A randomised crossover design study comparing the pharmacokinetics and pharmacodynamics of two single Doses of ORal Aspirin (75 mg v 150mg) in pregnant women at risk of pre-eclampsia (DORA): implications on assessing aspirin response and patient adherence to therapy.

BACKGROUND: Pregnancy is associated with physiological changes that can alter the pharmacokinetic and pharmacodynamic profile of many drugs. Low-dose aspirin is used for pre-eclampsia (PE) prevention; however aspirin's pharmacokinetics and pharmacodynamics are poorly studied in pregnant women. OBJECTIVE: The aim of this study was to compare the pharmacodynamics of two common doses of aspirin (75 and 150 mg) used for PE prevention in high-risk women by examining their effect on thromboxane B2 (TbxB2) inhibition. A secondary objective sought to assess if salicylic acid could be used as means to evaluate adherence to aspirin. STUDY DESIGN: Fourteen pregnant women from a large maternity unit in England, eligible for prophylactic aspirin according to NICE guidance, were recruited into 2 x 2 randomised crossover trial. Blood samples were collected at baseline, 1, 2, 3, 4, 15, 16, 17, 18 and 19-hours post ingestion of either 75 or 150 mg of aspirin with a 7-day washout period. Plasma concentrations of salicylic acid (SA), the primary metabolite of aspirin, were determined using high performance liquid chromatography. Pharmacodynamic response to aspirin was assessed by measuring serum thromboxane B2 (TbxB2) concentrations by an enzyme-linked immunosorbent assay. Analyte data were compared using nonparametric test statistics for paired values (Wilcoxon Signed Rank Test) and areas under serum SA concentration versus time curve (AUC). Pharmacokinetic modelling was used to bridge the data arising from the overnight sampling break. The trial was registered with the ISRCTN (reg number ISRCTN14693054). RESULTS: A single dose of 150 mg of aspirin produced higher plasma exposure of SA in comparison to 75 mg (median SA AUC0-19 16.7 µg*h/ml (IQR 15.2-19.3) vs 6.8 µg*h/ml (IQR 6.1- 8.3), p<0.001). Pharmacokinetic models suggest that plasma SA concentrations could be detected above the maximum concentration recorded at baseline for the first 11 hours after 75 mg and for 12 hours after 150 mg aspirin dosing, providing a time frame to confirm recent aspirin ingestion. The 150 mg aspirin dose produced a greater normalised reduction in serum TbxB2 (median normalised reduction 95.7% (IQR 92.6%- 97.3%) than the 75 mg dose (median normalised reduction 84.6% (IQR 77.3-92.3%), p<0.007. CONCLUSION: Compared to the 75 mg dose, 150 mg of aspirin more effectively inhibits TbxB2, providing rationale for further investigation of effectiveness of higher doses for pre-eclampsia prevention. Despite limitations, measuring serum SA concentration could still be used in future models to test adherence if done within 11-12 hours after ingestion.

Errors associated with co-names of medicines: The nomenclature of combination medicinal products.

In comparison to the efforts required to bring a new drug or formulation to the clinic, bestowing a name on a medicine is relatively simple. However, if the name we choose causes confusion-by making its contents ambiguous or if it is too alike another drug-it can precipitate clinical errors. This prompted the World Health Organization to set up the International Nonproprietary Naming Committee in the 1970s to select unambiguous names for drugs. Unfortunately, multidrug products-which are becoming increasingly popular-do not fall under the remit of conventional International Non-proprietary Nomenclature. We have identified 26 combination formulations that have been historically named with the co-drug format in the United Kingdom. Most of them have also been prescribed in the United Kingdom in the past year, and although several of them are not prescribed very often, 11 were prescribed more than 2000 times. In this paper, we have explored the literature to identify prescribing errors with co-drug products and found several idiosyncrasies that have caused drug errors in the past. We advocate for a standard nomenclature (state the international nonproprietary name [INN] of each component followed by dose information in the x + y format) for these products on the box and in prescribing resources. We hope that this will enhance clarity and safety during prescribing and administration, particularly for high-volume drugs like paracetamol + codeine (co-codamol), amoxicillin + clavulanic acid (co-amoxiclav) and trimethoprim + sulfamethoxazole (co-trimoxazole).

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.

Cystine crystal nucleation and decay in the context of cystinuria pathogenesis and treatment.

Cystinuria is a rare disease which results in the precipitation of cystine in the renal filtrate, which may cause acute kidney injury due to mechanical trauma. In this work, we attempt to explore the origin of supersaturated cystine in this context to understand disease pathogenesis. This has enabled us to reproduce the clinical habit of cystine following a comprehensive study of cystine nucleation and growth in saline, artificial and human urine. Then, we describe the physical behaviour of these crystals in the presence of: cysteamine, sodium bicarbonate, captopril, tiopronin, penicillamine, glutathione and α-lipoic acid. Surprisingly, we observe that, in vitro, only cysteamine and saturated sodium bicarbonate dissolve crystals at a faster rate than saline, and that when solution pH is adjusted to physiological conditions, crystal dissolution for all agents is reduced to the rate of saline alone. We highlight that the conventional hypothesis of mixed disulphide formation in cysteamine is not the fastest mechanism of cystine dissolution, but rather that cystine dissolution (in the order of hours) is dominated by pH effects. This, combined with cysteamine's ability to take part in disulfide exchange reactions may explain cysteamine's effectiveness in this condition. Overall, our findings not only contribute to an understanding of cystinuria pathogenesis but also offer insights into how we should evaluate emerging treatments.

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.

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.

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.

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.