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A phytochemical investigation of the ethyl acetate fraction of root bark extract of Synadenium glaucescens Pax (Euphorbiaceae) led to the isolation of two derivatives of ellagic acid. These included one new 3′,4′ -di-O-methylellagic acid-4α, L-rhamnopyranoside (1) and a known 3,4,3′-tri-O-methylellagic acid (2). Their structures were elucidated by 1D and 2D NMR, while a High res. MS (FTMS-ESI–) was used for accurate mass measurement, which was compared with SciFinder data as well as with available literature. The BSLT results indicated that both 1 (LC50 = 2736.03 μg/mL) and 2 (LC50 = 531.19 μg/mL) were nontoxic at a maximum test concentration of 2400 ppm. [ABSTRACT FROM AUTHOR]

Lansoprazole has been determined in the presence of its five related compounds by the Rapid Resolution RP-HPLC method, using Zorbax Eclipse XDB C18 4.6 mm × 50 mm, 1.8 µm particle size column at 25°C and acetonitrile-1% TEA (41.0:59.0 v/v) at pH 6.6 as mobile phase. The total time for chromatographic separation was approximately 3 min. Experimental design was used for experimental screening (Full factorial 23 design) and optimization (Response surface methodology). The quality of separation is measured by resolution (Rs) and a Chromatographic Response Function. The method was validated for its selectivity, linearity, precision, and accuracy. [ABSTRACT FROM AUTHOR]

A Rapid Resolution Reversed Phase High-Performance Liquid Chromatography (RR RP-HPLC) method has been developed and validated for the simultaneous determination of atorvastatin and seven related compounds specified as impurities. Experimental design was used during method optimization (full factorial 32 design) and robustness testing (central composite design). Chromatography was performed with mobile phase containing phosphate buffer pH 3.5 and a mixture of 10% (v/v) tetrahydrofuran in acetonitrile as organic modifier. A Zorbax Eclipse XDB C18 Rapid Resolution HT 4.6 mm × 50 mm, 1.8 µm particle size column was used. The developed method allowed determination of Atorvastatin Calcium (ATV Ca) purity and level of impurities in drug substances. [ABSTRACT FROM AUTHOR]

1. Sixteen naturally occurring flavonoids were investigated as substrates for cytochrome P450 in uninduced and Aroclor 1254-induced rat liver microsomes. Naringenin, hesperetin, chrysin, apigenin, tangeretin, kaempferol, galangin and tamarixetin were all metabolized extensively by induced rat liver microsomes but only to a minor extent by uninduced microsomes. No metabolites were detected from eriodictyol, taxifolin, luteolin, quercetin, myricetin, fisetin, morin or isorhamnetin. 2. The identity of the metabolites was elucidated using lc-ms and H-nmr, and was consistent with a general metabolic pathway leading to the corresponding 3 ,4-dihydroxylated flavonoids either by hydroxylation or demethylation. Structural requirements for microsomal hydroxylation appeared to be a single or no hydroxy group on the B-ring of the flavan nucleus. The presence of two or more hydroxy groups on the B-ring seemed to prevent further hydroxylation. The results indicate that demethylation only occurs in the B-ring when the methoxy group is positioned at C , and not at the C-position. 3. The CYP1A isozymes were found to be the main enzymes involved in flavonoid hydroxylation, whereas other cytochrome P450 isozymes seem to be involved in flavonoid demethylation. [ABSTRACT FROM AUTHOR]

1. Four glucuronic acidconjugates of licochalcone A(Lica),and their metabolites,have been synthesized using rabbit and pig liver microsomes and purified by preparative hplc. 2. The glucuronides were identified as E -Lica 4- O - beta -glucuronide, E and Z -Lica 4-O beta -glucuronide and a mono-glucuronide conjugate of a beta -hydroxylated Lica metabolite. The metabolites were identified by hplc-nmr (one and two-dimensional nmr) as well as hplc-ms. 3. At pH 8 5 Lica reacted with N -acetyl-L-cysteine giving the twoepimeric conjugates, which were then isolated by preparative hplc and identified by one and two-dimensional nmr spectroscopic methods. 4. Only twoglucuronic acid conjugates ( E - and Z -Lica 4- O - beta -glucuronide) were found in the urine of rat after i.p. administration of a single dose of Lica. [ABSTRACT FROM AUTHOR]

Additively manufactured drug products, typically produced using small-scale, on-demand batch mode, require rapid and non-destructive quantification methods. A tunable modular design (TMD) approach combining porous polymeric freeze-dried modules and an additive manufacturing method, inkjet printing, was proposed in an earlier study to fabricate accurate and patient-tailored doses of an antidepressant citalopram hydrobromide. This approach addresses the unmet medical needs associated with antidepressant tapering. Non-destructive quantification of printed porous structures is challenging due to the presence of residual solvents and frequent fluctuation of the material density. These shortcomings were mitigated by utilizing a spinning near-infrared spectroscopy (NIRS) measurement setup and a post-print drying step. A machine learning algorithm (ML), specifically support vector regression, was implemented to lessen potential non-linearities caused by the complex structure of TMD drug products. The non-linear support vector regression models performed better than linear partial least squares (PLS) models when modeling the entire sample set (prediction error improved by 19 %). By dividing the TMD samples into subtypes and creating individual models for each subtype improved model performance: linear PLS models performed better or equally to non-linear models. It was hypothesized that this outcome was due to the structural differences between different TMD sample subtypes that was later confirmed by stimulated Raman scattering (SRS) microscopy. It was demonstrated that for complex porous drug products ML algorithms can improve NIRS model performance when a single universal robust model is preferred, and SRS is a powerful tool to explain the challenges that printing onto porous drug products can introduce to the NIRS quantification., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ilari Ahola reports equipment, drugs, or supplies and travel were provided by NordForsk for the Nordic University Hub project. Co-author prof. Clare Strachan is the Editor of the journal. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Current guidelines recommend treatment of patients with asymptomatic carotid stenosis when stroke/death rates less than 3% can be achieved. However, in the Pacific Northwest region of the Vascular Quality Initiative, elevated stroke/death rates have been reported. This study aims to characterize regional and center-specific outcomes for transcarotid artery revascularization (TCAR) and transfemoral carotid artery stenting (TF-CAS) and investigate potential underlying drivers., Methods: A retrospective review of asymptomatic patients undergoing TCAR and TF-CAS in the Vascular Quality Initiative for the Pacific Northwest region from 2016 to 2022 was performed. The primary outcome was the composite of stroke or death within 30 days of index hospitalization. Overall regional outcomes and center-specific outcomes were assessed. A high stroke/death rate was defined as greater than 3%. Demographics, comorbidities, and operative risk factors were then compared between centers with high and low stroke/death rates., Results: A total of 1154 asymptomatic patients across 27 centers underwent carotid stenting in the Pacific Northwest from 2016 to 2022, of which 886 (76.8%) underwent TCAR and 268 (23.2%) underwent TF-CAS. The overall stroke/death rates were 2.5% and 3.0% for TCAR and TF-CAS, respectively. Among centers with stroke/death rates above 3%, for both TCAR and TF-CAS, all were in the top one-half of centers by volume. When patients undergoing TCAR were assessed, those treated at centers with high stroke/death rate underwent revascularization at higher volume centers (12 vs 7 cases per year; P = .03), which treated fewer patients with >80% stenosis (42.1% vs 52.2%; P < .01) and more patients with high-risk anatomy (42.3% vs 35.3%; P = .01), and high-risk physiology as defined by an American Society of Anesthesiologists (ASA) class of 4 or 5 (25.5% vs 17.5%; P < .01). Among patients undergoing TF-CAS, those treated at centers with a high stroke/death rate were more likely to have high-risk anatomy (63.5% vs 48.6%; P = .03), and high-risk physiology as defined by an ASA class of 4 or 5 (23.5% vs 10.4%; P < .01)., Conclusions: High stroke/death rates in the Pacific Northwest appear to be driven by the selection of high-risk patients with less than 80% stenosis. Decreasing the frequency of carotid revascularization in asymptomatic patients with very high physiologic risk including those with ASA class 4 and those with less than 80% stenosis may offer the opportunity for improved outcomes., Competing Interests: Disclosures None., (Copyright © 2025. Published by Elsevier Inc.)

Defense against intracellular acidification of breast cancer tissue depends on net acid extrusion via Na + ,HCO 3 - -cotransporter NBCn1/Slc4a7 and Na + /H + -exchanger NHE1/Slc9a1. NBCn1 is increasingly recognized as breast cancer susceptibility protein and promising therapeutic target, whereas evidence for targeting NHE1 is discordant. Currently, selective small molecule inhibitors exist against NHE1 but not NBCn1. Cellular assays-with some discrepancies-link NHE1 activity to proliferation, migration, and invasion; and disrupted NHE1 expression can reduce triple-negative breast cancer growth. Studies on human breast cancer tissue associate high NHE1 expression with reduced metastasis and-in some molecular subtypes-improved patient survival. Here, we evaluate Na + /H + -exchange and therapeutic potential of the NHE1 inhibitor cariporide/HOE-642 in murine ErbB2-driven breast cancer. Ex vivo, cariporide inhibits net acid extrusion in breast cancer tissue (IC 50  = 0.18 μM) and causes small decreases in steady-state intracellular pH (pH i ). In vivo, we deliver cariporide orally, by osmotic minipumps, and by intra- and peritumoral injections to address the low oral bioavailability and fast metabolism. Prolonged cariporide administration in vivo upregulates NBCn1 expression, shifts pH i regulation towards CO 2 /HCO 3 - -dependent mechanisms, and shows no net effect on the growth rate of ErbB2-driven primary breast carcinomas. Cariporide also does not influence proliferation markers in breast cancer tissue. Oral, but not parenteral, cariporide elevates serum glucose by ∼1.5 mM. In conclusion, acute administration of cariporide ex vivo powerfully inhibits net acid extrusion from breast cancer tissue but lowers steady-state pH i minimally. Prolonged cariporide administration in vivo is compensated via NBCn1 and we observe no discernible effect on growth of ErbB2-driven breast carcinomas., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ebbe Boedtkjer reports equipment, drugs, or supplies was provided by Sanofi-Aventis Deutschland GmbH. Kristoffer B. Kristensen reports financial support was provided by Danish Cancer Society. Ebbe Boedtkjer reports financial support was provided by Danish Cancer Society. Ebbe Boedtkjer reports financial support was provided by Novo Nordisk Foundation. Stine F. Pedersen reports a relationship with Solid Therapeutics ApS that includes: board membership and equity or stocks. Ebbe Boedtkjer has patent #EP-3271402 issued to Aarhus University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a tunable modular design (TMD) approach to produce flexible and accurate doses of CHB is proposed. This design consists of two parts: 1) a module with a fixed amount of preloaded CHB in a freeze-dried polymer matrix, and 2) fine-tuning the CHB dose by inkjet printing. A noncontact food-grade printer, used for the first time for printing pharmaceuticals, is modified to allow for accurate printing of the highly concentrated CHB ink on the porous CHB-free or CHB-preloaded modules. The produced modules with submilligram precision are bench-marked with commercially available CHB tablets that are manually divided. The TMD covers the entire range of doses needed for the tapering (0.5-23.8 mg). The greatest variance is 13% and 88% when comparing the TMD and self-tapering, respectively. Self-tapering is proven inaccurate and showcases the need for the TMD to make available accurate and personalized doses to wean off treatment with CHB., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Individual participant data (IPD) meta-analyses of randomised trials are considered a reliable way to assess participant-level treatment effect modifiers but may not make the best use of the available data. Traditionally, effect modifiers are explored one covariate at a time, which gives rise to the possibility that evidence of treatment-covariate interaction may be due to confounding from a different, related covariate. We aimed to evaluate current practice when estimating treatment-covariate interactions in IPD meta-analysis, specifically focusing on involvement of additional covariates in the models. We reviewed 100 IPD meta-analyses of randomised trials, published between 2015 and 2020, that assessed at least one treatment-covariate interaction. We identified four approaches to handling additional covariates: (1) Single interaction model (unadjusted): No additional covariates included (57/100 IPD meta-analyses); (2) Single interaction model (adjusted): Adjustment for the main effect of at least one additional covariate (35/100); (3) Multiple interactions model: Adjustment for at least one two-way interaction between treatment and an additional covariate (3/100); and (4) Three-way interaction model: Three-way interaction formed between treatment, the additional covariate and the potential effect modifier (5/100). IPD is not being utilised to its fullest extent. In an exemplar dataset, we demonstrate how these approaches lead to different conclusions. Researchers should adjust for additional covariates when estimating interactions in IPD meta-analysis providing they adjust their main effects, which is already widely recommended. Further, they should consider whether more complex approaches could provide better information on who might benefit most from treatments, improving patient choice and treatment policy and practice., (© 2023 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Background: Traumatic atlanto-occipital dislocation (AOD) is most commonly treated with cranio-cervical fusion. We present a unique case in which a partial neurological recovery was made after non-operative treatment was done for AOD. Reports of non-operative treatment of this condition are rare in the literature., Case Description: An 18-year-old male sustained a traumatic AOD and atlanto-axial dislocation. His injury was characterized by bony avulsion fractures of the occipital condyles bilaterally as well as atlanto-axial dissociation. Non-operative treatment was done because of his comorbidities, primarily his morbid obesity. He was treated in a hard cervical collar for 6 months. He showed radiographic evidence of healing after being treated non-operatively in a rigid cervical collar for 6 months. Follow up at 17 months showed a partial neurological recovery with ability to ambulate assisted with a walker., Conclusions: Successful outcomes are possible with non-operative treatment of AOD. A predominant factor contributing to this patient's successful outcome with non-operative management was likely related to the bony avulsion fractures he had which allowed bone to bone healing and settling of the fracture with gravity assisted reduction in a collar. Non-operative treatment may be considered in patients who are too unhealthy or unstable to undergo surgical intervention, although the standard of care remains surgical cranio-cervical fusion., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jss.amegroups.com/article/view/10.21037/jss-23-60/coif). The authors have no conflicts of interest to declare., (2023 Journal of Spine Surgery. All rights reserved.)

Quality of life is often reduced in patients with sleep-wake disorders. Insomnia is commonly treated with benzodiazepines, despite their well-known side effects. Pellotine ( 1 ), a Lophophora alkaloid, has been reported to have short-acting sleep-inducing properties in humans. In this study, we set out to evaluate various in vitro and in vivo properties of 1 . We demonstrate that 1 undergoes slow metabolism; e.g. in mouse liver microsomes 65% remained, and in human liver microsomes virtually no metabolism was observed after 4 h. In mouse liver microsomes, two phase I metabolites were identified: 7-desmethylpellotine and pellotine- N -oxide. In mice, the two diastereomers of pellotine -O -glucuronide were additionally identified as phase II metabolites. Furthermore, we demonstrated by DESI-MSI that 1 readily enters the central nervous system of rodents. Furthermore, radioligand-displacement assays showed that 1 is selective for the serotonergic system and in particular the serotonin (5-HT) 1D , 5-HT 6 , and 5-HT 7 receptors, where it binds with affinities in the nanomolar range (117, 170, and 394 nM, respectively). Additionally, 1 was functionally characterized at 5-HT 6 and 5-HT 7 , where it was found to be an agonist at the former (EC 50 = 94 nM, E max = 32%) and an inverse agonist at the latter (EC 50 = 291 nM, E max = -98.6). Finally, we demonstrated that 1 dose-dependently decreases locomotion in mice, inhibits REM sleep, and promotes sleep fragmentation. Thus, we suggest that pellotine itself, and not an active metabolite, is responsible for the hypnotic effects and that these effects are possibly mediated through modulation of serotonergic receptors., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

The 'entourage effect' term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the 'entourage effect' is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the 'entourage effect' from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the 'entourage effect' is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).

Study Design: This is a retrospective observational study., Objective: This study aims to determine the efficacy of liposomal bupivacaine in postoperative analgesia and long-term outcomes in patients undergoing one-level and two-level posterior lumbar fusion., Summary of Background Data: Multiple studies have investigated the use of liposomal bupivacaine in spine surgery with varying results. The potential benefits of its use include decreasing postoperative opioid use, improved pain control, and a shorter hospital stay. Several studies have supported its use in spine surgery with others showing minimal to no benefit. No studies have investigated its possible impact on long-term outcomes., Materials and Methods: A total of 42 patients (22 one-level, 20 two-level) received liposomal bupivacaine injection just before surgical closure and were compared with a historical control group of 42 patients (27 one-level, 15 two-level) that did not receive liposomal bupivacaine. Daily opioid consumption was collected and converted to oral morphine equivalents. Length of stay and daily average pain scores using the visual analog scale were also recorded. In addition, SF-36 bodily pain and physical function outcome measures were collected preoperatively and at 6 months, 1 year and 2 years postoperatively., Results: The liposomal bupivacaine group was found to have a significantly lower total opioid consumption compared with the control group ( P =0.001). The liposomal bupivacaine group was also found to use significantly fewer opioids on the day of surgery compared with the control group ( P <0.0001). There was no significant difference shown in the average visual analog scale pain scores, length of stay, or long-term outcomes between the 2 groups., Conclusions: The use of liposomal bupivacaine in one-level and two-level posterior lumbar fusions shows promise as an adjuvant for postoperative analgesia by decreasing postoperative opioid consumption. With the varying results demonstrated with the utilization of liposomal bupivacaine in spine surgery, further investigation is warranted, namely a larger prospective randomized control study., Level of Evidence: Level III., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The analgesic potential of Cannabis sativa L.-based medicinal cannabis products for treatment of cancer associated chronic pains has gained increased interest in recent years. To ensure a controlled distribution of these products and investigate their therapeutic potential, several countries have established so-called pilot trials. Many doctors, however, are hesitant to prescribe medicinal cannabis primarily due to lack of research evidence regarding the products' efficacy, safety and thus questionable dosing guidelines. This review aims to elucidate clinical research supporting administration of medicinal cannabis in cancer patients for analgesic purposes. The cannabinoids' effects on the endocannabinoid system (ECS) and its implication in pain regulation is included to illustrate the complexity related to this research field. Published clinical studies on medicinal cannabis primarily consist of observational studies and only one pilot randomized controlled trial (RCT), where more RCTs exist on the cannabis-based product, Sativex ® (GW Pharma Ltd., Cambridge, UK). The studies indicate analgesic potential, however non-significantly, for most patients and with acceptable safety profile. Summarizing, high-quality RCTs are scarce in this research field, and the limitations of the observational studies complicates interpretation of clinical outcomes. Despite discrepancy among the studies, they do show indications for administration and dosing regimens providing analgesic effects for some cancer patients.

Objective: To determine the synovial fluid (SF) concentrations of lidocaine and mepivacaine after intra-articular injection with clinically relevant doses to the distal interphalangeal (DIP), metacarpophalangeal (MCP), middle carpal (MC), and tarsocrural (TC) joint at two different time points after injection in order to be able to compare concentrations with previously established concentrations associated with cytotoxicity and antimicrobial activity., Procedures: In the first of two experiments, 20 joints (5 MC, 5 MCP, 10 DIP joints) of five horses under general anesthesia were injected with clinically referenced doses of 2% lidocaine. Simultaneously, the horses had 19 joints (5 MC, 5 MCP, 9 DIP joints) injected with clinically referenced doses of 2% mepivacaine. Synovial fluid samples were collected ~7 min after injection. In experiment 2, 23 joints of seven horses under standing sedation were injected with clinically referenced doses of 2% lidocaine. Similarly, the horses had 21 joints injected with 2% mepivacaine. Synovial fluid samples were collected ~23 min after injection. The concentration of mepivacaine and lidocaine in the obtained SF samples was assessed using high-performance-liquid-chromatography with mass spectrometry detection (HPLC MS)., Results: Synovial fluid was obtained 6.8 ± 1.5 (experiment 1) and 23 ± 4.3 (experiment 2) min following intra-articular injection of mepivacaine and lidocaine. Synovial fluid concentrations of experiment 1 for lidocaine and mepivaciane were 6.46-19.62 mg/mL (mean 11.96 ± SD 3.89 mg/mL) and 5.01-13.38 mg/mL (mean 8.18 ± SD 1.76 mg/mL), respectively. In experiment 2, concentrations were 2.94-10.40 mg/mL (mean 6.31± SD 2.23 mg/mL) for lidocaine and 2.10-8.70 mg/mL (mean 4.97 ± SD 1.77 mg/mL) for mepivacaine., Conclusions and Clinical Relevance: Intra-articular LA injections in horses resulted in SF concentrations above those previously associated with cytotoxic effects in vitro but also above those associated with beneficial antimicrobial activities. Local anesthetic concentration was 33-60% lower after 23 min (experiment 2) than after 7 min (experiment 1)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Adler, Jørgensen and Cornett.)

Data-enriched edible pharmaceuticals (DEEP) is an approach to obtain personalized medicine, in terms of flexible and precise drug doses, while at the same time containing data, embedded in quick response (QR) codes at a single dosage unit level. The aim of this study was to fabricate DEEP with a patient-tailored dose, modify drug release and design to meet patients' preferences. It also aimed to investigate physical stability in terms of the readability of QR code patterns of DEEP during storage. Cannabinoids, namely, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were used as the model active pharmaceutical ingredients (APIs). Three different substrates and two colorants for the ink were tested for their suitability to fabricate DEEP by desktop inkjet printing. Flexible doses and customizable designs of DEEP were obtained by manipulating the digital design of the QR code, particularly, by exploring different pattern types, embedded images and the physical size of the QR code pattern. Modification of the release of both APIs from DEEP was achieved by applying a hydroxypropyl cellulose (HPC) polymer coating. The appearance and readability of uncoated and polymer-coated DEEP did not change on storage in cold and dry conditions; however, the HPC polymer layer was insufficient in preserving the readability of the QR code pattern in the extreme storage condition (40 °C and 75% relative humidity). To sum up, the DEEP concept provides opportunities for the personalization of medicines, considering also patients' preferences.

Medical cannabis has shown to be effective in various diseases that have not successfully been treated with other marketed drug products. However, the dose of cannabis is highly individual and additionally, medical cannabis is prone to misuse. To combat these challenges, the concept of data-enriched edible pharmaceuticals (DEEP) is introduced. Quick Response (QR) code patterns containing lipophilic cannabinoids, i.e., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were printed using a desktop inkjet printer. This allows for simultaneously printing an individual dose and encapsulating information relevant to the end-users and other stakeholders in a single dosage unit, which is readable by a standard smartphone. Different doses of CBD and THC were incorporated in the DEEP by printing various (1-10) layers of the cannabinoid-containing ink on porous substrates, i.e., solid foams, prepared by solvent casting and subsequent freeze-drying. The printed DEEP were still readable after 8 weeks of storage in dry and cold conditions. This approach of 'in-drug labeling' instead of 'drug package labeling' provides a new possibility for developing a more efficient supply chain of pharmaceuticals and safer medication schemes by increasing the traceability of drug products at a single dosage unit level., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Species of the genus Cinchona (Rubiaceae) have been used in traditional medicine, and as a source for quinine since its discovery as an effective medicine against malaria in the 17th century. Despite being the sole cure of malaria for almost 350 years, little is known about the chemical diversity between and within species of the antimalarial alkaloids found in the bark. Extensive historical Cinchona bark collections housed at the Royal Botanic Gardens, Kew, UK, and in other museums may shed new light on the alkaloid chemistry of the Cinchona genus and the history of the quest for the most effective Cinchona barks., Aim of the Study: We used High-Pressure Liquid Chromatography (HPLC) coupled with fluorescence detection (FLD) to reanalyze a set of Cinchona barks originally annotated for the four major quinine alkaloids by John Eliot Howard and others more than 150 years ago., Materials and Methods: We performed an archival search on the Cinchona bark collections in the Economic Botany Collection housed in Kew, focusing on those with historical alkaloid content information. Then, we performed HPLC analysis of the bark samples to separate and quantify the four major quinine alkaloids and the total alkaloid content using fluorescence detection. Correlations between historic and current annotations were calculated using Spearman's rank correlation coefficient, before paired comparisons were performed using Wilcox rank sum tests. The effects of source were explored using generalized linear modelling (GLM), before the significance of each parameter in predicting alkaloid concentrations were assessed using chi-square tests as likelihood ratio testing (LRT) models., Results: The total alkaloid content estimation obtained by our HPLC analysis was comparatively similar to the historical chemical annotations made by Howard. Additionally, the quantity of two of the major alkaloids, quinine and cinchonine, and the total content of the four alkaloids obtained were significantly similar between the historical and current day analysis using linear regression., Conclusions: This study demonstrates that the historical chemical analysis by Howard and current day HPLC alkaloid content estimations are comparable. Current day HPLC analysis thus provide a realistic estimate of the alkaloid contents in the historical bark samples at the time of sampling more than 150 years ago. Museum collections provide a powerful but underused source of material for understanding early use and collecting history as well as for comparative analyses with current day samples., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Asthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of the device and wrong inhalation technique. This study aims to design and fabricate an acoustic dry powder inhaler (ADPI) for monitoring inhalation flow and related drug administration in order to evaluate whether the patient receives the complete dose out of the inhaler., Methods: The devices were fabricated using 3D printing and the impact of the acoustic element geometry and printing resolution on the acoustic signal was investigated. Commercial Foradil (formoterol fumarate) capsules were used to validate the availability of the ADPI for medication dose tracking. The acoustic signal was analysed with Partial-Least-Squares (PLS) regression., Results: Indicate that specific acoustic signals could be generated at different air flow rates using a passive acoustic element with specific design features. This acoustic signal could be correlated with the PLS model to the air flow rate. A more distinct sound spectra could be acquired at higher printing resolution. The sound spectra from the ADPI with no capsule, a full capsule and an empty capsule are different which could be used for medication tracking., Conclusions: This study shows that it is possible to evaluate the medication quality of inhaled medicaments by monitoring the acoustic signal generated during the inhalation process.

Study Design: This is a level III retrospective cohort study., Objective: To investigate association between prophylactic tranexamic acid (TXA) administration before 1 and 2-level posterior lumbar interbody fusion operations and perioperative blood loss (including intraoperative blood loss and postoperative drain output), mean operative time, postoperative transfusion, and postoperative venous thromboembolic events., Summary of Background Data: TXA is a systemic antifibrinolytic that competitively inhibits lysine binding sites on plasminogen, reversibly blocking its binding to fibrin and impeding fibrinolysis and clot degradation. TXA's role in routine spinal surgery remains poorly described. Most spinal literature on perioperative TXA administration has considered operations performed for major adult and pediatric spinal deformity., Methods: Two groups, a study group composed of 75 patients who underwent 1 and 2-level posterior lumbar interbody fusion operations for degenerative indications who received TXA before the start of the procedure, and a control group composed of 75 patients who underwent similar surgeries for the same indications and did not receive TXA preoperatively, were retrospectively enrolled. Demographic, laboratory, and surgical data were collected and analyzed., Results: No statistically significant differences were found between groups with respect to surgery type, home anticoagulation, postoperative anticoagulation, preoperative hemoglobin and hematocrit, estimated intraoperative blood loss, postoperative day 2 drain output, postoperative day 3 drain output, rate of postoperative transfusion, and rate of postoperative thromboembolic events. Statistically significant reductions were noted in the TXA group with regards to postoperative day 1 drain output (P<0.0041), total postoperative drain output (P=0.027), and mean surgical time (P<0.0001)., Conclusions: In the present study, perioperative TXA administration was associated with reduced postoperative drain output and surgical time. Further higher-level studies are required to investigate the safety and utility of TXA's routine use in 1 and 2-level posterior lumbar fusion operations performed for degenerative indications.

The original version of this article [1] unfortunately contained an error which has since been acknowledged in this Correction article. The URL link in the Reference 19 was broken and it needs to be replaced with the active link given below.

Background: Funding for graduate medical education is at risk despite the services provided by residents., Objective: We quantified the potential monetary value of services provided by on-call orthopedic surgery residents., Methods: We conducted a prospective, cross-sectional, multicenter cohort study design. Over a 90-day period in 2014, we collected data on consults by on-call orthopedic surgery residents at 4 tertiary academic medical centers in the United States. All inpatient and emergency department consults evaluated by first-call residents during the study period were eligible for inclusion. Based on their current procedural terminology codes, procedures and evaluations for each consult were assigned a relative value unit and converted into a monetary value to determine the value of services provided by residents. The primary outcome measures were the total dollar value of each consult and the percentage of resident salaries that could be funded by the generated value of the resident consult services., Results: In total, 2644 consults seen by 33 residents from the 4 institutions were included for analysis. These yielded an average value of $81,868 per center for the 90-day study period, that is, $327,471 annually. With a median resident stipend of $53,992, the extrapolated average percentage of resident stipends that could be funded by these consult revenues was 73% of the stipends of the residents who took call or 36% of the stipends of the overall resident cohort., Conclusions: The potential monetary value generated by on-call orthopedic surgery residents is substantial., Competing Interests: Conflict of interest: The authors declare they have no competing interests. These data were presented at the Southern Orthopaedic Association Annual Meeting, Naples, Florida, July 27–30, 2016; the South Carolina Orthopaedic Association & South Carolina Association of Orthopaedic Executives Annual Meeting, Kiawah Island, South Carolina, August 4–6, 2016; and the American Academy of Orthopaedic Surgeons Annual Meeting, San Diego, California, March 14–18, 2017.

The present study investigates the use of free drug sensors (FDS) to measure free ionized drug concentrations in colloidal systems, including micellar solutions, emulsions, and lipid formulations during in vitro lipolysis. Diphenhydramine hydrochloride (DPH) and loperamide hydrochloride (LOP) were selected as model drugs. Self-diffusion nuclear magnetic resonance studies were performed and confirmed the entrapment of drugs in micelles in Brij 35 and sodium taurodeoxycholate (TDC)/phosphatidylcholine (PC) micellar solutions. The FDS measurements indicated that with a constant level of drug, the percentage of free DPH and LOP decreased from 84% to 57% and from 51% to 18%, respectively, as the concentration of Brij 35 was increased from 4.7 to 22 mM; and from 99% to 46% and from 100% to 21%, respectively, as the concentration of TDC/PC was increased from 0.49/0.04 to 8.85/0.78 mM. During the in vitro lipolysis of a lipid formulation, free drug concentration decreased with lipolysis time. The percentage of free DPH was higher than for LOP in the same colloidal system because DPH is less lipophilic than LOP. The study showed that FDS can be used to monitor the free drug concentration in colloidal systems with fast response, no sample treatment and simple data analysis., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Introduction: Authentication of herbal products to ensure efficacy and safety require efficient separation and quantification of constituents. Standard assays for Cinchona bark used for the treatment of malaria and production of quinine, either use only spectrophotometry to detect two pairs of diastereoisomers of quinine and cinchonine type alkaloids (European Pharmacopoeia, Ph.Eur.) or liquid chromatography primarily optimised for detection of the four major alkaloids. However, numerous minor alkaloids occur in Cinchona and related species and efficient separation including gradient elution is necessary in order to obtain the full pattern of constituents in bark samples., Objective: To develop an optimised HPLC method for separation and quantitative analysis of the four major alkaloids in Cinchona bark using UV detection., Methodology: Dimethyl sulphoxide (DMSO) extracts of 50 mg of pulverised barks were prepared using ultrasonication. The chromatographic separation was performed on an XB-C18 column packed with 2.6 μm particles. Gradient elution using an ammonium formate buffer and methanol as organic modifier over 26 min was based on non-chiral separation of the diastereoisomers and the high solvent selectivity of methanol. Post column UV detection was performed at 250 nm and 330 nm. Fluorescence detection was performed using 330 nm for excitation and 420 nm for emission., Results: The optimised HPLC method facilitates efficient separation and quantification of the four major alkaloids in 26 min with a limit of quantification of 5 μg/g from 50 mg bark sample., Conclusion: The optimised HPLC method offers a simple and efficient quantification of the four major alkaloids. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Considerable inter- and intraspecific variation with respect to the quantity and composition of plant natural products exists. The processes that drive this variation remain largely unknown. Understanding which factors determine chemical diversity has the potential to shed light on plant defenses against herbivores and diseases and accelerate drug discovery. For centuries, Cinchona alkaloids were the primary treatment of malaria. Using Cinchona calisaya as a model, we generated genetic profiles of leaf samples from four plastid (trnL-F, matK, rps16, and ndhF) and one nuclear (ITS) DNA regions from twenty-two C. calisaya stands sampled in the Yungas region of Bolivia. Climatic and soil parameters were characterized and bark samples were analyzed for content of the four major alkaloids using HPLC-UV to explore the utility of evolutionary history (phylogeny) in determining variation within species of these compounds under natural conditions. A significant phylogenetic signal was found for the content of two out of four major Cinchona alkaloids (quinine and cinchonidine) and their total content. Climatic parameters, primarily driven by changing altitude, predicted 20.2% of the overall alkaloid variation, and geographical separation accounted for a further 9.7%. A clade of high alkaloid producing trees was identified that spanned a narrow range of altitudes, from 1,100 to 1,350 m. However, climate expressed by altitude was not a significant driver when accounting for phylogeny, suggesting that the chemical diversity is primarily driven by phylogeny. Comparisons of the relative effects of both environmental and genetic variability in determining plant chemical diversity have scarcely been performed at the genotypic level. In this study we demonstrate there is an essential need to do so if the extensive genotypic variation in plant biochemistry is to be fully understood.