Sphingosine-1-phosphate receptor-3 (S1PR3) has been implicated in the maintanence of cerebrovascular integrity during cerebral ischemia. This study aimed to elucidate the impact of S1PR3 inactivation on oxidative stress-induced cerebrovascular endothelial cell permeability and to explore the potential mechanisms. In bEnd3 cells, blockade of S1PR3 exacerbated H 2O 2-induced endothelial hyperpermeability and ZO-1 redistribution. Previous study indicated that the activation of p38 and ERK pathway was essential for H 2O 2-mediated cPLA 2 phosphorylation in bEnd3 cells. This study revealed that the activation of JNK is crucial for H 2O 2-induced stat3 phosphorylation. In bEnd3 monolayer, either blockade or genetic knockdown of S1PR3 further enhanced the phosphorylation level of p38, ERK, cPLA 2, JNK and stat3 in response to H 2O 2 exposure. Furthermore, lentivirus-mediated knockdown of S1PR3 intensified H 2O 2-induced ZO-1 redistribution and paracellular hyperpermeability. These results underscored the role of S1PR3 as a critical modulator of endothelial monolayer permeability via both cPLA 2 and stat3 phosphorylation in the context of oxidative stress.

Gadolinium-based contrast agents (GBCAs), widely used in Magnetic Resonance Imaging (MRI) procedures, raise safety concerns due to their potential cytotoxic and genotoxic effects, especially at high doses or repeated exposures. In this study, the cytogenotoxic potential of gadoteric acid in NIH3T3 fibroblast cells was evaluated using both in vitro and in silico approaches. NIH3T3 cells were treated with increasing concentrations of gadoteric acid. Cytotoxicity was evaluated by MTS assay and genotoxicity by Comet Assay; 75 μM hydrogen peroxide was used as a positive control. In addition, the interaction of gadoteric acid with DNA topoisomerase IIα, DNA topoisomerase IIβ, DNA polymerase β and B-DNA was examined by molecular docking assays. MTS assay results showed a dose-dependent decrease in cell viability and an IC 50 value of 28.19 mM. Comet Assay analysis revealed significant DNA damage only at the highest concentration (56.38 mM) (p < 0.05). In silico analysis revealed that gadoteric acid showed the highest binding affinity with DNA polymerase β (-11.7 kcal/mol). The data obtained support that gadoteric acid may exhibit cytotoxic and moderately genotoxic effects at high concentrations by directly interacting with DNA and DNA-related enzymes.

Monoclonal antibodies during breastfeeding - challenges with relative infant dosePaulina Flis*1, Gro C. Havnen*2, Elisabet Nordmo2, Annika Asplund1, Eva Wikström1*shared first authorship1 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institute and Clinical pharmacology, Medical Diagnostics Karolinska, Karolinska University Hospital2Regional Medicines Information and Pharmacovigilance Centre (RELIS), Oslo/Tromsø, NorwayCorrespondence: paulina.flis@ki.seDisclosure statement : The autors declares no conflicts of interests related to this paper.

Introduction: Raltegravir, an HIV integrase inhibitor, although generally well-tolerated may cause severe reactions such as DRESS syndrome. DRESS is associated with impaired drug metabolism, viral reactivation, and alleles like HLA-B*53:01. This study examines the prevalence of HLA-B*53:01 and its association with DRESS in raltegravir-treated patients. Methodology: Medical records from Hospital Universitario de La Princesa (2008–2020) were reviewed to identify patients genotyped for HLA-B*53 who received raltegravir. Suspected DRESS cases were assessed using the RegiSCAR scoring system and Naranjo algorithm. A literature review identified additional cases. Results: Among 109 patients treated with raltegravir, three (2.8%) carried HLA-B53. Two carriers (66.7%) developed DRESS, while no adverse reactions were reported in non-carriers. The first case, a 43-year-old male, presented fever, rash, lymphadenopathy, liver dysfunction, and HHV-6 reactivation (RegiSCAR score 6). The second, a 59-year-old male, showed eosinophilia, rash, and pulmonary symptoms (score 4). The third carrier remained asymptomatic. Relative risk for HLA-B*53 carriers was 128.75. Nine additional DRESS cases associated with raltegravir were found in the literature and summarized in a table including clinical features and HLA-B*53 status. Conclusion: Findings support a genetic predisposition involving HLA-B*53:01 in DRESS. Given overlap with IRIS, further research on diagnosis and treatment is needed. Screening for HLA-B*53 may be useful before raltegravir use in high-prevalence populations.

Background: Understanding patient’s attitudes towards deprescribing is important for implementation of deprescribing in practice. These attitudes may differ within a patient depending on the medication. Objective: To assess whether there are within-patient differences in attitudes towards deprescribing the following cardiovascular and diabetes medications: statins, antihypertensives, sulfonylureas and insulins. Methods: We administered the revised Patient Attitudes Towards Deprescribing questionnaire to Dutch primary care patients. The ‘appropriateness’ and ‘concerns’ subscales were adapted to measure medication-specific attitudes. Pairwise comparisons of unreversed appropriateness and concerns sum scores were tested with Wilcoxon signed-rank tests, and differences in underlying items were explored. Results: Out of 280 patients that completed the questionnaire, 160 patients (median age: 79 years, 34% frail) did so for at least two medication classes. Patients’ perceived deprescribing of their insulins less appropriate as compared to the other medication classes (all p<.031), and deprescribing sulfonylureas less appropriate as compared to antihypertensives (p=.036) or statins (p=.006). No differences were found for the concerns sum scores but differences were observed in underlying items. Conclusion: Patients were more positive towards deprescribing statins and antihypertensives as compared to sulfonylureas and particularly insulins. Healthcare providers should be aware that patients can experience medication-specific barriers when discussing options for deprescribing.

The prevalence of patients being diagnosed with inflammatory bowel disease is increasing. While several studies have shown that, in general, it is possible to improve patients’ quality of life with the incorporation of a clinical pharmacist, data on the potential benefits of clinical pharmacist in the treatment of inflammatory bowel disease is more limited. The aim of the present study was to provide a systematic review of benefits of adherence to treatment of inflammatory bowel disease with focus on the potential role of clinical pharmacist counseling. Three databases (PubMed, Medline, and Embase) were used to identify relevant literature. Keywords generated from the PICO model were used for the search. Seven full text articles were identified. They all indicated that pharmacist involvement in treatment could improve quality of life in patients with IBD. Results showed that patient perception of pharmacist involvement was positive following information about pharmacist services and education. Furthermore, results suggest that pharmacist demand better knowledge of inflammatory bowel disease in order to provide better service for IBD patients. The available literature is scarce but indicates that clinical pharmacist involvement in treatment of IBD had positive outcome, and helped improving the patients’ quality of life and their adherence to medication.

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopamine neurons and aberrant deposits of alpha-synuclein (a-syn) in the brain. The symptomatic treatment is started after the onset of motor manifestations in a late stage of the disease. Preclinical studies show promising results of disease-modifying neuroprotective or even neurorestorative therapies with neurotrophic factors (NTFs). Three NTFs have entered phase I-II clinical trials with inconclusive outcomes. This is not surprising since the preclinical evidence is from acute early-stage disease models but the clinical trials included advanced PD patients. In order to conclude the value of NTF therapies, clinical studies should be performed in early-stage patients with prodromal symptoms, i.e. before motor manifestations. In this review, we summarize currently available diagnostic and prognostic biomarkers that could help identify at-risk patients benefiting from NTF therapies. Focus is on biochemical and imaging biomarkers, but also other modalities are discussed. Neuroimaging is the most important diagnostic tool today, but a-syn imaging is not yet viable. Modern techniques allow measuring various forms of a-syn in cerebrospinal fluid, blood, saliva and skin. Digital biomarkers and artificial intelligence offer new means for early diagnosis and longitudinal follow-up of degenerative brain diseases.

Aim: The objective of this registry study is to assess the utilization of PGx drugs among patients with CKD Methods: This study was a retrospective study of patients affiliated to the Department of Nephrology, Aalborg University Hospital, Denmark during 2021. Patients diagnosed with CKD were divided into CKD without dialysis and CKD with dialysis. PGx prescription drugs were retrieved from the Patient Administration System. Actionable dosing guidelines (AG) for specific drug-gene pairs for CYP2D6, CYP2C9, CYP2C19 and SLCO1B1were retrieved from the PharmGKB homepage. Results: Out of 1241 individuals, 25.5% were on dialysis. The median number of medications for each patient was 9 within the non-dialysis group, and 16 within the dialysis group. Thirty-one distinct PGx drugs were prescribed. Altogether, 76.0% (943 individuals) were prescribed at least 1 PGx drugs and the prevalence of prescriptions of PGx drugs was higher the dialysis group compared to the non-dialysis group. The most frequently prescribed drugs with AG were metoprolol, pantoprazole, atorvastatin, simvastatin, warfarin. Conclusion: This study demonstrated that a substantial proportion of patients with CKD are exposed to drugs or drug combinations for which there exists actionable dosing guidelines related to PGx of CYP2D6, CYP2C19, CYP2C9, and SLCO1B1.

Neurodegenerative diseases have complex etiologies, however, neuroinflammation and oxidative stress are important markers in this pathogenesis and, in this sense, cannabinoids, especially CBD, have been identified as potential therapeutics for playing a neuroprotective role. Studies have demonstrated the neuroprotective effect of cannabinoids and derivatives of Cannabis sativa L in diseases of the central nervous system due to their interaction with the endocannabinoid system through receptors and other molecular targets. The aim of this review was to provide an overview of the endocannabinoid system and a summary of the clinical and preclinical findings of the therapeutic use of cannabinoids in epilepsy, multiple sclerosis and Parkinson’s disease, pointing out interactions with molecular targets and the potential for neuroprotection of CBD. Electronic searches were carried out in international databases, including studies that presented consistent data on this subject. Significant therapeutic effects of CBD were shown for epilepsy and Parkinson’s disease, while nabiximols contributed to the reduction of spasticity, being a frequent option for the treatment of multiple sclerosis. Although much has been projected on the therapeutic potential of cannabinoids for neurological disorders, there is a long way to go in the search for strong scientific evidence of their pharmacological effectiveness.

Brain-specific angiogenesis inhibitor 1 (BAI1) belongs to the adhesion G-protein-coupled receptors, which exhibit large multi-domain extracellular N-termini that mediate cell-cell and cell-matrix interactions. To explore the existence of BAI1 isoforms, we queried genomic datasets for markers of active chromatin and new transcript variants in the ADGRB1 gene. Two major types of mRNAs were identified in human and mouse brain, those with a start codon in exon 2 encoding a full-length protein of a predicted size of 173.5 kDa and shorter transcripts starting from alternative exons at the intron 17/exon 18 boundary with new or exon 19 start codons, predicting shorter isoforms of 76.9 and 70.8 kDa, respectively. Immunoblots on wild-type and Adgrb1 exon 2-deleted mice, reverse transcription PCR and promoter-luciferase reporters confirmed that the shorter isoforms originate from an alternative promoter in intron 17. The shorter BAI1 isoforms lack most of the N-terminus and are very close in structure to the truncated BAI1 isoform generated through GPS processing from the full-length receptor, except that the latter exhibits a 19 amino acid extracellular stalk that can serve as a receptor agonist. Further studies are warranted to compare the functions of these isoforms and examine the distinct roles they play in different tissues and cell types.