Customizable orodispersible films: Inkjet printing and data matrix encoding for personalized hydrocortisone dosing.

The aim of this study was to exploit the versatility of inkjet printing to develop flexible doses of drug-loaded orodispersible films that encoded information in a data matrix pattern, and to introduce a specialised data matrix-generator software specifically focused on the healthcare sector. Pharma-inks (drug-loaded inks) containing hydrocortisone (HC) were developed and characterised based on their rheological properties and drug content. Different strategies were investigated to improve HC solubility: formation of ß-cyclodextrin complexes, Soluplus® based micelles, and the use of co-solvent systems. The software automatically adapted the data matrix size and identified the number of layers for printing. HC content deposited in each film layer was measured, and it was found that the proportion of co-solvent used directly affected the drug solubility and simultaneously played a role in the modification of the viscosity and surface tension of the inks. The formation of ß-cyclodextrin complexes improved the drug quantity deposited in each layer. On the contrary, micelle-based inks were not suitable for printing. Orodispersible films containing flexible and low doses of personalised HC were successfully prepared, and the development of a code generator software oriented to medical use provided an additional, innovative, and revolutionary advantage to personalised medicine safety and accessibility.

Bioprospection of Phytotoxic Plant-Derived Eudesmanolides and Guaianolides for the Control of Amaranthus viridis, Echinochloa crus-galli, and Lolium perenne Weeds.

The phytotoxicities of a selection of eudesmanolides and guaianolides, including natural products and new derivatives obtained by semisynthesis from plant-isolated sesquiterpene lactones, were evaluated in bioassays against three weeds of concern in agriculture (Amaranthus viridis L., Echinochloa crus-galli L., and Lolium perenne L.). Both eudesmanolides and guaianolides were active against the root and shoot growth of all the species, with the eudesmanolides generally showing improved activities. The IC50 values obtained for the herbicide employed as positive control (on root and shoot growth, respectively, A. viridis: 27.8 and 85.7 µM; E. crus-galli: 167.5 and 288.2 µM; L. perenne: 99.1 and 571.4 µM) were improved in most of the cases. Structure-activity relationships were discussed, finding that hydroxylation of the A-ring and C-13 as well as the position, number, and orientation of the hydroxyl groups and the presence of an unsaturated carbonyl group can significantly influence the level of phytotoxicity. γ-Cyclocostunolide was the most active compound in the series, followed by others such as dehydrozaluzanin C and α-cyclocostunolide (outstanding their IC50 values on A. viridis)─natural products that can therefore be suggested as models for herbicide development if further research indicates effectiveness on a larger scale and environmental safety in ecotoxicological assessments.

Simultaneous fabrication of multiple tablets within seconds using tomographic volumetric 3D printing.

3D printing is driving a shift in patient care away from a generalised model and towards personalised treatments. To complement fast-paced clinical environments, 3D printing technologies must provide sufficiently high throughputs for them to be feasibly implemented. Volumetric printing is an emerging 3D printing technology that affords such speeds, being capable of producing entire objects within seconds. In this study, for the first time, rotatory volumetric printing was used to simultaneously produce two torus- or cylinder-shaped paracetamol-loaded Printlets (3D printed tablets). Six resin formulations comprising paracetamol as the model drug, poly(ethylene glycol) diacrylate (PEGDA) 575 or 700 as photoreactive monomers, water and PEG 300 as non-reactive diluents, and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) as the photoinitiator were investigated. Two printlets were successfully printed in 12 to 32 s and exhibited sustained drug release profiles. These results support the use of rotary volumetric printing for efficient and effective manufacturing of various personalised medicines at the same time. With the speed and precision it affords, rotatory volumetric printing has the potential to become one of the most promising alternative manufacturing technologies in the pharmaceutical industry.

Host-guest complexation of phthalimide-derived strigolactone mimics with cyclodextrins. Application in agriculture against parasitic weeds.

Parasitic weeds are noxious plants that damage crops of economic relevance, especially in Mediterranean and African countries. The strategy of suicidal germination was proposed to deal with this plague by using seed germination inducers that work as a pre-emergence herbicide and reduce the parasitic seed load before sowing. N-Substituted phthalimides with a furanone ring were found to be efficient in inducing the germination of Phelipanche ramosa and Orobanche cumana, two of the most problematic parasitic weeds of crops. However, the solubility of these compounds in water is low. A strategy for enhancing their aqueous solubility is the synthesis of host-guest complexes with cyclodextrins. Three bioactive phthalimide-lactones (PL01, PL04, and PL07) were selected and studied to form complexes of increased water solubility with α-, ß-, HP-ß-, and γ-cyclodextrin. The complexes obtained by the coprecipitation method, with increased aqueous solubility (up to 3.8 times), were studied for their bioactivity and they showed similar or slightly higher bioactivity than free phthalimide-lactones, even without the addition of organic solvents. A theoretical study using semiempirical calculations of molecular models including a solvation system confirmed the physicochemical empirical results. These results demonstrated that cyclodextrins can be used to improve the physicochemical and biological properties of parasitic seed germination inducers.

Evaluation of the phytotoxic and antifungal activity of C17 -sesquiterpenoids as potential biopesticides.

BACKGROUND: Natural products are a promising source for the development of new pesticides with alternative mechanisms of action. In this study, we evaluated the phytotoxic and antifungal activity of a novel family of natural C17 -sesquiterpenoids and performed a study of the effect caused by the elimination of the α-methylene-γ-butyrolactone system and its importance to their biological activity. RESULTS: Many tested compounds exhibited a strong phytotoxic activity. Lappalone and pertyolide B were the most potent molecules from the tested group. Lappalone displayed a strong inhibition profile against selected weed species, reaching a half-maximal inhibitory concentration (IC50 ) value of 5.0 µm against Echinochloa crus-galli L. shoot and 5.7 µm against the germination rate of Amaranthus viridis L., as well as a good stimulation of the germination of Phelipanche ramosa L. Pertyolide B demonstrated excellent inhibition against Amaranthus viridis L. (IC50 : 56.7, 70.3 and 24.0 µm against the root and shoot growth, and germination rate, respectively) and Allium cepa L. (representative of the Liliaceae family, with IC50 values of 25.3 and 64.4 µm against root and shoot growth). Regarding the antifungal activity, pertyolide B presented significant activity against Colletotrichum fragareae and Fusarium oxysporum with a minimum inhibitory concentration of 6.6 µg µL-1 . CONCLUSION: The bioassays revealed that frequently the presence of the α-methylene-γ-butyrolactone system is not essential for the bioactivities of sesquiterpene lactones, and suggest that C17 -sesquiterpenoids may function through a different mechanism of action not related to the widely assumed Michael addition. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Encapsulation of Cynara Cardunculus Guaiane-type Lactones in Fully Organic Nanotubes Enhances Their Phytotoxic Properties.

The encapsulation of bioactive natural products has emerged as a relevant tool for modifying the poor physicochemical properties often exhibited by agrochemicals. In this regard, natural guaiane-type sesquiterpene lactones isolated from Cynara cardunculus L. have been encapsulated in a core/shell nanotube@agrochemical system. Monitoring of the F and O signals in marked sesquiterpenes confirmed that the compound is present in the nanotube cavity. These structures were characterized using scanning transmission electron microscopy-X-ray energy-dispersive spectrometry techniques, which revealed the spatial layout relationship and confirmed encapsulation of the sesquiterpene lactone derivative. In addition, biological studies were performed with aguerin B (1), cynaropicrin (2), and grosheimin (3) on the inhibition of germination, roots, and shoots in weeds (Phalaris arundinacea L., Lolium perenne L., and Portulaca oleracea L.). Encapsulation of lactones in nanotubes gives better results than those for the nonencapsulated compounds, thereby reinforcing the application of fully organic nanotubes for the sustainable use of agrochemicals in the future.

Strigolactones: New players in the nitrogen-phosphorus signalling interplay.

Nitrogen (N) and phosphorus (P) are among the most important macronutrients for plant growth and development, and the most widely used as fertilizers. Understanding how plants sense and respond to N and P deficiency is essential to optimize and reduce the use of chemical fertilizers. Strigolactones (SLs) are phytohormones acting as modulators and sensors of plant responses to P deficiency. In the present work, we assess the potential role of SLs in N starvation and in the N-P signalling interplay. Physiological, transcriptional and metabolic responses were analysed in wild-type and SL-deficient tomato plants grown under different P and N regimes, and in plants treated with a short-term pulse of the synthetic SL analogue 2'-epi-GR24. The results evidence that plants prioritize N over P status by affecting SL biosynthesis. We also show that SLs modulate the expression of key regulatory genes of phosphate and nitrate signalling pathways, including the N-P integrators PHO2 and NIGT1/HHO. The results support a key role for SLs as sensors during early plant responses to both N and phosphate starvation and mediating the N-P signalling interplay, indicating that SLs are involved in more physiological processes than so far proposed.

Methoxyflurane in Non-Life-Threatening Traumatic Pain-A Retrospective Observational Study.

Pain management is a key issue in prehospital trauma. In Switzerland, paramedics have a large panel of analgesic options. Methoxyflurane was recently introduced into Switzerland, and the goal of this study was to describe both the effect of this medication and the satisfaction of its use. This was a retrospective cohort study, performed in one emergency ambulance service. It included adult patients with traumatic pain and a self-assessment of 3 or more on the visual analogue scale or verbal numerical rating scale. The primary outcome was the reduction in pain between the start of the care and the arrival at the hospital. Secondary outcomes included successful analgesia and staff satisfaction. From December 2018 to 4 June to October 2020, 263 patients were included in the study. Most patients had a low prehospital severity score. The median pain at arrival on site was 8 and the overall decrease in pain observed was 4.2 (95% CI 3.9-4.5). Regarding secondary outcomes, almost 60% had a successful analgesia, and over 70% of paramedics felt satisfied. This study shows a reduction in pain, following methoxyflurane, similar to outcomes in other countries, as well as the attainment of a satisfactory level of pain reduction, according to paramedics, with the advantage of including patients in their own care.

Smartphone-enabled 3D printing of medicines.

3D printing is a manufacturing technique that is transforming numerous industrial sectors, particularly where it is key tool in the development and fabrication of medicinees that are personalised to the individual needs of patients. Most 3D printers are relatively large, require trained operators and must be located in a pharmaceutical setting to manufacture dosage forms. In order to realise fully the potential of point-of-care manufacturing of medicines, portable printers that are easy to operate are required. Here, we report the development of a 3D printer that operates using a mobile smartphone. The printer, operating on stereolithographic principles, uses the light from the smartphone's screen to photopolymerise liquid resins and create solid structures. The shape of the printed dosage form is determined using a custom app on the smartphone. Warfarin-loaded Printlets (3D printed tablets) of various sizes and patient-centred shapes (caplet, triangle, diamond, square, pentagon, torus, and gyroid lattices) were successfully printed to a high resolution and with excellent dimensional precision using different photosensitive resins. The drug was present in an amorphous form, and the Printlets displayed sustained release characterises. The promising proof-of-concept results support the future potential of this compact, user-friendly and interconnected smartphone-based system for point-of-care manufacturing of personalised medications.

Synthesis of Pertyolides A, B, and C: A Synthetic Procedure to C17-Sesquiterpenoids and a Study of Their Phytotoxic Activity.

C17-sesquiterpenoids are a group of natural products that have been recently discovered. These compounds have the peculiarity of lacking the α,ß-methylene butyrolactone system, which is known to be quite relevant for many of the biological activities reported for sesquiterpene lactones. Unfortunately, the biological interest of C17-sesquiterpenoids has not been studied in-depth, mainly due to the poor isolation yields in which they can be obtained from natural sources. Therefore, in order to allow a deeper study of these novel molecules, we have worked out a synthetic pathway that provides C17-sesquiterpenoids in enough quantities from easily accessible sesquiterpene lactones to enable a more thorough investigation of their bioactivities. With this synthesis method, we have successfully synthesized, for the first time, three natural C17-sesquiterpenoids, pertyolides A, B, and C, with good overall yields. Furthermore, we have also evaluated their phytotoxicity against etiolated wheat coleoptiles and corroborated that pertyolides B and C present strong phytotoxic activity.

Search of New Tools for Weed Control Using Piptocarpha rotundifolia, a Dominant Species in the Cerrado.

Piptocarpha rotundifolia (Less.) Baker stands out as one of the species with the highest frequency, density, and relative dominance in the Cerrado formations. However, no phytochemical studies have been carried out with this species to date. The aim of this study was to evaluate the phytotoxic activity of P. rotundifolia leaves in the search of new environmentally friendly tools for weed control. Thus, a wheat coleoptile and phytotoxic bioassay, using relevant agricultural weeds, was used to identify the most active extracts and fractions. The subsequent purification process allowed the isolation of 11 compounds, the phytotoxicity of which was evaluated in terms of wheat coleoptile elongation and with the most sensitive weeds. Piptocarphin A was found to be the major compound and the most active. To confirm its phytotoxic potential, the effect on Ipomea grandifolia grown in a hydroponic culture and on metaxylem cells was studied. The results obtained in this study demonstrate that the inhibitory activity displayed by P. rotundifolia leaf extract is mainly due to the presence of piptocarphin A. The phytotoxicity shown by P. rotundifolia leaf extract, and the isolated compounds, on weeds could provide new tools for weed control in agricultural fields.

Pharmacological Activities of Aminophenoxazinones.

Aminophenoxazinones are degradation products resulting from the metabolism of different plant species, which comprise a family of natural products well known for their pharmacological activities. This review provides an overview of the pharmacological properties and applications proved by these compounds and their structural derivatives during 2000-2021. The bibliography was selected according to our purpose from the references obtained in a SciFinder database search for the Phx-3 structure (the base molecule of the aminophenoxazinones). Compounds Phx-1 and Phx-3 are among the most studied, especially as anticancer drugs for the treatment of gastric and colon cancer, glioblastoma and melanoma, among others types of relevant cancers. The main information available in the literature about their mechanisms is also described. Similarly, antibacterial, antifungal, antiviral and antiparasitic activities are presented, including species related directly or indirectly to significant diseases. Therefore, we present diverse compounds based on aminophenoxazinones with high potential as drugs, considering their levels of activity and few adverse effects.

Effect of Shading on the Sesquiterpene Lactone Content and Phytotoxicity of Cultivated Cardoon Leaf Extracts.

The work described here follows on from a previous study focused on the influence of the genotype and harvest time on the sesquiterpene lactone (STL) profile of Cynara cardunculus L. leaf extracts. The aim of this study was to investigate the effect that 60% plant shading in cultivated cardoon (C. cardunculus var. altilis) leaf extracts harvested in winter and spring had on the composition of STLs and the phytotoxicity. The phytotoxicity of leaf extracts was evaluated by assessing wheat coleoptile elongation along with seed germination and the root and shoot length of the weeds Amaranthus retroflexus L. and Portulaca oleracea L. Shading increased the production of STLs in spring, and this effect correlated positively with the phytotoxic activity. The induction of shading can therefore be used to modulate STL concentrations and their phytotoxic potential in cultivated cardoon leaves for industrial applications.

Synthesis of Active Strigolactone Analogues Based on Eudesmane- and Guaiane-Type Sesquiterpene Lactones.

Strigolactones are natural products that are exuded by plants and stimulate parasitic weed germination. Their use in herbicides is limited since they are produced in small quantities, but the synthesis of bioactive analogues provides an alternative source. In this work, eleven analogues have been synthesized. Among them, nine compounds belong to a novel family named eudesmanestrigolactones. The procedure is short (3-6 steps), the starting materials are isolated on a multigram scale, and global yields are up to 8%, which significantly enhance isolated yields. In bioassay, the compounds germinated high percentages of Phelipanche ramosa, Orobanche cumana, and Orobanche crenata seeds, even at nanogram doses (100 nM). Bioactivity was stereochemistry-dependent, and it was discussed in terms of the presence and geometry of the enol ether, orientation of the butenolide, and unsaturation of ring A. The reported compounds provide a set of readily obtained allelochemicals with potential applications as preventive herbicides.

Phytochemical Study of Safflower Roots (Carthamus tinctorius) on the Induction of Parasitic Plant Germination and Weed Control.

Weeds have been a major threat in agriculture for several generations as they lead to decreases in productivity and cause significant economic losses. Parasitic plants are a specific type of weed causing losses in crops of great relevance. A new strategy has emerged in the fight against parasitic plants, which is called 'suicidal germination' or the 'honey-pot strategy'. Regarding the problem of weed control from an ecological point of view, it is interesting to investigate new natural compounds with allelopathic activity with the aim of developing new natural herbicides that can inhibit the growth of weeds without damaging the environment. Safflower crops have been affected by parasitic plants and weeds and, as a consequence, the secondary metabolites exuded by safflower roots have been studied. The sesquiterpene lactone dehydrocostuslactone was isolated and characterised, and the structurally related costunolide was identified by UHPLC-MS/MS in safflower root exudates. These sesquiterpene lactones have been shown to stimulate germination of Phelipanche ramosa and Orobanche cumana seeds. In addition, these compounds were phytotoxic on three important weeds in agriculture, namely Lolium perenne, Lolium rigidum and Echinochloa crus-galli. The exudation of the strigolactones solanacol and fabacyl acetate have also been confirmed by UHPLC-MS/MS. The study reported here contributes to our knowledge of the ecological role played by some secondary metabolites. Moreover, this knowledge could help identify new models for the development of future agrochemicals based on natural products.

Association between boarding in the emergency department and in-hospital mortality: A systematic review.

IMPORTANCE: Boarding in the emergency department (ED) is a critical indicator of quality of care for hospitals. It is defined as the time between the admission decision and departure from the ED. As a result of boarding, patients stay in the ED until inpatient beds are available; moreover, boarding is associated with various adverse events. STUDY OBJECTIVE: The objective of our systematic review was to determine whether ED boarding (EDB) time is associated with in-hospital mortality (IHM). METHODS: A systematic search was conducted in academic databases to identify relevant studies. Medline, PubMed, Scopus, Embase, Cochrane, Web of Science, Cochrane, CINAHL and PsychInfo were searched. We included all peer-reviewed published studies from all previous years until November 2018. Studies performed in the ED and focused on the association between EDB and IHM as the primary objective were included. Extracted data included study characteristics, prognostic factors, outcomes, and IHM. A search update in PubMed was performed in May 2019 to ensure the inclusion of recent studies before publishing. RESULTS: From the initial 4,321 references found through the systematic search, the manual screening of reference lists and the updated search in PubMed, a total of 12 studies were identified as eligible for a descriptive analysis. Overall, six studies found an association between EDB and IHM, while five studies showed no association. The last remaining study included both ICU and non-ICU subgroups and showed conflicting results, with a positive association for non-ICU patients but no association for ICU patients. Overall, a tendency toward an association between EDB and IHM using the pool random effect was observed. CONCLUSION: Our systematic review did not find a strong evidence for the association between ED boarding and IHM but there is a tendency toward this association. Further well-controlled, international multicenter studies are needed to demonstrate whether this association exists and whether there is a specific EDB time cut-off that results in increased IHM.

[Acute pain management†: the role of inhaled methoxyflurane in clinical practice]. / Traitement de la douleur aiguë†: la place du méthoxyflurane inhalé dans la pratique clinique.

Since 2018, a new analgesic drug has been made available in Switzerland : methoxyflurane. This halogenated gas, controlled by the patient, offers a very effective analgesic effect comparable to opiates. Known since the 1960s and used mainly in pre-hospital emergency medicine in Australia and New Zealand, its use in Europe is increasing alongside standard analgesic treatments in the traumatic setting. Administered by inhalation, it does not require an intravenous access, which is ideal in prehospital emergency situations. This treatment could be used for the management of acute pain of various origins, such as renal lithiasis, or to facilitate different procedures, such as closed fracture reduction or chest tube insertion. Its indications are growing and its use will probably become commonplace with clinicians in a near future.

Depuis 2018, une nouvelle modalité antalgique est disponible en Suisse : le méthoxyflurane. Ce gaz halogéné, contrôlé par le·la patient·e, offre une antalgie très efficace, comparable aux opiacés. Utilisé depuis les années 1960 en médecine préhospitalière dans les régions d'Australie et de Nouvelle-Zélande, il fait ses preuves en Europe où on l'emploie avec les différents antalgiques habituels dans les situations traumatiques d'urgence. Par son administration inhalée, il ne nécessite aucune perfusion. Ce traitement pourrait être utilisé pour la gestion de douleurs aiguës d'origines diverses, telles que la colique néphrétique, ou encore faciliter différentes procédures, comme la réduction fermée de fracture ou la pose de drains. Son indication thérapeutique est croissante et son utilisation deviendra vraisemblablement commune.

Exogenous strigolactones impact metabolic profiles and phosphate starvation signalling in roots.

Strigolactones (SLs) are important ex-planta signalling molecules in the rhizosphere, promoting the association with beneficial microorganisms, but also affecting plant interactions with harmful organisms. They are also plant hormones in-planta, acting as modulators of plant responses under nutrient-deficient conditions, mainly phosphate (Pi) starvation. In the present work, we investigate the potential role of SLs as regulators of early Pi starvation signalling in plants. A short-term pulse of the synthetic SL analogue 2'-epi-GR24 promoted SL accumulation and the expression of Pi starvation markers in tomato and wheat under Pi deprivation. 2'-epi-GR24 application also increased SL production and the expression of Pi starvation markers under normal Pi conditions, being its effect dependent on the endogenous SL levels. Remarkably, 2'-epi-GR24 also impacted the root metabolic profile under these conditions, promoting the levels of metabolites associated to plant responses to Pi limitation, thus partially mimicking the pattern observed under Pi deprivation. The results suggest an endogenous role for SLs as Pi starvation signals. In agreement with this idea, SL-deficient plants were less sensitive to this stress. Based on the results, we propose that SLs may act as early modulators of plant responses to P starvation.

Quantification of Strigolactones.

Strigolactones (SLs) are a family of natural products produced by the plants as shoot branching factors and responsible for the induction of hyphal branching in arbuscular mycorrhizal (AM) fungi. They have been also used by parasitic plant seeds as stimulators of their germination as a strategy to ensure the presence of a host in the environment. For all these bioactivities, SLs have kept the attention of the researchers in the last years, increasing the number of published papers, and have opened new areas of research in the multiple roles that they play in the rhizosphere and as plant hormones. However, the low amount of them produced by plants and their rapid degradability make it crucial to develop fast analytical methods with very low limits of quantification. Herein, it is described a protocol for the development of an LC-MS/MS method for the quantification of SLs, using GR24 as IS, in roots exudates and extracts.