heroin solubility. If heroin users mistakenly add too much acid, the low solution pH can cause damage to their veins and, after repeated injury, could result in the loss of that injection site. Currently, advice cards supplied with these exchange kits suggest that the acid should be measured in pinches, which could result in considerable error. This work employs Henderson-Hasselbalch models to analyse the risk of venous damage by placing solution pH within the context of the buffer capacity of the blood. These models also highlight the significant risk of heroin supersaturation and precipitation within the vein, an event that has the potential to cause further harm to the user. This perspective closes with a modified administration method which could be included as part of a wider harm reduction package.

Synchronization of Cocrystal Dissolution and Drug Precipitation to Sustain Drug Supersaturation.

A graphical analysis of both drug and coformer concentrations contributed by dissolving cocrystals is presented in the context of a simplified cocrystal phase diagram. The conceptual basis and analysis identify parameters that control cocrystal dissolution-drug supersaturation-precipitation (DSP) behavior. The important effects of coformer concentration, cocrystal dose, and cocrystal solubility on drug supersaturation levels are demonstrated and quantified by the DSPindex. While the studies presented rely on high and nonstoichiometric coformer concentrations contributed by the dissolving cocrystals, the concepts and findings can answer the question of whether and how much coformer should be added to cocrystal dissolution media or formulations.

Comparing the efficacy of photodynamic and sonodynamic therapy in non-melanoma and melanoma skin cancer.

Sonodynamic therapy (SDT) involves the activation of a non-toxic sensitiser drug using low-intensity ultrasound to produce cytotoxic reactive oxygen species (ROS). Given the low tissue attenuation of ultrasound, SDT provides a significant benefit over the more established photodynamic therapy (PDT) as it enables activation of sensitisers at a greater depth within human tissue. In this manuscript, we compare the efficacy of aminolevulinic acid (ALA) mediated PDT and SDT in a squamous cell carcinoma (A431) cell line as well as the ability of these treatments to reduce the size of A431 ectopic tumours in mice. Similarly, the relative cytotoxic ability of Rose Bengal mediated PDT and SDT was investigated in a B16-melanoma cell line and also in a B16 ectopic tumour model. The results reveal no statistically significant difference in efficacy between ALA mediated PDT or SDT in the non-melanoma model while Rose Bengal mediated SDT was significantly more efficacious than PDT in the melanoma model. This difference in efficacy was, at least in part, attributed to the dark pigmentation of the melanoma cells that effectively filtered the excitation light preventing it from activating the sensitiser while the use of ultrasound circumvented this problem. These results suggest SDT may provide a better outcome than PDT when treating highly pigmented cancerous skin lesions.

An analysis of multidrug multicomponent crystals as tools for drug development.

In a typical tablet or capsule formulation, the active drug is often present as a crystalline solid. This solid emerges from the relationships between the individual atoms within the crystal, which confer a distinct set of physical properties. Then, it follows that if we modify the packing arrangement of the individual molecules within these crystals, we can modulate their properties. This can be achieved by crystal engineering. Crystal engineering has also seen teams arrange multiple drug molecules within the same crystal, resulting in dramatic improvements to drug properties in the lab. The success of drugs like SEGLENTIS® and Entresto® have revitalised interest in these forms, but controversy surrounding their translation has prompted this reconsideration of their clinical utility. I reflect on the current academic, clinical, and commercial interest in multidrug multicomponent crystals, drawing parallels with developments pre-Bragg, contributing to a nuanced understanding of the potential and limitations of crystal engineering in pharmaceutical applications.

Meta-analysis guided development of a standard artificial urine.

In this study, we present the first meta-analysis of human urine reported in the literature, drawing data from a total of 35 articles with a combined participant count of 14,021. Through this analysis, we have developed an artificial urine (AU) composition that can be adjusted within typical physiological parameters for in vitro applications. Our findings demonstrate the utility of this AU in determining the solubility of nitrofurantoin, particularly in the context of crystalluria. Notably, we observe that in saline, nitrofurantoin solubility, within the framework of its urinary pharmacokinetics, suggests a risk of crystalluria. However, in AU, this risk is mitigated due to complexation with urea. More broadly, we anticipate that our developed formulation will serve as a foundation for translational studies across biomedical and pharmaceutical sciences.

Harmonising nomenclature in pharmacopeial texts.

Nomenclature has always been a source of debate in the scientific literature. In the context of pharmaceutical regulation, varying interpretations of technical language can emerge due to philosophical or linguistic differences between two expert groups, which may undo efforts to harmonise regulatory approval mechanisms for new medicines. This letter describes three examples of divergence within pharmacopeial texts produced in the US, EU and Japan and suggests how these have emerged. Ultimately, I advocate for a consensus and an all agreed upon terminology that would be helpful for the global pharmaceutical industry, as opposed to many agreements between individual manufacturers and regulators of medicines, which may reintroduce variation in regulatory standards.

Pharmacy students' experience of technology-enhanced learning during the COVID-19 pandemic.

Background: With the advent of the COVID-19 pandemic, pharmacy students and educators experienced an abrupt shift as programmes that were previously taught exclusively in-person were then predominantly taught online. This sudden change provided little time for students to prepare for the new learning environment. Objectives: The study objective was to explore pharmacy students' experiences of technology-enhanced learning during the COVID-19 pandemic. Methods: A cross-sectional survey was developed and distributed by email to all 3rd year (N = 76) and 4th year (N = 68) pharmacy students undertaking an MPharm programme in an Irish university. Results: A total of 32 responses were collected, including 20 third year and 12 fourth year pharmacy students (response rates of 26.3% and 17.6%, respectively). The majority of respondents reported good or very good internet speed (71%) and stability (59%). Almost all were confident or very confident using Canvas (97%) prior to the onset of online learning. Respondents preferred engaging with other students in-person rather than online for coursework (68.8%) and learning new material (56.3%). Students favoured face-to-face delivery, with a recording of the session available online afterwards, for lectures (68.8%), workshops (50%) and tutorials (56.3%). Analysis of free-text comments indicates that respondents used recorded content to support exam revision and that a key drawback of online learning was social isolation. Implications: Pharmacy students favoured a blended learning approach, with in-person learning being recorded to support study and revision. Students' experience of TEL during the pandemic should be considered in the development and ongoing review of pharmacy programmes.

Tuning the Pharmacokinetic Performance of Quercetin by Cocrystallization.

Quercetin (QUE) is a widely studied nutraceutical with a number of potential therapeutic properties. Although QUE is abundant in the plant kingdom, its poor solubility (≤20 µg/mL) and poor oral bioavailability have impeded its potential utility and clinical development. In this context, cocrystallization has emerged as a useful method for improving the physicochemical properties of biologically active molecules. We herein report a novel cocrystal of the nutraceutical quercetin (QUE) with the coformer pentoxifylline (PTF) and a solvate of a previously reported structure between QUE and betaine (BET). We also report the outcomes of in vitro and in vivo studies of QUE release and absorption from a panel of QUE cocrystals: betaine (BET), theophylline (THP), l-proline (PRO), and novel QUEPTF. All cocrystals were found to exhibit an improvement in the dissolution rate of QUE. Further, the QUE plasma levels in Sprague-Dawley rats showed a 64-, 27-, 10- and 7-fold increase in oral bioavailability for QUEBET·MeOH, QUEPTF, QUEPRO, and QUETHP, respectively, compared to QUE anhydrate. We rationalize our in vivo and in vitro findings as the result of dissolution-supersaturation-precipitation behavior.

Alkalising agents in urinary tract infections: theoretical contraindications, interactions and synergy.

Introduction: Alkalising agents have the potential to enhance the efficacy of many antimicrobial agents used in the treatment of Urinary Tract Infections; they also have the potential to cause significant patient harm if used incorrectly. This work seeks to illustrate and quantify these risks and synergies by modelling drug solubility and supersaturation against pharmacokinetic data for commonly used antibiotic agents. Methods: Solubility-pH relationships are employed to quantify the crystalluria risk for compounds which may be reasonably expected to be co-prescribed-or co-administered-with urinary alkalisers (amoxicillin, nitrofurantoin, trimethoprim, sulfamethoxazole and ciprofloxacin). These results are correlated against reports of crystalluria in the literature and in the EU Adverse Drug Reaction database. Results and Discussion: We find a correlation between the maximum theoretical supersaturation attainable and crystalluria reports for sulfamethoxazole, amoxicillin and ciprofloxacin. Shifts in urine pH which can be induced by alkalising agents may produce supersaturated states (and thus induce crystalluria) and may also affect antimicrobial efficacy. The importance of employing biorelevant media to improve predictive capacity of this analysis is also discussed. Conclusion: Despite their widespread use, alkalising agents have significant effects on the pharmacokinetics of the most common drugs used to treat UTIs. With self-care set to increase, all OTC products should be critically re-evaluated to ensure patient safety, particularly within contexts where healthcare professionals are not involved in treatment selection. This analysis suggests a need for consistency across patient and healthcare professional documents to improve clarity. Plain Language Summary OTC Alkalising agents need additional warning information Alkalising agents (e.g., sodium and potassium citrate) can be purchased in many locations without the supervision of a healthcare professional.Although they are thought as innocuous agents, alkalisers can greatly influence the way some antibiotics behave in the body and this can potentially cause patient harm.This work illustrates these risks and synergies by modelling drug solubility and supersaturation against pharmacokinetic data for commonly used antibiotic agents.Manufacturers and patients should be aware that the use of alkalising agents with these drugs (and potentially many others) may cause unintended consequences.

Providing pharmaceutical care remotely through medicines delivery services in community pharmacy.

Background: The delivery of pharmaceutical care - and what that means - has been at the centre of many transformations of the pharmacy profession in the last century. Today, the exponential growth of pharmacies which provide pharmaceutical care exclusively online has placed increased scrutiny on the quality of the care they provide. Aim: As more patients are managed by remote pharmaceutical care (via medicines delivery services), we sought to critically evaluate this service to identify new research directions. Methods: The COnsolidated criteria for REporting Qualitative research and Standards for reporting qualitative research guideline provided the methodological framework throughout this process. Results: We reveal that although home delivery services ensure that many patients have access to their medicines, it may reduce time available to provide comprehensive pharmaceutical care, particularly in traditional brick-and-mortar pharmacies. Conclusion: We highlight a critical need for research in this area and suggest a variety of research directions: is remote pharmaceutical care a matter of convenience? Does remote pharmaceutical care help patients adhere to their medicines? How do digital health innovations impact care across patient demographics? What does comprehensive pharmaceutical care mean for patients?

Hydroxychloroquine Does Not Function as a Direct Zinc Ionophore.

Drug-mediated correction of abnormal biological zinc homeostasis could provide new routes to treating neurodegeneration, cancer, and viral infections. Designing therapeutics to facilitate zinc transport intracellularly is hampered by inadequate concentrations of endogenous zinc, which is often protein-bound in vivo. We found strong evidence that hydroxychloroquine, a drug used to treat malaria and employed as a potential treatment for COVID-19, does not bind and transport zinc across biological membranes through ionophoric mechanisms, contrary to recent claims. In vitro complexation studies and liposomal transport assays are correlated with cellular zinc assays in A549 lung epithelial cells to confirm the indirect mechanism of hydroxychloroquine-mediated elevation in intracellular zinc without ionophorism. Molecular simulations show hydroxychloroquine-triggered helix perturbation in zinc-finger protein without zinc chelation, a potential alternative non-ionophoric mechanism.

Modulation of the powder properties of lamotrigine by crystal forms.

The mechanical properties of powders determine the ease of manufacture and ultimately the quality of the oral solid dosage forms. Although poor mechanical properties of an active pharmaceutical ingredient (API) can be mitigated by using suitable excipients in a formulation, the effectiveness of that approach is limited for high dose drugs or multidrug tablets. In this context, improving the mechanical properties of the APIs through solid form optimisation is a good strategy to address such a challenge. This work explores the powder and tableting properties of various lamotrigine (LAM) solid forms with the aim to facilitate direct compression by overcoming the poor tabletability of LAM. The two drug-drug crystals of LAM with nicotinamide and valproic acid demonstrate superior flowability and tabletability over LAM. The improved powder properties are rationalised by structure analysis using energy framework, scanning electron microscopy, and Heckel analysis.

Investigating Structural Property Relationships to Enable Repurposing of Pharmaceuticals as Zinc Ionophores.

The importance of zinc in biology has gained greater recognition in recent years due to its essential contributions to the function of many endogenous enzymes. Disruption of zinc homeostasis may be useful in treating pathological conditions, such as Alzheimer's, and for antiviral purposes. Despite the growth of knowledge and increased interest in zinc, little is known about the structure and function of zinc ionophores. In this study we analyse the Cambridge Structural Database and solution complexation studies found in the literature to identify key functional groups which may confer zinc ionophorism. Pharmaceuticals, nutraceuticals and amino acids with these functionalities were selected to enable us to explore the translatability of ionophoric activity from in vitro assays to cellular systems. We find that although certain species may complex to zinc in the solid and solution states, and may carry ions across simple membrane systems, this does not necessarily translate into ionophoric activity. We propose that the CSD can help refine key functionalities but that ionophoric activity must be confirmed in cellular systems.

Formulating a Stable Mannitol Infusion while Maintaining Hyperosmolarity.

Mannitol infusion is commonly used in the treatment of intracranial hypertension following traumatic brain injury. It has long been known to have stability issues, specifically, mannitol recrystallises from solutions greater than 10% w/v in ambient conditions. This can happen at any time, whether on the pharmacy shelf or during a medical procedure. This study describes the stability limits of 20% w/v mannitol infusion (the most common strength used clinically) and proposes a number of safer, stable and tuneable hyperosmotic formulations of mannitol in combination with clinically acceptable osmotic agents (NaCl, sorbitol and glycerol).

More than coffee - a World Café to explore enablers of pharmacy practice research.

BACKGROUND: Pharmacists are in demand now more than ever to provide high-quality expertise about the effectiveness, safety and use of medications. Amidst an increasingly complex and costly healthcare system, policy makers need robust evidence to justify public spending on pharmacy services. Research on the impact of existing and emerging pharmacy practices is required. OBJECTIVE: To explore barriers and opportunities to enhance research among pharmacists in Ireland utilising a World Café methodology. METHODS: A pharmacy research discussion day was held in November 2018, open to all pharmacists in Ireland. A World Café methodology was utilised as a mechanism to facilitate group discussions about pharmacy practice research. RESULTS: Discussions with 63 attendees identified four themes and seventeen subthemes. The four themes were challenges undertaking research, research motivations, leadership and training. Subthemes included robust evidence, clinical, economic and societal outcomes, alignment with national and international health system priorities, need for incentives from professional training bodies, competitive business model and embed within schools of pharmacy. CONCLUSIONS: The most commonly discussed barriers inhibiting research were workload, technology limitations and financial considerations. Organisational leadership to prioritise and coordinate research efforts, training to build research capacity, building on existing examples of excellence and initiation of bottom-up community-based research projects were identified in our study as opportunities to enhance pharmacist involvement in research and ultimately patient health outcomes.

Inhaled hydroxychloroquine to improve efficacy and reduce harm in the treatment of COVID-19.

Current formulations and dose regimens of hydroxychloroquine (HCQ) put patients at risk of harm. An analysis of clinical trials registered on ClinicalTrials.gov revealed that this may continue as many studies combine HCQ with agents that prolong the QT interval. Further, almost all of the trials registered do not consider dosage adjustment in the elderly, a patient population most likely to require HCQ treatment. Here we describe an inhaled formulation of HCQ which has passed safety studies in clinical trials for the treatment of asthma and discuss how this approach may reduce side-effects and improve efficacy. As this simple formulation progressed to phase II studies, safety data can be used to immediately enable phase II trials in COVID-19.

Pharmaceutical cocrystals: from serendipity to design to application.

The field of pharmaceutical cocrystals has reached a tipping point, particularly because cocrystals can improve the physicochemical properties of drugs without compromising their therapeutic benefit. Accounts of cocrystal investigations in the literature started in earnest in 2003 and patent applications soon followed. The frequency of both has steadily accelerated, demonstrating an enhanced understanding of the design, characterisation, and manufacture of cocrystals and heightened interest from industry. Indeed, there were four new product approvals from 2014 to 2017 and more are in the pipeline. Here, we review all marketed drug products that are based upon pharmaceutical cocrystal drug substances, starting with the first recorded example, Beta-Chlor® in 1963, with a particular emphasis on their discovery, rationale for use, and market impact.

Maximising success in multidrug formulation development: A review.

Patient compliance will soon become one of the most critical challenges in modern healthcare. Due in part to our aging population, the rise in the number of chronic conditions will cause increasing stress on global healthcare systems, magnifying current problems. The solutions employed to improve compliance have failed to deliver and the medical community have turned to Multidrug Formulations (MDFs), to provide an answer. This work summarises key challenges and subsequent solutions developed by formulation scientists when designing new MDFs, examining their rationale and highlighting successes to-date. Current and emerging MDF strategies are reviewed alongside a discussion of how the scientific community can bring these ideas from the benchtop to the clinic. Examples have been highlighted where teams have delivered scientific novelty, but a lack of clinical appreciation reduces their likelihood of patient impact. Potential gaps within the literature are identified where new, novel or modernised approaches could make a significant impact on patients.