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Leishmaniasis may occur in three different clinical forms, namely, visceral, mucocutaneous and cutaneous, which are caused by different species of trypanosomatid protozoans of the genus Leishmania. Pentavalent antimonials are the leading treatment for cutaneous leishmaniasis despite the hepatic, renal, and cardiac toxicity. In addition, the response of some Leishmania species to pentavalent antimonials is increasingly poorer, and therefore new and more potent therapeutic alternatives are needed. Arnica montana L., Asteraceae, is a traditional medicinal plant of Europe and preparations of its flowers are commonly used externally to treat disorders of the musculoskeletal system as well as superficial inflammatory conditions. Previous studies have shown that Arnica tincture (AT), an ethanolic extract prepared from the flowerheads of Arnica montana as well as isolated Arnica sesquiterpene lactones (STLs) have antileishmanial activity in vitro against L. donovani and L. infantum, as well as in vivo against L. braziliensis. In this work, we studied the in vitro cytotoxicity and antileishmanial activity of AT and STLs against both L. braziliensis and L. tropica. The in vivo therapeutic effect of AT was studied in hamsters with cutaneous Leishmaniasis (CL) caused by experimental infection with L. braziliensis and L. tropica. Furthermore, various semisolid Arnica preparations were also evaluated against L. braziliensis. The STLs and the AT possess a very high in vitro activity against both Leishmania species with median effective concentrations (EC50) ranging from 1.9 to 5.9 μg/mL. The AT was not cytotoxic for human tissue macrophages, skin fibroblasts, and hepatic cells. The therapeutic response of hamsters infected with L. braziliensis to the topical treatment with AT was 87.5% at a dose of 19.2 μg STL/2× day/60 d, 72.7% at doses of 19.2 μg STL/1× d/60 d and 67% at a dose of 38.4 μg STL/2× d/60 d. In turn, the therapeutic response in hamsters infected with L. tropica was 100% when treated at a dose of 19.2 μg STL/2× day/60 d and 71% at a dose of 38.4 μg STL/2× d/60 d. On the other hand, the effectiveness of treatment with glucantime administered intralesionally at a dose of 200 mg/every three days for 30 days was 62.5% for L. braziliensis and 37.5% for L. tropica infection. These results are promising and encourage the implementation of clinical trials with AT in CL patients as a first step to using AT as a drug against CL., Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster)., This research was funded by the Wilhelm Doerenkamp-Foundation, grant specification: NATVANTAGE RESEARCH GRANT 2018.

Aims Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). Methods We searched the literature regarding withdrawn drugs due to safety-related issues (n = 391) to compare them with all available small-molecule drugs (n = 1633). We examined their chiral status and assigned as achiral compound, chiral mixture or pure enantiomer. We compared the mean survival (i.e., nonwithdrawal) time and withdrawal rates of drugs by their chirality, with further stratification by the launch year, ATC-1 (Anatomical Therapeutic Chemical) level and ADR. Results We identified higher withdrawal rate in achiral drugs (hazard ratio 2.1, 95% CI: 1.6-2.7) and chiral mixtures (hazard ratio 2.6, 95% CI: 1.9-3.5) compared to that in pure enantiomers. Pure enantiomers had the longest mean survival time (62.4 +/- 0.8 years), followed by achiral drugs (55.4 +/- 0.9 years, P < .01) and chiral mixtures (52.4 +/- 1.4 years, P < .01). Pure enantiomers had higher survival rates than chiral mixtures if launched before 1941 (P = .02), in 1961-1980 (P < .001) or 1981-2000 (P < .001). Pure enantiomers had lower withdrawal rate (18.2%) vs. chiral mixtures (35.1%, P = .02) in nervous system drugs. Pure enantiomers had lower withdrawal rate than chiral mixtures in hepatotoxic (P < .01) and cardiovascular ADRs (P < .01). Conclusion Our study showed lower likelihood of withdrawal for pure enantiomers compared to that in chiral mixtures and achiral drugs, which was more remarkable for those launched in certain time periods and several ADRs, including hepatotoxicity and cardiovascular toxicity.

Swallowing oral solid dosage forms is challenging in patients with dysphagia who are at risk of aspiration or choking. The most common method to facilitate drug administration in dysphagia patients is to mix the powdered drug with a small amount of thickened water, however little is known about the effects of this method on in vivo bioavailability of drugs. This study aimed to evaluate the impact of thickened liquids on dissolution rate and bioavailability of levetiracetam as a model drug. Powdered commercial tablets of levetiracetam, carbamazepine, atenolol and cefixime were mixed with water thickened with two commercial thickeners, modified maize starch (MS) and xanthan gam (XG), at three thickness levels: nectar, honey and pudding in test groups, and mixed with only water in the control group. At the first stage, the effects of thickened water on in vitro drug release of 4 drugs (levetiracetam, carbamazepine, atenolol and cefixime) were tested by using dialysis membrane method. Addition of both thickeners significantly reduced the release of three drugs compared to the control group, except carbamazepine. Levetiracetam which had the highest solubility was chosen as the model drug for in vivo experiments. In the second stage, New Zealand albino female rabbits (n=24) were divided into two groups as: control group (water+drug, n=6) and test group (thickened water+drug, n=18). Powdered levetiracetam tablets were mixed with water thickened with XG (n=9, 1.2%, 2.4%, 3.6%) and MS (n=9, 4%, 6%, 8%) at three thickness levels and administered to the rabbits by intragastric gavage. Blood samples were collected at 9 time points following administration. After two-weeks of wash-out, test groups were crossed over and sample collection was repeated. Blood samples were analysed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). An in vitro-in vivo correlation (IVIVC) model was developed using in vitro drug dissolution (%) and in vivo plasma concentrations of levetiracetam for control group and test groups. The peak plasma concentration (C-max) was lower and time to reach C-max (t(max)) was relatively higher in test groups compared to control group. The lowest C-max was detected at the highest thickness level, however, the differences between groups were not statistically significant (p=0.117 and p=0.495 for C-max and t(max), respectively). No significant difference in total amount of levetiracetam absorbed (AUC) was found between groups (p=0.215 and p=0.183 for AUC(infinity) and AUC(last), respectively). The comparisons according to the type of thickener also revealed that pharmacokinetic parameters did not significantly differ between groups, except for a significantly lower C-max when drug was mixed with MS-thickened water at nectar consistency (1.2%) compared to drug mixed with XG (4%) at the same thickness level (p=0.038). A good correlation was observed between in vitro and in vivo data, which was characterized by higher r(2) values as the concentration of the thickening agents was increased, but not for all thickness levels studied, indicating an inability of this in vitro model to fully predict the in vivo response. These results suggest that regardless of the thickness level, the administration of levetiracetam with two commercial thickening agents commonly used in dysphagia for safe swallowing, do not affect the pharmacokinetic efficiency and thus, the bioavailability of the drug.

Objectives Aspergillus fumigatus causes several diseases in humans and azole resistance in A. fumigatus strains is an important issue. The aim of this multicentre epidemiological study was to investigate the prevalence of azole resistance in clinical and environmental A. fumigatus isolates in Turkey. Methods Twenty-one centres participated in this study from 1 May 2018 to 1 October 2019. One participant from each centre was asked to collect environmental and clinical A. fumigatus isolates. Azole resistance was screened for using EUCAST agar screening methodology (EUCAST E.DEF 10.1) and was confirmed by the EUCAST E.DEF 9.3 reference microdilution method. Isolates with a phenotypic resistance pattern were sequenced for the cyp51A gene and microsatellite genotyping was used to determine the genetic relationships between the resistant strains. Results In total, resistance was found in 1.3% of the strains that were isolated from environmental samples and 3.3% of the strains that were isolated from clinical samples. Mutations in the cyp51A gene were detected in 9 (47.4%) of the 19 azole-resistant isolates, all of which were found to be TR34/L98H mutations. Microsatellite genotyping clearly differentiated the strains with the TR34/L98H mutation in the cyp51A gene from the strains with no mutation in this gene. Conclusions The rate of observed azole resistance of A. fumigatus isolates was low in this study, but the fact that more than half of the examined strains had the wild-type cyp51A gene supports the idea that other mechanisms of resistance are gradually increasing., Bursa Uludag University Scientific Research Projects Commission [QUAP[T]-2015-5]; Ener Private Health Service Company, This work was partly supported by Bursa Uludag University Scientific Research Projects Commission (QUAP[T]-2015-5) and Ener Private Health Service Company.

Colorectal cancer (CRC) is the third most commonly occurring cancer. While there have been improvements in treatment options for patients, it remains the second leading cause of cancer-related deaths worldwide. CRC develops in a complex multicellular microenvironment, with patients diagnosed with mesenchymal-rich tumours having the lowest disease-free survival. However, the role mesenchymal stromal cells (MSCs) play in tumour promotion and immune invasion has yet to be fully elucidated. Macrophages are the most abundant immune cell type found in CRC, and following the promising results from T cell targeting immunotherapies, macrophages are now under investigation for their potential to be target therapeutically in CRC. The focus of my PhD project was to investigate the role of the inflammatory tumour microenvironment on stromal cell-mediated modulation of macrophage phenotype and function. Inflammatory tumour conditioned media (TCM) generated from CRC cells treated with TNF-α increased the mRNA expression of immunomodulatory factors and pathways related to the regulation of immune cell function in Balb/c MSCs. Inflammatory tumour conditioned MSCdisplayed increased surface expression of the immunomodulatory markers PD-L1 and CD47. CD47 expression was found to be higher on MSC than on cancer cells, while PD-L1 levels were comparable. TCM generated from treating CRC cells with low dose cyclophosphamide (CTX) significantly increased the expression of MSC PD-L1 and CD47. These induced changes in the MSCs were mediated by changes in the cancer cell secretome. Bioinformatic and immunohistochemical analysis of CRC tumours revealed an association between MSCs and macrophages in the tumour microenvironment. Macrophages that were co-cultured with control, TCM or inflammatory TCM treated MSCs showed reduced expression of SIRPα, MHC II, arginase1 and IL-10 while increasing CD206 expression and a suppression of macrophage phagocytic capacity. Targeting PD-1 and SIRPα with receptor blocking antibodies was used to assess if MSC PD-L1 or CD47 were modulating the changes in macrophage phenotype and function. Neither targeting PD-1 nor CD47 altered MSC mediated changes in macrophage expression profile. However, blocking both PD-1 and SIRPα showed a strong trend towards the restoration of macrophage phagocytosis. Furthermore, blocking SIRP-α led to reduced TNF-α secretion following co-culture of macrophages with inflammatory conditioned MSCs. Following from this, a viable 3D hydrogel system containing CRC cells, MSCs and monocytes was developed to better study the complex tumour microenvironment in a more physiologically relevant model. The addition of monocytes and MSCs to the culture system alters the mRNA expression of ECM remodelling proteins fibronectin 1 and MMP2 and altered cancer cell expression of PD-L1, CD47 and EGFR. The presence of MSCs in the 3D model increased the expression of tumour promoting molecules such as serpin E1, CXCL12 and macrophage inhibitory factor. The secretome was further altered by treatment with TNF-α, resulting in the induction of different cytokines and chemokines including IL-6 and GM-CSF. The treatment of the 3D CRC model with PD153035, an EGFR inhibitor, revealed that hydrogels containing MSCs responded differently to this treatment. Taken together, this data demonstrates the role of inflammation on the ability of CRC cells to modulate the mesenchymal stromal compartment of the tumour and how stromal cells, in particular, MSCs, can alter macrophage phenotype and function. We have demonstrated that targeting the PD-L1/PD-1 or CD47/SIRPα signalling axis in MSC-rich inflammatory CRC tumours may aid the restoration of macrophage phagocytosis. Finally, we have a developed a 3D model to study the complex interactions that occur in CRC and that can be used to identify novel targets and test novel therapies. Overall, this project demonstrates that stromal cells in the inflammatory tumour microenvironment can influence macrophage function through the expression of PD-L1 and CD47. We propose that these factors could represent novel therapeutic targets in stromal rich CRC. 2026-06-27

Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI’s Development Therapeutic Program (DTP) division to determine GI50, TGI, and LC50 parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI50 values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possible BrPQ5 interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity of BrPQ5 was assessed, and IC50 values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects of BrPQ5 on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed that BrPQ5 caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However, BrPQ5 did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.

Background and Objective: Infectious diseases constitute a large share of the diseases in the world. The use of irrational antimicrobial treatments causes failure in the treatment and toxic side effects in the patient.The aim of our study is to evaluate the knowledge level and attitudes of the patients who applied to the community pharmacy with an antibiotic prescription regarding the use of antibiotics. Setting and Method: This cross-sectional study was conducted in one community pharmacy in Istanbul (Turkey) between November 2021- February 2022. Each patient’s profile was recorded and a selfstructured questionnaire consisted 14 questions was administered to the patients who applied to the pharmacy with an antibiotic prescription. The questionnaire, which was prepared by the researchers on the basis of the relevant literature studies (1,2) and the answer options were determined as ‘‘true, false, I do not know’’. The questionnaire results were scored according to the relevant articles. All data were analyzed using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) version 13. Main outcome measures: To evaluate the knowledge level and attitudes of the patients regarding the use of antibiotics. Results: Of the 39 patients 66.7% were female, and the mean age was 35.2 ± 1.6. Sixty-one percent of the patients were not working in any job. The majority of the patients (79.5%) applied to the pharmacy with the diagnosis of upper respiratory tract disease. The mean awareness score of the patients regarding the use of antibiotics was determined as 7.8 ± 0.4, and it was found to be higher in those who were actively employed than in those who did not (8.8 ± 0.5 vs. 7.1 ± 0.4; p = 0.022). It was determined that 77% of the patients had a moderate level of knowledge about antibiotics. Conclusion: According to the results of the study, awareness, and knowledge regarding the use of antibiotics were insufficient. Community pharmacists as specialist health professionals have a vital role in the rational use of antibiotics via patient education and monitoring. References: 1. Ling Oh A, Hassali MA, Al-Haddad MS, Syed Sulaiman SA, Shafie AA, Awaisu A. Public knowledge and attitudes towards antibiotic usage: a cross-sectional study among the general public in the state of Penang, Malaysia. J Infect Dev Ctries. 2011;5(5):338–347. Published 2011 May 28. doi:10. 3855/jidc.1502 2. Zaidi SF, Baroom MW, Ibrahim Hanbashi A, et al. Cross-Sectional Survey among General Population Regarding Knowledge and Attitude toward Antibiotic Usage in Western Saudi Arabia. Pharmacy (Basel). 2021;9(2):98. Published 2021 May 1. doi:10. 3390/pharmacy9020098 Disclosure of Interest: None Declared.

Background and Objective Hypertension is the most prevalent chronic disease in older adults. Antihypertensive drug use increases with aging. In some studies, hypotension developing under antihypertensive medication use has been indicated as a potential risk factor for morbidity and mortality in older adults. Our objective was to assess the relationship between hypotension under antihypertensive treatment and incident hospitalization of nursing home residents. Methods We detailed blood pressure measurements of the previous 1-year period that were noted regularly at 2-week intervals and studied their mean values. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) thresholds to define low SBP (

© 2022, AVES. All rights reserved.Background: The objective of the current study was to assess how the coronavirus disease 2019 pandemic has affected mental health services compared to the same period of the year before the pandemic. Methods: The data in the study were retrieved from the databases of the computer systems of the hospitals. All referrals in the child psychiatry outpatient clinic between March 1 and June 30, 2019, and between March 1 and June 30, 2020, constituted the sample. Results: Of the 3110 referrals, 2246 were cases and 864 were repeating examinations. Of the 2246 cases, 70.5% (n = 1583) were admitted in 2019, while 29.5% (n = 663) were admitted in 2020. Of the cases who referred in 2019, 37.3% (n = 590) were female, while this rate was 43.9% (n = 291) in 2020. The mean age of 2019 cases was found to be 9.51 ± 4.17, while the mean age of 2020 cases was found to be 10.39 ± 4.06. While attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, depressive disorder, panic disorder, school refusal, and sleep disorder rates increased significantly, specific learning disorders and mental retardation rates were found to be on the decrease in 2020. In 2019, 47.6% (n = 754) of the cases were followed with medication, and in 2020, this rate increased to 63.2% (n = 419). Conclusion: Pandemic conditions affected the content of public hospital psychiatry referrals significantly. It can be thought that the significant decrease in the number of referrals may be the result of citizens obeying the prohibitions and the fear of disease transmission in families with the onset of the pandemic that precedes the existing psychiatric problems of children.

Background and Objective: Vaccine hesitancy leads to decreases in vaccination rates and causes an increase in preventable epidemics and diseases. The aim of this study is to evaluate the attitudes of patients applying to a community pharmacy regarding vaccine hesitancy during COVID-19. Setting and Method: This study was conducted in one community pharmacy for any reason between September and December 2021, Istanbul, Turkey. The ‘‘Scale of Vaccine Hesitancy’’ (1) (consisted of 12-items) was applied to the patients face to face. Sociodemographic characteristics of the patients were recorded. The results of the questionnaire were calculated according to the scale guideline. The higher score represents the higher vaccine hesitancy. Main outcome measures: Scores obtained from the scale of vaccine hesitancy and correlation of the scores with patients’ parameters such as chronical diseases, Covid-19 disease and vaccination history. Results: Of the 43 patients 90% were female. The mean age was 37.5. Thirty-five percent of the participants had COVID-19 and 69.8% had a family history of COVID-19. About 79.1% have had the COVID-19 vaccine and 76% of those were vaccinated with BioNTech and the rest with Sinovac. The mean of the vaccine hesitancy score was calculated as 27.4 (min 12-max 50). Vaccine hesitancy score was higher for patients who were not vaccinated than who were vaccinated (41.0 vs 24.2; p \0.001). The vaccine hesitancy score was higher in patients with chronic disease (28.1), in chronic medication users (28.8), in those who had COVID-19 history (29.5), and those with a family history of COVID-19 (28.2). Cronbach alpha value of the scale is 0.846. Conclusion: It was determined that unvaccinated patients had higher vaccine hesitancy scores. In addition, vaccine hesitancy score was higher in the patients with chronic disease and who had COVID-19. It is very important to have a high rate of vaccination, especially in a pandemic or life-threatening disease. Therefore, educating and relieving patients can be an important step in overcoming this problem. As pharmacists, the closest position to patients, we have a great responsibility in order to change the perspective on vaccination. References: 1. Kılınc¸arslan MG, Sarıgu¨l B, Toraman C¸, S¸ ahin EM. Development of valid and reliable Scale of Vaccine Hesitancy in Turkish language. Konuralp Medical Journal. 2020;12(3):420–429. doi: 10. 18521/ktd.693711 Disclosure of Interest: None Declared.

Diabetes mellitus (DM) affects the biology of multipotent cardiac stem/progenitor cells (CSCs) and adult myocardial regeneration. We assessed the hypothesis that senescence and senescence-associated secretory phenotype (SASP) are main mechanisms of cardiac degenerative defect in DM. Accordingly, we tested whether ablation of senescent CSCs would rescue the cardiac regenerative/reparative defect imposed by DM. We obtained cardiac tissue from nonaged (50- to 64-year-old) patients with type 2 diabetes mellitus (T2DM) and without DM (NDM) and postinfarct cardiomyopathy undergoing cardiac surgery. A higher reactive oxygen species production in T2DM was associated with an increased number of senescent/dysfunctional T2DM-human CSCs (hCSCs) with reduced proliferation, clonogenesis/spherogenesis, and myogenic differentiation versus NDM-hCSCs in vitro. T2DM-hCSCs showed a defined pathologic SASP. A combination of two senolytics, dasatinib (D) and quercetin (Q), cleared senescent T2DM-hCSCs in vitro, restoring their expansion and myogenic differentiation capacities. In a T2DM model in young mice, diabetic status per se (independently of ischemia and age) caused CSC senescence coupled with myocardial pathologic remodeling and cardiac dysfunction. D + Q treatment efficiently eliminated senescent cells, rescuing CSC function, which resulted in functional myocardial repair/regeneration, improving cardiac function in murine DM. In conclusion, DM hampers CSC biology, inhibiting CSCs' regenerative potential through the induction of cellular senescence and SASP independently from aging. Senolytics clear senescence, abrogating the SASP and restoring a fully proliferative/differentiation-competent hCSC pool in T2DM with normalization of cardiac function. ispartof: DIABETES vol:71 issue:5 pages:1081-1098 ispartof: location:United States status: published

Arnica tincture is a traditional herbal medicine used to treat blunt injuries, e.g., bruises and squeezes. In addition, a potential new use in the treatment of cutaneous leishmaniasis is currently under investigation. Therefore, detailed information about the dermal absorption of the tincture and especially its bioactive constituents, sesquiterpene lactones (STLs) of the helenalin- and 11α,13-dihydrohelenalin type, is mandatory. Consequently, this article reports on dermal absorption studies of Arnica tincture using diffusion cells and porcine skin as well as two human skin samples with different permeability. The amounts of STLs on the skin surfaces, in skin extracts and in the receptor fluids were quantified by ultra-high-performance liquid chromatography with high-resolution mass spectrometry (UHPLC-HRMS). It was found that Arnica STLs permeated into the receptor fluid already 4 h after the application, but the amount was rather low. Within 48 h, a maximum of 8.4%, 14.6% and 36.4% of STLs permeated through porcine skin, human skin A (trans-epidermal water loss (TEWL) = 11.518 g·m−2·h−1) and the more permeable human skin B (TEWL = 17.271 g·m−2·h−1), respectively. The majority of STLs was absorbed (penetrated into the skin; 97.6%, 97.8% and 99.3%) after 48 h but a huge portion could not be extracted from skin and is expected to be irreversibly bound to skin proteins. To better visualize the analytes in different skin layers, a fluorescence-labeled STL, helenalin 3,4-dimethoxycinnamate, was synthesized. Fluorescence microscopic images depict an accumulation of the fluorescent derivative in the epidermis. For the treatment of local, cutaneous complaints, an enrichment of the bioactive substances in the skin may be considered beneficial., Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster)., This research was funded by the Wilhelm Doerenkamp-Foundation, grant specification: NATVANTAGE RESEARCH GRANT 2018.

Background and Aims: Dapagliflozin (DAPA) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of type 2 diabetes mellitus (T2DM) as a monotherapy or combination therapy with other antidiabetic medicines. The Food and Drug Administration (FDA) recently approved DAPA to minimize the risk of hospitalization due to heart failure in patients with T2DM because of its antihypertensive and antihyperglycemic activities. However, further study of DAPA is necessary to ensure the safety of patients.Methods: T2DM was induced by streptozotocin (STZ) injection (35 mg/kg b.w. i.p.) in male rats that were fed a high-fat diet for two weeks before STZ injection. The diabetic rats were exposed to 10 mg/kg DAPA by oral gavage during sub-acute treat- ment. Total cholesterol levels and oxidative stress parameters were evaluated. Heart tissues were histologically examined, and cardiac troponin T (cTnT) levels were measured.Results: DAPA has the potential to inhibit diabetes-induced oxidative stress and morphologic damage to heart tissue, and increased cTnT levels of the heart, which is important for cardiac contractility.Conclusion: DAPA might have a protective effect on the heart at a 10 mg/kg oral dose; however, further experimental and clinical studies are required to clarify the cardio-protective potential of DAPA.

Aims: We aimed to investigate putative neuroprotective effects of nesfatin-1 on oxidative brain injury and memory dysfunction induced by a single epileptic seizure and to compare these effects with those of antiepileptic phenytoin. Main methods: Wistar albino rats were randomly divided into a control group and pentylenetetrazole (PTZ)-seizure groups pretreated intraperitoneally (ip) with saline or nesfatin-1 (NES-1; 0.3, 1 or 3 μg/kg/day) or phenytoin (PHE; 40 mg/kg/day) or PHE + NES-1 (0.3 μg/kg/day) at 30 min before the single-dose PTZ injection (45 mg/kg; ip). All treatments were repeated at the 24th and 48th h of the provoked epileptic seizure. Passive-avoidance test was performed to assess memory function. The rats were decapitated at the 72nd hour of seizures and brain tissues were analyzed for histopathological changes and for measuring levels of malondialdehyde, glutathione, myeloperoxidase activity and reactive oxygen/nitrogen species. Key findings: In parallel to the effects of phenytoin, NES-1 reduced seizure score, elevated antioxidant glutathione content, depressed generation of nitric oxide and protected against seizure-induced neuronal damage. Additionally, increased malondialdehyde levels and elevated glial fibrillary acidic protein immunoreactivity in the cortex and hippocampus were decreased and memory dysfunction was improved by NES-1. However, NES-1 had no impact on myeloperoxidase activity or production of reactive oxygen species in the brain. Significance: The findings of the present study demonstrate that nesfatin-1 treatment provides neuroprotection against seizure-induced oxidative damage and memory dysfunction by inhibiting reactive nitrogen species and upregulating antioxidant capacity, indicating its potential in alleviating memory deficits and increasing the effectiveness of conventional anti-convulsant therapies. © 2022 2-s2.0-85124233306 35123998

Anksiyete; nedeni bilinmeyen, içten gelen, belirsiz, korku, kaygı, sıkıntı, kötü bir şey olacakmış endişesi ile yaşanan bir bunaltı duygusudur. Anksiyete bozuklukları toplumda en yaygın görülen ruhsal bozukluklardır. 1990’lardan bu yana anksiyete bozuklukları üzerinde daha fazla durulmaktadır. Dünyada çeşitli ülkelerde yapılan çalışmalarda yaşam boyu yaygınlığa ilişkin benzer oranlar saptanmıştır. Tedavi genellikle farmakoterapi ve / veya psikoterapiden oluşur. Antidepresan ajanlar, seçici serotonin geri alım inhibitörleri (SSRI'lar) gibi eski trisiklik antidepresanlardan (TCA'lar) daha güvenli bir yan etki profiline ve daha yüksek kullanım kolaylığına sahip daha yeni ajanlar olup anksiyete bozukluklarının tedavisinde tercih edilen ilaçlardır. Çalışmanın amacı; anksiyete tedavisinde en çok kullanılan SSRI ve SNRI grubu etken maddelerin tayini için son yıllarda yapılmış analitik çalışmaları araştırmak ve sunmaktır. SSRI ve SNRI grubu etken maddelerin analizleri HPLC-ESI-MS, MAE/UPLC-TOF-MS, FPSE/HPLC-DAD, UPLC-MS-MS, HPTLC, SPE/HPLC, LC-MS-MS gibi yöntemlerle incelenmiştir. İncelenen çalışmaların sonuçlarında araştırmacılar etken maddelerin miktar tayinleri için geliştirdikleri yöntemlerin basit, kesin, doğru, hassas, hızlı ve ekonomik olduğunu doğrulamışlardır. Anxiety; it is a feeling of anxiety, with an unknown reason, sincere, uncertain, fear, anxiety, distress, worry that something bad will happen. Anxiety disorders are the most common mental disorders in the general public. Since the 1990s, more attention has been paid to anxiety disorders. Similar rates of lifetime prevalence were found in studies conducted in various countries around the world. Treatment usually consists of pharmacotherapy and / or psychotherapy. Antidepressant agents are the drugs of choice for the treatment of anxiety disorders, which are newer agents that have a safer side effect profile and higher ease of use than old tricyclic antidepressants (TCAs), such as selective serotonin reuptake inhibitors (SSRIs). Purpose of the study; to research and present analytical studies conducted in recent years for the determination of SSRI and SNRI group active substances that are most commonly used in the treatment of anxiety. Analysis of SSRI and SNRI group active substances were analyzed by methods such as HPLC-ESI-MS, MAE/UPLC-TOF-MS, FPSE/HPLC-DAD, UPLC-MS-MS, HPTLC, SPE/HPLC, LC-MS-MS. In the results of the studies examined, the researchers confirmed that the methods they developed for the quantification of active substances were simple, precise, accurate, sensitive, fast and economical.

© 2021 Elsevier LtdRemoval of hazardous herbicides from the aqueous solution is critical for overcoming health-related issues across the wider population. In the current work, we have prepared sodium alginate (SAlg), dextrin, and acrylic acid (AA) based cross-linked hydrogels, composed of bentonite incorporated in the biocompatible hydrogel matrix. This hydrogel composite can remove highly toxic herbicide paraquat (PQ). As-synthesised hydrogel (SAlg/dextrin-cl-PAA) and hydrogel composite (SAlg/dextrin-cl-PAA/bentonite) were further analysed by infra-red spectroscopy (FTIR), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and thermogravimetric analysis (TGA/DSC). For the first time, PQ adsorption onto sodium and dextrin-based hydrogel was also evaluated. The measured highest removal capacities were 76.923 and 90.909 mg g−1 for the SAlg/dextrin-cl-PAA and SAlg/dextrin-cl-PAA/bentonite, respectively. Pseudo-second-order (PSO) and Langmuir isotherm models have shown to be best suited for accurately describing the adsorption mechanism. A thermodynamics study verified that the adsorption of PQ on adsorbents is spontaneous, favourable and exothermic. Moreover, reusability analysis shows that the adsorbents possess good reproducibility even after six successive cycles. The adsorption results demonstrate that the synthesised adsorbents are very efficient for removing herbicides (PQ) from wastewater.

Compared with standard glycemic control, intensive glycemic control caused increased mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Preliminary data from several studies suggest that intensive glycemic control is associated with QT prolongation, which may lead to ventricular arrhythmias as a possible explanation of this increased mortality. We sought to assess the effects of intensive glycemic control and intensive blood pressure control on the risk of incident QT prolongation. Cox proportional hazards models were used to compare the risk of incident QT prolongation (>460 ms in women or >450 ms in men) in the intensive versus standard glycemic control arms. Over a combined 48,634 person-years of follow-up (mean 4.9), 634 participants (6.4%) developed a prolonged QTc. Participants in the intensive glycemic control arm did not have an increased risk of QT prolongation. Similarly, a strategy of intensive blood pressure control did not result in a significant change in risk of prolonged QTc. Sensitivity analyses using alternative QT correction formulas (Hodges and Bazett) yielded overall similar findings. In conclusion, the increased mortality observed in the intensive glycemic control arm in the ACCORD trial is not likely to be explained by QT prolongation leading to lethal ventricular arrhythmias.

Sulfonylureas (SUs) provide an efficacious first-line treatment in patients with hepatocyte nuclear factor 1α (HNF1A) diabetes, but SUs have limitations due to risk of hypoglycemia. Treatment based on the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) is characterized by their glucose-dependent insulinotropic actions without risk of hypoglycemia. The effect of SUs together with GIP or GLP-1, respectively, on insulin and glucagon secretion in patients with HNF1A diabetes is currently unknown. To investigate this, 10 HNF1A mutation carriers and 10 control subjects without diabetes were recruited for a double-blinded, placebo-controlled, crossover study including 6 experimental days in a randomized order involving 2-h euglycemic-hyperglycemic clamps with coadministration of: 1) SU (glimepiride 1 mg) or placebo, combined with 2) infusions of GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min), or saline (NaCl). In HNF1A mutation carriers, we observed: 1) hypoinsulinemia, 2) insulinotropic effects of both GIP and GLP-1, 3) additive to supra-additive effects on insulin secretion when combining SU+GIP and SU+GLP-1, respectively, and 4) increased fasting and arginine-induced glucagon levels compared with control subjects without diabetes. Our study suggests that a combination of SU and incretin-based treatment may be efficacious in patients with HNF1A diabetes via potentiation of glucose-stimulated insulin secretion.

We assessed whether oral insulin slowed metabolic decline after 1 year of treatment in individuals at high risk for type 1 diabetes. Two oral insulin trials that did not show efficacy overall and had type 1 diabetes as the primary end point were analyzed: the Diabetes Prevention Trial–Type 1 (DPT-1) and the TrialNet oral insulin trials. Oral glucose tolerance tests at baseline and after 1 year of treatment were analyzed. Among those at high risk (with a Diabetes Prevention Trial–Type 1 Risk Score [DPTRS] ≥6.75), the area under the curve (AUC) C-peptide increased significantly from baseline to 1 year in each oral insulin group, whereas the AUC glucose increased significantly in each placebo group. At 1 year, the AUC C-peptide/AUC glucose (AUC Ratio) was significantly higher in the oral insulin group than in the placebo group in each trial (P < 0.05; P = 0.057 when adjusted for age in the TrialNet trial) and in both trials combined (P < 0.01 with or without adjustment for age). For a DPTRS

Schwann cell–derived exosomes communicate with dorsal root ganglia (DRG) neurons. The current study investigated the therapeutic effect of exosomes derived from healthy Schwann cells (SC-Exos) on diabetic peripheral neuropathy (DPN). We found that intravenous administration of SC-Exos to type 2 diabetic db/db mice with peripheral neuropathy remarkably ameliorated DPN by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. These functional improvements were associated with the augmentation of epidermal nerve fibers and remyelination of sciatic nerves. Quantitative RT-PCR and Western blot analysis of sciatic nerve tissues showed that SC-Exo treatment reversed diabetes-reduced mature form of miRNA (miR)-21, -27a, and -146a and diabetes-increased semaphorin 6A (SEMA6A); Ras homolog gene family, member A (RhoA); phosphatase and tensin homolog (PTEN); and nuclear factor-κB (NF-κB). In vitro data showed that SC-Exos promoted neurite outgrowth of diabetic DRG neurons and migration of Schwann cells challenged by high glucose. Collectively, these novel data provide evidence that SC-Exos have a therapeutic effect on DPN in mice and suggest that SC-Exo modulation of miRs contributes to this therapy.

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110δ, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform δ is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110δ inactivation was found to attenuate pathological retinal angiogenesis. p110δ inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110δ constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.

Objective: Salicylic acid (SA) is a keratinolytic agent also used as preservative in cosmetic products. Green chemistry, known as sustainable chemistry, is the design of products and processes eliminating the use of chemicals. It is applicable throughout a chemical product's life cycle, including its design, manufacture, use, and final disposal. The aim of this study was to synthesize SA with green chemistry methods using different amounts of wintergreen oil and to optimize the relevant steps in this path.Materials and Methods: The SA was synthesized from natural wintergreen oil using green chemistry methods. First laboratory-scale synthesis was developed and 15 laboratory-scale synthesis trial patterns, using reaction temperature, wintergreen oil-sodium hydroxide molar ratio, sodium hydroxide-water weight ratio, reaction time and pH were performed. Purity was analysed with gas chromatography-mass spectrometry (GC-MS) and moisture analysis was performed.Results and Conclusion: As a result of pilot production run with 1 kg, 5 kg, and three batches of 20 kg of wintergreen oil, SA was produced with a yield range of 91.06-93.92 %. The resulting SA batches had a purity of approximately 99%. This is a sufficient degree of purity for SA to be used as a raw material in cosmetics products. Filtering the SA solution using a filter press reduced crystal drying time and brought down the total production time to eight days

Introduction Underlying liver disease and the intrinsic chemoresistance have historically hampered the development of efficacious treatments in HCC. However, in the last few years, immunotherapy-based combinations have emerged as efficacious therapeutic strategy in this setting. This paper critically summarizes the recent therapeutic progress in the systemic treatment of HCC. Area covered This paper examines the preclinical rationale of the following combinations in HCC: dual checkpoint inhibitors, immune checkpoint inhibitors plus anti-angiogenic agents, and immune checkpoint inhibitors plus tyrosine kinase inhibitors. Results of recent clinical studies are presented, along with a brief overview of ongoing and future trials. Expert opinion The approval of atezolizumab plus bevacizumab and the positive results of the HIMALAYA trial have broadened the therapeutic scenario for advanced HCC, opening, at the same time, new challenges. First of all, predictive biomarkers to allocate patients to the best treatment are eagerly required; second, specific studies are urgently needed to define the use of new combinations in patients usually excluded from clinical trials, e.g. those with deranged liver function and HIV or transplant recipients. Finally, with new combinations being translated into earlier stages, profound changes are soon expected in the adjuvant and neoadjuvant setting.

© 2022, Faculdade de Ciencias Farmaceuticas (Biblioteca). All rights reserved.Testicular damage is one of the most hazardous effects of chemotherapy as it is frequently associated with oligozoospermia and azoospermia. This study aimed at evaluating the protective effect of melatonin in a rat model of busulfan-induced testicular injury. Rats were divided into four groups: control, melatonin, busulfan, busulfan plus melatonin. After 15 days, the semen was collected from the epididymis and testes were assessed. Sperm removed from cauda epididymis and analyzed for sperm count and viability. Testis tissues were also removed, fixed in formalin and were embedded in paraffin. Sections of testis tissue were stained with hematoxylin-eosin for histological examination and prepared for TUNEL (Terminal deoxynucleotide transferase dUTP Nick End Labeling) assay to detect apoptosis and PCNA (proliferating cell nuclear antigenassay) to detect proliferation cells. Serum and testes supernatants were separated to detect testosteron level and oxidative stress parameters. In histological examination, degenerative changes in seminiferous tubules were observed in the experimental groups. In biochemical examination, the total oxidant status (TOS) levels in Busulfan group were significantly higher than in the control group while the total antioxidant status (TAS) levels of all the groups were similar. In conclusion, the beneficial properties of melatonin treatment by its potent anti-oxidants may reduce adverse effects of chemotherapy in the reproductive system in a rodent system.

© 2022 Marmara University Press.Cisplatin (CP), which is the most commonly used anticancer agent to treat several solid tumors, may cause acute kidney injury (AKI) as the major limiting factor for its clinical use. Obestatin (OB) is a ghrelin gene-derived peptide produced in several tissues and has shown anti-oxidant, anti-apoptotic, and anti-inflammatory effects in many experimental models. This study investigated the effect of OB treatment on nephrotoxicity induced by CP. Rats were divided into 4 groups as two control (1 ml/kg, saline, intraperitoneal (ip), single dose) and two CP-induced (7 mg/kg, ip, single dose) AKI groups (8 rats in each group). Immediately after the CP injection and the following two days, injections of OB (10 µg/kg, ip) were performed. Rats were decapitated at the end of 72 hours. Blood and kidney tissue samples were taken for biochemical and histopathological measurements. The results of the present study revealed that serum creatinine and BUN levels were significantly increased in the CP-induced AKI group when compared to the control group. Treatment with OB improved kidney functions and ameliorated renal oxidative injury and maintained oxidative balance in the CP-induced AKI model, which was revealed by elevated malondialdehyde and depleted glutathione levels. TUNEL scores also demonstrated that CP increased the apoptotic response, while OB treatment abolished it. CP-induced medullary and cortical injuries were also partially reversed by OB treatment. Thus, our findings show that OB alleviates CP-induced nephrotoxicity in rats through the abolishment of oxidative stress and apoptosis.

Favipiravir displays a rapid viral clearance, a high recovery rate and broad therapeutic safety; however, its oral administration was associated with systemic side effects in susceptible patients. Considering that the pulmonary route could provide a high drug concentration, and a safer application with less absorption into systemic circulation, it was aimed to elucidate whether favipiravir delivered via soft-mist inhaler has any deleterious effects on lung, liver and kidney tissues of healthy rats. Wistar albino rats of both sexes (n = 72) were placed in restrainers, and were given either saline or favipiravir (1, 2.5, 5 or 10 mg/kg in 1 mL saline) by inhalation within 2 min for 5 consecutive days. On the 6th day, electrocardiographic recording was obtained, and cardiac blood and lung tissues were collected. Favipiravir did not alter cardiac rhythm, blood cell counts, serum levels of alanine transaminase, aspartate transaminase, blood urea nitrogen, creatinine, urea or uric acid, and did not cause any significant changes in the pulmonary malondialdehyde, myeloperoxidase activity or antioxidant glutathione levels. Our data revealed that pulmonary use of favipiravir via soft-mist inhaler enables a high local concentration compared to plasma without oxidative lung injury or cardiac or hepatorenal dysfunction. WOS:000883575200001 Q1

In this research, the effect of thiol functional groups on bovine serum albumin (BSA)/chitosan (Chi) based buccal mucoadhesive patch was investigated. Thiolated BSA (BSA-SH) was prepared via 2-mercaptoethanol. FTIR and 1H NMR results confirmed that BSA-SH was synthesized successfully. The buccal mucoadhesive patches were fabricated by the solvent casting method. Following the structural characterization of BSA/Chi and BSA-SH/Chi buccal patches, the mechanical characterization was performed by tensile tests. The drug release from triam- cinolone acetonide (TR) loaded buccal patches was evaluated in-vitro in simulated salivary. According to the ex- vivo buccal adhesion experiments, the mechanical and mucoadhesion properties of BSA-SH/Chi buccal patch had improved compared to BSA/Chi buccal patch. The total cumulative TR permeated after 12 h was higher for BSA- SH/Chi than BSA/Chi buccal patches. The developed mucoadhesive buccal patches were found to be biocom- patible in vitro. To conclude, the thiolated BSA-SH/Chi buccal adhesive patch is a promising biomaterial for a satisfied drug delivery, which provides advantages for various oral applications. 2-s2.0-85132367698

Objective: This study aimed to evaluate the effects of potential risk factors on antihypertensive treatment success. Methods: Patients with hypertension who were treated with antihypertensive medications were included in this study. Data from the last visit were analyzed retrospectively for each patient. To evaluate the predictive models for antihypertensive treatment success, data mining algorithms (logistic regression, decision tree, random forest, and artificial neural network) using 5-fold cross-validation were applied. Additionally, study parameters between patients with controlled and uncontrolled hypertension were statistically compared and multiple regression analyses were conducted for secondary endpoints. Results: The data of 592 patients were included in the analysis. The overall blood pressure control rate was 44%. The performance of random forest algorithm (accuracy = 97.46%, precision = 97.08%, F1 score = 97.04%) was slightly higher than other data mining algorithms including logistic regression (accuracy = 87.31%, precision = 86.21%, F1 score = 85.74%), decision tree (accuracy = 76.94%, precision = 70.64%, F1 score = 76.54%), and artificial neural network (accuracy = 86.47%, precision = 83.85%, F1 score = 84.86%). The top 5 important categorical variables (predictive correlation value) contributed the most to the prediction of antihypertensive treatment success were use of calcium channel blocker (−0.18), number of antihypertensive medications (0.18), female gender (0.10), alcohol use (−0.09) and attendance at regular follow up visits (0.09), respectively. The top 5 numerical variables contributed the most to the prediction of antihypertensive treatment success were blood urea nitrogen (−0.12), glucose (−0.12), hemoglobin A1c (−0.12), uric acid (−0.09) and creatinine (−0.07), respectively. According to the decision tree model; age, gender, regular attendance at follow-up visits, and diabetes status were identified as the most critical patterns for stratifying the patients. Conclusion: Data mining algorithms have the potential to produce predictive models for screening the antihypertensive treatment success. Further research on larger populations and longitudinal datasets are required to improve the models.

© 2022 Marmara University Press.The aim of this study is to perform therapeutic drug monitoring for isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) in pediatric tuberculosis patients. The study was carried out in 3 different training-research hospitals in Istanbul, Türkiye between 2011 and 2012. The pediatric patients (aged ≤14 years) who initiated the standard primary anti-tuberculosis therapy were included in this study. The serum samples were collected 3 hours after the first medication doses were given on the 5th day of treatment. Chromatographic experiments were performed on an Agilent 1100 High-Performance Liquid Chromatography (HPLC) system, and the separation was carried out on a Nova-Pak C18 (3.9x150 mm, 5 μm, Merck) analytical column. In this HPLC method, the gradient elusion delivered 3% to 40% (v/v) acetonitrile in phosphate buffer was used, and diode array detector. Twenty-three children (60.9% male) patients were included with a mean age of 111.70 ± 59.94 months. Plasma levels were measured sub-therapeutically for INH in 14, RIF in 10, and PZA in 5 patients, according to the normal range of adult patients. Maximum plasma concentrations after three hours were found between 0.53-14.02 mg/L for INH, 11.17-60.39 mg/L for PZA, 2.15-16.75 mg/L for RIF. In conclusion, this method has been successfully applied to simultaneously determine RIF, INH, and PZA plasma levels in pediatric tuberculosis patients. RIF and INH plasma levels were found to be lower in pediatric patients with tuberculosis compared to target range of adult patients.

Obesogens affect lipid metabolism, and genetic or epigenetic factors may also contribute to the progression of obesity. Endocrine-disrupting chemicals (EDCs) are the most striking among obesogens. Bisphenol A (BPA) is an estrogenic EDC used in food containers, adhesives, dye powders, and dental fillers. We aimed to elucidate molecular mechanisms of BPA’s obesogenic effects focusing on obesogenic pathways in the liver including fibroblast growth factor (FGF) and Dnmt3a which is its epigenetic regulator, oxidant-antioxidant status, and inflammatory cytokines. Zebrafish were divided into three groups as control, low-dose BPA (1 μm BPA), and high-dose BPA groups (10 μm BPA). At the end of 30 days, oral glucose tolerance test (OGTT) was performed, fasting blood glucose levels were measured, and hepatopancreas tissues were taken. Malondialdehyde (MDA) levels, superoxide dismutase (SOD), glutathione S-transferase (GST), and nitric oxide (NO) activities were examined in the hepatopancreas. Inflammatory cytokines, lepa, fgf21, and dnmt3a expressions were determined by RT-PCR. BPA exposure increased the body weights, il1ß, tnfα, il6, lepa, fgf21, and dnmt3a expressions, impaired glucose tolerance, and oxidant–antioxidant status in a dose-dependent manner. Hepatocyte degeneration, lipid vacuolization, and vasocongestion were observed in both BPA-exposed groups. Our study suggests impaired glucose tolerance, oxidant–antioxidant balance, increased inflammatory response, fgf21 expression, and dnmt3a expressions as the possible mechanisms for the BPA-induced obesity model in zebrafish.

Integrating clinical pharmacists in a multidisciplinary patient care team improves the treatment process by identifying and resolving drug-related problems (DRPs). The aim of the study was to determine the effect of clinical pharmacist intervention for DRPs in the gastroenterology service. The first period of the study was conducted between 15.06.2018 and 15.02.2019. Eighty patients admitted to the gastroenterology ward, who used at least one medication, were included in \"the study group\". The clinical pharmacist participated in ward rounds and made interventions to solve identified DRPs. In the second period of the study, the control group consisted of 80 patients admitted to the same ward between 01.03.2019 and 06.06.2019. DRPs were determined only from the data obtained from the hospital system in the control group. DRPs were classified according to the European Pharmaceutical Care Network (PCNE V9.1). A total of 136 and 46 with an average of 1.7 and 0.57 DRPs per patient (p

© 2023 by the authors.Pharmaceutical residues in water and wastewater have become a worldwide problem with environmental and public health consequences. Antibiotics are of special importance because of the emergence of antibiotic-resistant genes. This study evaluates the adsorptive removal of four common fluoroquinolone antibiotics by using natural colemanite as an alternative adsorbent for the first time. Batch adsorption experiments were conducted for the mixture of fluoroquinolones as well as for individual compounds during the isotherm studies. Adsorption kinetic results indicated that the process followed the pseudo-second-order (PSO) model, while the Langmuir model described the sorption isotherms. The effects of pH and temperature on adsorption performance were determined, and the results indicated that the adsorption was endothermic and spontaneous, with increasing randomness at the solid–liquid interface. The effects of real water and wastewater matrices were tested by using tap water, surface water, and wastewater samples. Reusability experiments based on five adsorption–desorption cycles indicated that the adsorption performance was mostly retained after five cycles. The adsorption mechanism was elucidated based the material characterization before and after adsorption. The results indicate that colemanite can be used as an effective and reusable adsorbent for fluoroquinolone antibiotics as well as for other pollutants with similar physicochemical properties.

Human microsomal prostaglandin E synthase (mPGES)-1 is a glutathione-dependent membrane-bound enzyme which is involved in the terminal stage of prostaglandin E2 (PGE2) synthesis. It has been well reported as a key target for the discovery of new anti-inflammatory and anti-cancer drugs. Specific in- hibitors of mPGES-1 are anticipated to selectively restrain the generation of PGE2 induced by the in- flammatory stimuli, without obstructing of the regular biosynthesis of other homeostatic prostanoids. Therefore, the design of mPGES-1 inhibitors can represent a better choice to take control of PGE2 asso- ciated diseases, compared with conventional non-steroidal anti-inflammatory drugs and cyclooxygenase (COX) inhibitors, which are known for their serious side effects. Although there is an intensive effort for the identification of mPGES-1 inhibitors, none of the unveiled molecules so far have reached the clini- cal market. Therefore, the development of novel mPGES-1 inhibitors with proper drug-like properties is still an unmet medical need. As a continuation of our research for the identification of new chemotypes which might inhibit this enzyme, we now report the design and synthesis of 3-aryloxymethyl-5-[(2-oxo- 2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as inhibitors of human mPGES-1. All syn- thesized compounds were characterized by FTIR, 1H NMR, 13C NMR (for compounds 12, 14, 15, 26, 27), HMBC (for compounds 6, 7, 8, 16, 19, 23, 28), and MS data. Twenty-four target compounds 7–30 were screened for their mPGES-1/COX-2 inhibitory activities as well as their cytotoxicity. Of these compounds, 20 and 24 showed potent mPGES-1 inhibition by IC50 values of 0.224±0.070 μM and 1.08±0.35 μM, re- spectively. These two compounds have also been observed to inhibit angiogenesis in matrigel tube forma- tion assay with no toxicity toward HUVEC cells. In silico studies were also held to understand inhibition mechanisms of the most active compounds using molecular docking, molecular dynamics calculations and ADMET predictions.

ObjectiveExploration of the factors that influence hospital doctors’ antibiotic prescribing decisions when treating children with respiratory symptoms in UK emergency departments.MethodsA qualitative study using semistructured interviews based on a critical incident technique with 21 physicians of different grades and specialties that treat children in the UK. Interviews were audio-recorded then transcribed verbatim and analysed using thematic analysis.ResultsFour themes were identified. These themes illustrate factors which influence clinician prescribing. The three principal themes were authorities, pressures and risk. The fourth transcending theme that ran through all themes was clinician awareness and complicity (‘knowing but still doing’).ConclusionsHospital doctors prescribe antibiotics even when they know they should not. This appears to be due to the influence of those in charge or external pressures experienced while weighing up the immediate and longer term risks but clinicians do this with full insight into their actions. These findings have implications for invested parties seeking to develop future antimicrobial stewardship programmes. It is recommended that stewardship interventions acknowledge and target these themes which may in turn facilitate behaviour change and antimicrobial prescribing practice in emergency departments.

It is considered as a rnusluoom with brQad therapeutic properties, having potential biological effects such as antiturnor, antioxidant activities, high cholesterol, immunomodulatory, antihypeftensive, antidiabetic, cancer therapy and antilipenlic. Maitake rnushrooms and the maitake D-fractiorr prepared from them include a type of polysacchalide called beta glucan. Beta glucans stirnulatg the immune system and attack cancer; macrophages, T-cells, natural killer cells, and interleukin 1 and p. lt has been found that the polysacchalides in the structure of Maitake mnshrooms have a very large mplecular weight. Maitake mushroorns can be found in ma4y ways in the food market. The preferred fonns for use here in are the maitake rnushrooms, in the form ofliquid extracts, the n-raitake mnshroom in the forrn of capsules and tl-re maitake mushroorn in the form of tea. The aim of this study is to ereate a reView gontaining up-to-date information about the antioxidant propefiies of Maitake mushroom(Grifulafrontlosa), its polysaccharides and analytical methods used in the detemination of beta slucan.

IntroductionCOVID-19 has caused millions of hospitalisations and deaths globally. A range of vaccines have been developed and are being deployed at scale in the UK to prevent SARS-CoV-2 infection, which have reduced risk of infection and severe COVID-19 outcomes. Those with COVID-19 are now being treated with several repurposed drugs based on evidence emerging from recent clinical trials. However, there is currently limited real-world data available related to the use of these drugs in routine clinical practice. The purpose of this study is to address the prevailing knowledge gaps regarding the use of dexamethasone, remdesivir and tocilizumab by conducting an exploratory drug utilisation study, aimed at providing in-depth descriptions of patients receiving these drugs as well as the treatment patterns observed in Scotland.Methods and analysisRetrospective cohort study, comprising adult patients admitted to hospital with confirmed or suspected COVID-19 across five Scottish Health Boards using data from in-hospital ePrescribing linked to the Early Estimation of Vaccine and Anti-Viral Effectiveness (EAVE II) COVID-19 surveillance platform. The primary outcome will be exposure to the medicines of interest (dexamethasone, remdesivir, tocilizumab), either alone or in combination; exposure will be described in terms of drug(s) of choice; prescribed and administered dose; treatment duration; and any changes in treatment, for example, dose escalation and/or switching to an alternative drug. Analyses will primarily be descriptive in nature.Ethics and disseminationEthical and information governance approvals have been obtained by the National Research Ethics Service Committee, South East Scotland 02 and the Public Benefit and Privacy Panel for Health and Social Care, respectively. Findings from this study will be presented at academic and clinical conferences, and to the funders and other interested parties as appropriate; study findings will also be published in peer-reviewed journals. Publications will be available on the EAVE II website (https://www.ed.ac.uk/usher/eave-ii/key-outputs/our-publications), alongside lay summaries and infographics aimed at the general public. Press releases will also be considered, if appropriate.

ObjectivesOpioid-induced respiratory depression (OIRD) and oversedation are rare but potentially devastating adverse events in hospitalised patients. We investigated which features predict an individual patient’s risk of OIRD or oversedation; and developed a risk stratification tool that can be used to aid point-of-care clinical decision-making.DesignRetrospective observational study.SettingTwelve acute care hospitals in a large not-for-profit integrated delivery system.ParticipantsAll inpatients ≥18 years admitted between 1 July 2016 and 30 June 2018 who received an opioid during their stay (163 190 unique hospitalisations).Main outcome measuresThe primary outcome was occurrence of sedation or respiratory depression severe enough that emergent reversal with naloxone was required, as determined from medical record review; if naloxone reversal was unsuccessful or if there was no evidence of hypoxic encephalopathy or death due to oversedation, it was not considered an oversedation event.ResultsAge, sex, body mass index, chronic obstructive pulmonary disease, concurrent sedating medication, renal insufficiency, liver insufficiency, opioid naïvety, sleep apnoea and surgery were significantly associated with risk of oversedation. The strongest predictor was concurrent administration of another sedating medication (adjusted HR, 95% CI=3.88, 2.48 to 6.06); the most common such medications were benzodiazepines (29%), antidepressants (22%) and gamma-aminobutyric acid analogue (14.7%). The c-statistic for the final model was 0.755. The 24-point Oversedation Risk Criteria (ORC) score developed from the model stratifies patients as high (>20%, ≥21 points), moderate (11%–20%, 10–20 points) and low risk (≤10%, ConclusionsThe ORC risk score identifies patients at high risk for OIRD or oversedation from routinely collected data, enabling targeted monitoring for early detection and intervention. It can also be applied to preventive strategies—for example, clinical decision support offered when concurrent prescriptions for opioids and other sedating medications are entered that shows how the chosen combination impacts the patient’s risk.

SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.

Parkinson’s disease is a multifaceted neurodegenerative disorder that currently has no cure. Chronic neuroinflammation is thought to play a crucial role in the progression of the disease, with neuroinflammation and neurotoxicity driving each other in a self-sustaining cycle that is detrimental to the survival of the neurons. Subsequently, the concept of anti-inflammatory disease therapy for the treatment of Parkinson’s disease has emerged in recent years. The cannabinoid CB2 receptor is an attractive target for anti-neuroinflammatory therapy due to its location on microglia and its immunomodulatory effect on these cells. Thus, the overarching aim of this body of research was to investigate the potential of targeting the CB2 receptor for Parkinson’s disease therapy. Firstly, we assessed the temporal expression of the CB2 receptor in a genetic model of Parkinson’s disease that was induced by administering an adeno-associated viral (AAV) vector which expressed human α-synuclein with the A53T mutation to the rat brain. Following on from this, we endeavoured to enhance the AAV-α-synuclein model using a small molecule α-synuclein aggregator to aid in further studies of the condition. Finally, we investigated the potential of targeting the CB2 receptor for anti-inflammatory disease modification by determining if the pharmacological targeting of this receptor could provide functional neuroprotection in inflammatory rat models. In the AAV-α-synuclein genetic model of Parkinson’s disease, we did not detect any alterations in CB2 gene expression despite a profound upregulation in human α-synuclein expression in the substantia nigra and the striatum. However, there was a decrease in the striatal levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and of the related N-acylethanolamine N-oleoyl ethanolamide (OEA), indicating a dysregulation of the cannabinoid system in this model. Interestingly, an overall decrease in the expression of microglial and astrocytic markers was observed in the substantia nigra, but these alterations were not accompanied by dopaminergic degeneration. Further to this, we sought to enhance the AAV-α-synuclein model of Parkinson’s disease by combining AAV-mediated α-synuclein overexpression with FN075-mediated α-synuclein aggregation. The α-synuclein aggregating molecule FN075 combined with the AAV-α-synuclein vectors exhibited a significant increase in the pathogenic phosphorylated form of α-synuclein, with visible anomalous accumulations. However, there was no significant degeneration of the nigrostriatal dopamine neurons in any group. Finally, we investigated if CB2 agonism produced anti-inflammatory or neuroprotective effects in a viral priming model and in an inflammatory LPS model. We did not observe a significant anti-inflammatory response, but such a role cannot be dismissed, as previous studies have shown the type of model and the particular agonist used results in disparate outcomes. To conclude, dysregulation of the endocannabinoid system may precede nigrostriatal degeneration, with alterations in the levels of 2-AG and OEA observed in a prodromal AAV-α-synuclein model. However, further studies are required to determine the viability of targeting the CB2 receptor for anti-inflammatory disease modification in Parkinson’s disease. Furthermore, this body of research suggests that, with refinement, the combination of AAV-α-synuclein and FN075 may be a promising novel animal model in which to study Parkinson’s disease in the future. 2023-12-16

ObjectivesTo analyse and present the occurrence and severity of spontaneous adverse drug reaction (ADR) reports prospectively registered at an ADR monitoring centre (AMC) in Central India.Setting and dataThe survey was conducted between 2013 and 2019 at an ADR Monitoring Centre in Central India. ADRs were recorded using the standard ‘Suspected ADR Reporting form’.Outcome measuresThe causality of the ADRs were categorised using the WHO causality assessment scale to assess the relationship between a drug and the occurrence of an ADR.ResultsTotally 1980 spontaneous ADRs were reported involving 960 patients and 1316 drugs prescriptions. The occurrence of ADRs was common among male patients (64%) and patients of age between 19 and 65 years (81%). Antimicrobials caused 29% ADRs, followed by drugs of antiretroviral therapy (19%). Zidovudine caused most ADRs (88%) followed by ethambutol and ciprofloxacin. The ADRs of skin and subcutaneous tissue disorders (28%) were most common among all system organ classes followed by gastrointestinal systems (18%). Four per cent of all reported ADRs were severe. A peak of ADR reports was attained in 2016 with 224 reports, which decreased to 127 in 2019.ConclusionA high number of ADRs caused by antimicrobials is an alarming situation, which adds up to antimicrobial resistance. Judicious use of antimicrobials is yet again proven as need of the hour. Under-reporting of ADRs is evident in our study and is a major factor for the delay in the withdrawal of drugs responsible for causing ADRs. Interventions in terms of training and feedback are suggested to encourage and improve ADR reporting.

ObjectiveInappropriate use of medicine is a global challenge with greater impact on developing countries. Assessment of drug use pattern is used to identify gaps in medicine utilisation to implement strategies for promoting rational drug use. This study aimed to assess drug use pattern using the WHO drug use indicators in selected general hospitals in Tigray region, Ethiopia.DesignA cross-sectional study was conducted using WHO drug use indicators in two public hospitals located in Tigray.SettingPrescriptions recorded from 1 January 2017 to 1 June 2019 were randomly selected, and participants who visited the public hospitals from 1 March 2019 to 30 August 2019 and hospital pharmacies were interviewed.Participants100 patients who visited both outpatient clinics and hospital pharmacy departments of the public hospitals.ResultsThe average number of medicines per prescription was 1.69 (±0.81). Prescriptions containing antibiotics and injectables were 58.2% and 15.9%, respectively. The percentages of medicines prescribed with a generic name from essential medicines list of Ethiopia were 97.5% (974) and 88.1% (970) in Mekelle Hospital and Quiha Hospital, respectively. The patients spent an average of 6.6(±3.5) min with their general practitioners, while only 22.8 (±21.7) s with their pharmacists. Of the patients interviewed, 56.9% knew their dosing regimen and 32.7% of them had their medication labelled.ConclusionThe finding of the present study revealed deviation of drug use pattern from the WHO optimal levels suggesting the hospitals had limitations in appropriate utilisation of medicines. Understanding the factors attributed to the observed gaps and implementing corrective measures are required to conform with the recommended standards of appropriate drug utilisation.

ObjectivesIt is unclear what is driving rising colorectal cancer (CRC) treatment costs in China, whether an adjustment in drug prices changes use and total cost. This study aims to estimate trends in drug use, prescribing patterns and spending for antineoplastic drug therapies for CRC in major cities of China.MethodsInformation from 128 811 antineoplastic drug prescriptions in CRC was retrospectively collected from the Hospital Prescription Analysis Cooperative Project. The prescriptions extracted included demographic information of patients, the generic name and the price of antineoplastic drugs. The Mann-Kendall and Cochran-Armitage trend test was used to estimate the trends of antineoplastic agent usage.ResultsThe number of antineoplastic prescriptions ranged from 18 966 in 2015 to 34 219 in 2019. Among the prescriptions collected in this study, the annual cost of antineoplastic drugs increased by 117.2%, and average prescription cost increased by 20%. Throughout the study period, the most prescribed antineoplastic drugs were capecitabine, oxaliplatin, fluorouracil and irinotecan, representing 49%, 27%, 21% and 9% of (per cent of visits (PV)). The PV of bevacizumab and cetuximab increased by 494% and 338% (from 1.8% and 1.3% in 2015 to 10.7% and 5.7% in 2019). In prescribing patterns of antineoplastic agents, monotherapy gradually decreased, while combination therapy, especially three-drug combination, increased significantly from 1.35% to 7.31%.ConclusionThis study estimated recent trends of antineoplastic drug use and expenditure for Chinese patients with CRC. These results would inform CRC treatment decisions, including health insurance negotiation, precision therapy access, allocation of research funding and evaluation of the financial burden of CRC drug treatment.