Unveiling Pharmacokinetics and Drug Interaction of Linagliptin and Pioglitazone HCl in Rat Plasma Using LC-MS/MS.

The linagliptin (LIN) and pioglitazone HCl (PIO) combination, currently undergoing phase III clinical trials for diabetes mellitus treatment, demonstrated significant improvements in glycemic control. However, the absence of an analytical method for simultaneous determination in biological fluids highlights a crucial gap. This underscores the pressing need for sensitive bioanalytical methods, emphasizing the paramount importance of developing such tools to advance diabetes management strategies and enhance patient care. Herein, a sensitive reverse-phase high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for simultaneous determination of LIN and PIO in rat plasma using alogliptin as an internal standard. Chromatographic separation was performed on an Agilent Eclipse Plus C18 (4.6 × 100 mm, 3.5 µm) using an isocratic mobile phase system consisting of ammonium formate (pH 4.5) and methanol using an acetonitrile-induced protein precipitation technique for sample preparation. Multiple reaction monitoring in positive ion mode was used for quantitation of the precursor to production at m/z 473.2 → 419.9 for LIN, 357.1 → 134.2 for PIO, and 340.3 → 116.1 for ALO. The linearity range was 0.5 to 100 and 1 to 2000 ng/mL for LIN and PIO, respectively. The developed method was validated as per US-FDA guidelines and successfully applied to clinical pharmacokinetic and drug-drug interaction studies with a single oral administration of LIN and PIO in rat plasma. Pharmacokinetic parameters of LIN were significantly influenced by the concomitant administration of PIO and vice versa. Molecular modeling revealed the significant interaction of LIN and PIO with P-glycoprotein. Therefore, the drug-drug interaction between LIN and PIO deserves further study to improve drug therapy and prevent dangerous adverse effects.

Identification of indole-grafted pyrazolopyrimidine and pyrazolopyridine derivatives as new anti-cancer agents: Synthesis, biological assessments, and molecular modeling insights.

In the current medical era, developing new PIM-1 inhibitors stands as a significant approach to cancer management due to the pivotal role of PIM-1 kinase in promoting cell survival, proliferation, and drug resistance in various cancers. This study involved designing and synthesizing new derivatives of pyrazolo[1,5-a]pyrimidines (6a-i) and pyrazolo[3,4-b]pyridines (10a-i) as potential anti-cancer agents targeting PIM-1 kinase. The cytotoxicity was screened on three cancer cell lines: A-549 (lung), PANC-1 (pancreatic), and A-431 (skin), alongside MRC5 normal lung cells to assess selectivity. Several pyrazolo[1,5-a]pyrimidines (6b, 6c, 6g, 6h, and 6i) and pyrazolo[3,4-b]pyridine (10f) demonstrated notable anticancer properties, particularly against A-549 lung cancer cells (IC50 range: 1.28-3.52 µM), also they exhibited significantly lower toxicity towards MRC5 normal cells. Thereafter, the compounds were evaluated for their inhibitory activity against PIM-1 kinase. Notably, 10f, bearing a 4-methoxyphenyl moiety, demonstrated good inhibition of PIM-1 with an IC50 of 0.18 µM. Additionally, 10f induced apoptosis and arrested cell cycle progression in A-549 cells. Molecular docking and dynamics simulations provided insights into the binding interactions and compounds' stability with PIM-1 kinase. The results highlight these compounds, especially 10f, as promising selective anticancer agents targeting PIM-1 kinase.

4-Azido-7-nitrobenzoxadiazole as innovative clickable fluorescence probe for trace and selective quantification of ethinylestradiol in human plasma.

Quantification of ethinylestradiol (EE) in biological matrices is challenging as it is a very potent drug with a very low Cmax (75 pg.ml-1 ). Despite the high sensitivity of fluorometric methods, the detection of EE was confined because its structure exhibited very limited fluorescence. Therefore, it must be derivatized first using a fluorogenic agent to produce a more potent fluorescence derivative to achieve the desired ultrasensitive bioanalysis. Here, for the first time, we proposed a promising click fluorescent probe, 4-azido-7-nitrobenzoxadiazole (NBD-AZ) to react with the alkyne group of EE, with the help of copper sulphate and l-ascorbic acid to give a highly fluorescent and stable 1,2,3-triazole derivative. Density functional theory calculation revealed how the triazole formation affects the quantum yield and fluorescence of click reaction product when compared with NBD-AZ. The resulting triazole exhibited a strong signal at a wavelength of 540 nm after excitation at 470 nm. Reaction parameters impacting the intensity of fluorescence were cautiously studied and optimized. The suggested approach has shown outstanding performance, high linearity (25-300 pg.ml-1 ) and a low detection limit of 7.5 pg.ml-1 . The enhanced sensitivity and selectivity were exploited for analyzing EE in plasma using liquid-liquid extraction for samples cleaning up without interference from any biological components and with a mean % recovery of 100.13 ± 0.39. Accuracy, sensitivity, selectivity, simplicity, and cost-effectiveness make this approach a convincing, promising, and appealing alternative to the reported analytical methods for EE bioanalysis in different matrices.

Mapping the implementation of pharmacogenomic testing in community pharmacies 2003-2021 using the Theoretical Domains Framework: A scoping review.

BACKGROUND: Pharmacogenetic (PGx) testing is an evidence-based approach to finding effective medication therapies. While community pharmacists are ideally situated to provide PGx testing, the extent of its implementation is limited within community pharmacies. OBJECTIVE: This study aimed to explore trends in the international peer-reviewed primary literature on community pharmacists' implementation of PGx and map the main findings on the Theoretical Domains Framework (TDF). METHODS: A literature search and 2-step screening were conducted per PRISMA Extension for Scoping Reviews. Inclusion criteria were English language, community pharmacy setting, full papers, and empirical research. Data were collated in a data extraction form. The main findings were deductively mapped on the TDF with a content analysis approach. RESULTS: Of 1176 identified documents screened, 39 were included in this scoping review. Four groups of research were identified: pre-implementation surveys (interviews, and focus groups [56%, n = 22]); PGx implementation (single cohort to assess feasibility [38%, n = 15]); PGx implementation (controlled study to assess feasibility [n = 1, 2.5%]); and efficacy of PGx (2.5%, n = 1). Most studies throughout the 4 groups sought pharmacists' perceptions (46%, n = 18) and used the quantitative paradigm (77%, n = 30). TDF mapping documented positive beliefs about the benefits of PGx testing as a part of the pharmacists' role. Barriers to PGx use included pharmacists' awareness of knowledge gaps, low confidence in interpreting and communicating PGx results, concerns about cost, privacy, and integration into pharmacy workflow. CONCLUSION: Research addressing PGx implementation within the community pharmacy evolved from assessing individuals' perceptions of PGx to determining the feasibility of PGx testing in pharmacies and evaluating the impact of PGx testing on patient outcomes in depression. Mapping the main findings on the TDF facilitates the development of multidimensional interventions, potentially targeting patients, pharmacists, and health policy.

Novel spectrofluorimetric quantification of alogliptin benzoate in biofluids exploiting its interaction with 4-chloro-7-nitrobenzofurazan.

The direct determination of alogliptin benzoate (ALO) using fluorescence has not yet been accomplished because ALO cannot fluoresce naturally. Accordingly, it should be derivatized first with a fluorogenic reagent to enhance the sensitivity required for its bioanalysis. This method is the first spectrofluorimetric assay for ALO quantification exploiting the nucleophilic nature of its amino group to react with 4-chloro-7-nitrobenzofurazan (NBD-Cl) in borate buffer at pH 8.5 to produce a strong fluorescent compound that is excited at and emits at wavelengths 470 and 527 nm, respectively. Experimental variables concerning the conditions of reaction and fluorogenic intensity were carefully investigated and optimized. Linearity was from 1-250 ng ml-1 with a lower detection limit of 0.29 ng ml-1 and a lower quantification limit of 0.88 ng ml-1 . Validation of the current study was accomplished with mean per cent recovery of 100.62 ± 1.59 in tablets and 99.86 ± 0.82 in human plasma. Furthermore, the current method has been utilized in the bioanalysis of ALO in real rat plasma after oral administration with a simple specimen preparation. The developed method has proven to be a promising alternative method for ALO analysis in bioequivalence studies.

Novel spectrofluorimetric quantification of linagliptin in biological fluids exploiting its interaction with 4-chloro-7-nitrobenzofurazan.

Direct determination of linagliptin (LIN) using fluorimetry has been limited because LIN releases a very weak fluorescence signal. Accordingly, it should be derivatized first with a fluorogenic reagent to enhance its fluorescence and consequentially the sensitivity required for its bioanalysis. This is the first description of a spectrofluorimetric method for LIN quantification in human plasma. The suggested method exploits the nucleophilic nature of its amino group to react with 4-chloro-7-nitrobenzofurazan (NBD-Cl) in borate buffer at pH 8.5 to yield a strong fluorescent product with excitation and emission wavelengths of 459 and 529 nm, respectively. Experimental variables concerning the conditions of reaction and fluorescence intensity were carefully investigated and optimized. The linearity range was from 1.0-100 ng ml-1 with a lower detection limit and a lower quantification limit of 0.60 ng ml-1 and 1.82 ng ml-1 , respectively. Validation of the suggested method has been accomplished and the application to LIN analysis in commercial tablets as well as in human plasma resulted in a mean per cent recovery of 100.12 ± 1.57 and 99.65 ± 1.22, respectively. The developed method was proven to be a promising, simple and fast alternative bioanalytical method for LIN quantification in clinical and bioequivalence research.

Development and evaluation of shared decision-making tools in rheumatology: A scoping review.

INTRODUCTION: Shared decision-making (SDM) tools are facilitators of decision-making through a collaborative process between patients/caregivers and clinicians. These tools help clinicians understand patient's perspectives and help patients in making informed decisions based on their preferences. Despite their usefulness for both patients and clinicians, SDM tools are not widely implemented in everyday practice. One barrier is the lack of clarity on the development and evaluation processes of these tools. Such processes have not been previously described in the field of rheumatology. OBJECTIVE: To describe the development and evaluation processes of shared decision-making (SDM) tools used in rheumatology. METHODS: Bibliographic databases (e.g., EMBASE and CINAHL) were searched for relevant articles. Guidelines for the PRISMA extension for scoping reviews were followed. Studies included were: addressing SDM among adults in rheumatology, focusing on development and/or evaluation of SDM tool, full texts, empirical research, and in the English language. RESULTS: Of the 2030 records screened, forty-six reports addressing 36 SDM tools were included. Development basis and evaluation measures varied across the studies. The most commonly reported development basis was the International Patient Decision Aids Standards (IPDAS) criteria (19/36, 53 %). Other developmental foundations reported were: The Ottawa Decision Support Framework (ODSF) (6/36, 16 %), Informed Medical Decision Foundation elements (3/36, 8 %), edutainment principles (2/36, 5.5 %), and others (e.g. DISCERN and MARKOV Model) (9/31,29 %). The most commonly used evaluation measures were the Decisional Conflict Scale (18/46, 39 %), acceptability and knowledge (7/46, 15 %), and the preparation for decision-making scale (5/46,11 %). CONCLUSION: For better quality and wider implementation of such tools, there is a need for detailed, transparent, systematic, and consistent reporting of development methods and evaluation measures. Using established checklists for reporting development and evaluation is encouraged.

Evidence for the use of cannabis-based medicines in osteoarthritis: a scoping review.

The purpose of this study was to conduct a scoping review to describe the evidence on the efficacy and safety of using cannabis-based medicines for osteoarthritis. The review was conducted following the framework proposed by Arksey and O'Malley and reported following PRISMA extension for scoping reviews guidelines. We conducted a comprehensive search across various databases including MEDLINE, Embase, Cochrane Library, CINAHL, Scopus, and Proquest, spanning from inception of each database to March 2023. We retrieved 2533 citations, and after deduplication, title and abstract screening, and full-text screening, 10 articles were included for analysis. These studies were composed of randomized-controlled trials (n = 4/10), cross-sectional surveys (n = 3/10), case studies (n = 2/10), and a cohort study (n = 1/10). Evidence for using cannabis-based medicines was mixed, with just 60% (n = 6/10) of included studies reporting statistically significant improvements in pain. Studies with larger samples sizes and longer durations of exposure did not find significant benefits for pain. The few adverse effects reported were generally mild and affected a minority of participants. Several studies also discovered that cannabis-based medicines were associated with a reduction in opioid use. Currently available data on the use of cannabis-based medicines in osteoarthritis is insufficient to make recommendations. Future research should address concerns regarding small sample sizes and short treatment durations to provide a more robust evidence base. Key Points • Current evidence remains mixed; studies that found a positive benefit with using cannabis-based medicines had limitations with small sample sizes and short durations of exposure • The use of cannabis-based medicines in osteoarthritis appears to be generally well tolerated, adverse effects are mild and experienced by a minority of participants • Cannabis-based medicines may decrease the use of opioids in patients with osteoarthritis • Future research should address the gaps in long-term efficacy and safety data.

Novel fluorescence approach for trace quantification of levonorgestrel in breast milk based on click reaction with benzonitrofurazan azide (NBD-AZ).

Although the great importance of oral contraceptive agents in birth control, their existence in breast milk became a cause for concern, since infant exposure to these hormones is associated with many health problems. Consequentially, developing a sensitive bioanalytical method for monitoring their concentrations in breast milk is an urgent demand to examine the safety or the risk of these compounds on infants. Levonorgestrel is one of the most common contraceptive hormones under concern. Despite the high sensitivity of the fluorometric methods, detection of Levonorgestrel by them is confined because its structure does not exhibit any fluorescence. For the first time, we proposed a promising click fluorescent probe, 4-azido-7-nitrobenzoxadiazole to react with the alkyne group of Levonorgestrel, to give a highly fluorescent triazole derivative that exhibited strong signal at wavelength of 544 nm after excitation at 470 nm. Reaction parameters impacting the fluorescence were cautiously studied and optimized. The suggested approach has been successfully applied in Levonorgestrel estimation in breast milk samples with linearity of (0.4-80 ng.ml-1) and low detection limit of 0.12 ng.ml-1without interferences from any biological components and with mean % recovery of 97.84 ± 2.73. Accuracy, sensitivity, selectivity, simplicity, and low-cost makes this approach a convincing, promising, and appealing alternative over reported analytical methods for Levonorgestrel bioanalysis in different matrices.

How to inform college students about meningitis B vaccine? Comparative effectiveness of an online theory-based text and video intervention.

Objective The purpose of this study was to compare the effect of text and video formats of an online theory-based Meningitis B (MenB) health message intervention on college students. Participants: College freshmen and transfer students admitted at a Southern U.S. University. Methods: In a 2-arm randomized study, knowledge, perceptions, and intention to receive the vaccine were compared pre- and post-intervention. Results: Post intervention, participants in both the written and video interventions had significantly higher scores of knowledge, perceptions, and intentions. Upon comparing the change in scores pre- to post-intervention between both text and video groups, no significant differences were found between both groups. Conclusions: This study, a first in using a theory-based MenB online education intervention and questionnaire to compare text and video formats, suggests that both text and video formats are equally effective in raising young adults' awareness about the MenB vaccine.

Ensuring quality qualitative research reporting in community pharmacy: a systematic literature review.

OBJECTIVES: To evaluate the reporting quality for a sample of community pharmacy qualitative research articles based on the Standards for Reporting Qualitative Research (SRQR) guidelines, data interpretation and use of theory. METHODS: A systematic literature search was conducted using Ovid MEDLINE to identify qualitative research related to community pharmacy. Data were extracted and evaluated based on the SRQR standards, data interpretation level and use of theory. Adherence to standards was analysed using descriptive statistics. KEY FINDINGS: Eighty-one studies were retrieved through the database search (n = 81). Then, 31 studies met the inclusion criteria after screening abstracts and full texts. Twelve out of 21 SRQR were present in more than 80% of the studies. However, essential standards, such as research approach, reflexivity and trustworthiness techniques, were absent or partially present in 30 (97%) studies, 30 (97%) studies and 21 (68%) studies, respectively. Data interpretation level was descriptive in 27 (87%) studies and interpretive or partially interpretive in 4 (13%) studies. Theory was absent in 19 (60%) and implied, partially integrated or retrospectively applied in 12 (40%) of the studies. CONCLUSION: Trustworthiness and quality of qualitative inferences within community pharmacy research could be enhanced with increasing awareness about reporting; the approach and paradigm, reflexivity, trustworthiness techniques, data interpretation level and theoretical use.

High-level curricular integration in pharmacy schools: A systematic literature review.

BACKGROUND: Pharmacy school accreditors recommend curricular integration. With today's complex health care system, there is also a need for more intentional and seamless blending, characterizing what we propose as "high-level curricular integration" (i.e. intentional "weaving" of multiple disciplines to form a coherent whole). Despite accreditors' recommendations, the practical definition and implementation guidelines of high-level curricular integration are not clear. We aimed to describe high-level curricular integration practices in pharmacy schools by systematically reviewing the literature addressing four elements of high-level curricular integration. These were (1) organizational thread, (2) pedagogies, (3) evaluation strategies, and (4) barriers. METHODS: A PRISMA-guided (preferred reporting items for systematic reviews and meta-analyses) literature search strategy was conducted to examine the scientific literature. Inclusion criteria were English written literature related to one or more of the four elements of high-level curricular integration in pharmacy schools. RESULTS: After screening titles, abstracts, and full texts, 28 articles were included. The most used organizational thread was disease-oriented (n = 8, 28.5%), and the most reported pedagogy was case studies (n = 11, 39%). Over half of the studies reported how the integration experience was evaluated. Most studies addressed barriers (n = 21, 75%), with the most reported barriers being time (n = 12, 42%) and workload (n = 12, 42%). IMPLICATIONS: This review aimed to define and describe high-level integration within schools of pharmacy through four elements. Numerous and diverse trends were identified, and these four elements should be considered when planning, implementing, evaluating, and reporting curriculum integration experiences.