Dear Editor,Cannabinol interactions with the melatonergic pathwayI read with interest the recent article by Anderson and colleagues highlighting the suppression of cytochrome P450 (CYP)1A2 by cannabinol, thereby upregulating melatonin availability [1]. As CYP1A2, like CYP2C19, can ‘backward convert’ melatonin to its precursor N-acetylserotonin (NAS) via O-demethylation [2], it will be important to investigate cannabinol effects on the NAS/melatonin ratio. NAS is brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor tyrosine receptor kinase (Trk)B [3], indicating that some of the benefits of cannabinol in cancer and other proliferative conditions may be mediated by decreasing the proliferative effects of NAS at TrkB and increasing the tumor apoptotic effects of melatonin, with potential significant consequences in proliferative conditions, such as cancer and endometriosis [4,5], which are powerfully regulated by the aryl hydrocarbon receptor (AhR), the major inducer of CYP1A2. This is given some support by cannabinol utility in a number of cancers [6], as well as in neurodegenerative conditions where the regulation of the melatonergic pathway is an important treatment target [7]. The association of cannabinol with the melatonergic pathway may therefore be a significant aspect of core pathophysiological processes across diverse medical presentations.Cannabinol also directly regulates mitochondrial function, including mitophagy [8]. As melatonin is produced within mitochondria and the AhR is also expressed on mitochondria where it regulates function [7], cannabinol has significant impacts on core processes of energy and oxidant production [8]. Cannabinol analogues also enhance mitochondrial function, indicating scope for pharmaceutical development [9], including via mitochondrial melatonergic pathway regulation. Cannabinol induces an M2-like macrophage phenotype, which previous data links to macrophage melatonin production and autocrine effects [10], indicating that the cannabinol regulation of CYP1A2 and the AhR, thereby upregulating the melatonergic pathway may be important to immune cells regulation of pathophysiological processes.The article by Anderson and colleagues therefore will therefore contribute to driving future research of core processes and novel treatments that are relevant across diverse medical presentations.Yours FaithfullyGeorge AndersonHead of ResearchCRC Scotland & London.References1. Anderson, Lyndsey L et al. “Preclinical Evidence for a Drug-Drug Interaction Between Cannabinol and Melatonin.” Basic & clinical pharmacology & toxicology  vol. 136,1 (2025): e14120. doi:10.1111/bcpt.14120.2. Mokkawes, Thirakorn et al. “Melatonin Activation by Human Cytochrome P450 Enzymes: A Comparison between Different Isozymes.” Molecules (Basel, Switzerland)  vol. 28,19 6961. 6 (2023), doi:10.3390/molecules28196961.3. Jang, Sung-Wuk et al. “N-acetylserotonin activates TrkB receptor in a circadian rhythm.” Proceedings of the National Academy of Sciences of the United States of America  vol. 107,8 (2010): 3876-81. doi:10.1073/pnas.09125311074. Anderson, George. “Tumor Microenvironment and Metabolism: Role of the Mitochondrial Melatonergic Pathway in Determining Intercellular Interactions in a New Dynamic Homeostasis.” International journal of molecular sciences  vol. 24,1 311 (2022), doi:10.3390/ijms240103115. Anderson, George. “Endometriosis Pathoetiology and Pathophysiology: Roles of Vitamin A, Estrogen, Immunity, Adipocytes, Gut Microbiome and Melatonergic Pathway on Mitochondria Regulation.” Biomolecular concepts  vol. 10,1 133-149. (2019), doi:10.1515/bmc-2019-00176. ALSalamat, Husam A et al. “Cannabis and cancer: unveiling the potential of a green ally in breast, colorectal, and prostate cancer.” Journal of cannabis research  vol. 6,1 24. (2024), doi:10.1186/s42238-024-00233-z7. Anderson, George. “Physiological processes underpinning the ubiquitous benefits and interactions of melatonin, butyrate and green tea in neurodegenerative conditions.” Melatonin Research vol 7, 1 (2024), doi: 10.32794/mr112500168. Gugliandolo, Agnese et al. “Transcriptome Highlights Cannabinol Modulation of Mitophagy in a Parkinson’s Disease In Vitro Model.” Biomolecules  vol. 13,8 1163. (2023), doi:10.3390/biom130811639. Liang, Zhibin et al. “Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders.” Redox biology  vol. 72 (2024): 103138. doi:10.1016/j.redox.2024.10313810. Muxel, Sandra Marcia et al. “NF-κB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene.” PloS one  vol. 7,12 (2012): e52010. doi:10.1371/journal.pone.0052010

Paclitaxel (PAC), derived from Taxus brevifolia, is commonly used to treat solid tumors but has significant adverse effects, including reproductive toxicity, driven by oxidative stress. PAC can damage the reproductive system, leading to histological changes and reduced sperm quality. Nerolidol (NRL), a sesquiterpene alcohol with antioxidant properties, has not been studied for its role in mitigating PAC-induced reproductive damage. This study investigates NRL’s potential to counteract PAC-induced reproductive toxicity in rats. Forty healthy adult male Spraque Dawley rats were randomly divided into four equal groups (Control, PAC, NRL, PAC+NRL). PAC was given intraperitoneally at a dose of 2 mg/kg once a week for four weeks. NRL was given orally at a dose of 100 mg/kg/day for four weeks. Control group received PAC and NRL vehicles. After four weeks, testis tissue samples were collected, and parameters, including oxidants, antioxidants, sperm motility, density, abnormal spermatozoon ratios and cytokines were measured. PAC administration increased oxidant levels and decreased antioxidant enzyme activities. Nerolidol mitigated these alterations significantly. Similarly, PAC elevated IL-1, IL-6, TNF-α levels and lowered IL-10 levels, these effects attenuated by nerolidol in the PAC+NRL group. In conclusion, it was determined that PAC induces reproductive toxicity through oxidative stress, and NRL demonstrates potential in ameliorating these effects through its antioxidant activity.

Background/Rationale Weekly cholecalciferol can be an alternative to daily supplementation to reduce pill burden in patients with complex medication regimens and hypovitaminosis D, but evidence supporting this switch is unclear. Objective We aimed to determine whether weekly cholecalciferol was superior to daily cholecalciferol to replete patients with hypovitaminosis D. Methods We conducted a systematic review of randomized controlled trials involving participants with baseline hypovitaminosis D (<30ng/ml) comparing weekly versus daily cholecalciferol dosing and where serum cholecalciferol was measured within 90 days of starting treatment. We searched MEDLINE, CINAHL and EMBASE from inception to May 7 th, 2024. A random-effects meta-analysis evaluated the odds ratio for repletion of serum Vitamin D levels. Findings Eight trials involving 542 patients were included in the analysis. Weekly D3 and daily cholecalciferol were not significantly different in correcting hypovitaminosis D (OR=1.5, 95% CI = 0.3-6.9, p=0.6, favoring weekly dosing, I 2=85.3%). A sensitivity analysis excluding otherwise healthy patients had similar findings (OR=0.8, 95% CI=0.3–2.1, p=0.6). Most studies were judged to be at risk of bias, the different doses being compared increased the heterogeneity (I 2=85.3%). Conclusions There is limited direct evidence supporting a switch from daily to weekly cholecalciferol dosing; however, weekly supplementation was not demonstrably worse at repleting levels and decreases a patient’s daily pill burden.

Over the past decade, increasing off-label use of quetiapine has been reported worldwide from various sources. We wanted to investigate how this is reflected in therapeutic drug monitoring (TDM) data. Requisitions for serum concentration measurements of quetiapine from a TDM service in Central Norway during 2001-2019 were obtained, and analyzed for trends in quetiapine doses, serum concentrations, demographics and indicators of diagnoses. 19759 samples from 7459 individuals were included. Daily doses of quetiapine decreased by 24 mg per year (95% CI -25.61 - -21.48, p<0.001, N=4505). A corresponding decrease in quetiapine serum concentrations was not seen. The proportion of requisitions with diagnoses indicating reimbursable use, i.e. within approved indications, was 13 % for the whole study period. Mean daily doses were slightly higher in the reimbursable group, but declined over time in these samples, as well. To our understanding, these results provide additional documentation of increasing low-dose usage of quetiapine, and signal both increasing off-label use, as well as possibly higher dose-intake than prescribed and incorrect filing of reimbursable use in this population. There is a continued need for investigation and characterization of quetiapine use and prescription practices, and the extent of and motivations for off-label prescription of the drug.

Background: Approximately 1% of Sweden’s 90,000 annual deaths are caused by poisoning. In this study we aim to describe this poisoning population’s characteristics, autopsy frequency, and results of toxicology testing. Method: A national cohort study based on Swedish national registers. All deceased patients older than 18 years with poisoning as the cause of death registered between 1 th January 2000 to 31 th December 2021 were included. Causes of death according to primary ICD-10-code were analysed along with the substances found in forensic chemistry testing. Results: There were 27,057 poisonous deaths during the study periods 2,018,495 total adult deaths. Patients deceased due to poisoning had a median age of 53 years and 18,838 (70%) were men. A private home was the most reported location of death (52%). In total did 23,260 (87%) undergo some sort post-mortem examination. Drugs (synthetic narcotics, opioids, heroin) caused 12,448 (46%) deaths and alcohols explained 9,056 cases (33%). Positive toxicological tests were found in 22,550 (83%) of the subjects. The most common separate substances were ethanol, zopiclone and, nordazepam. Conclusion: Poisoning causes 1.3% of Swedish deaths. Men in their fifties are the most common victims and their death are often cause by synthetic narcotics, other opioids, or alcohol. The autopsy frequency is lower than expected for poisonous deaths.

The healthcare sector is a major contributor of greenhouse gas emissions, and reduction and proper sorting of healthcare waste is essential to achieve sustainable healthcare. This study aimed to characterize the quantity and composition of pharmaceutical waste from a major Danish hospital. Pharmaceutical waste was collected from Odense University Hospital, including departments located in both Odense and Svendborg. The average daily production of pharmaceutical waste was 1150 g/day in Odense and 5967 g/day in Svendborg, with the operating rooms in Svendborg contributing 3143 g/day. The amount and composition of pharmaceutical waste varied greatly between departments, but some common patterns were identified. Propofol accounted for about one third of the pharmaceutical waste obtained from operating rooms. Antibiotics for systemic use constituted a significant proportion of the pharmaceutical waste from several departments, and were the therapeutic group from which most different drugs were identified. Paracetamol accounted for 33.5% of the discarded tablets/capsules in Odense and 12.6% in Svendborg. Medications dispensed by automated dose dispensing accounted for a significant proportion of the discarded tablets/capsules in departments using this service. This study highlights some key areas for reduction and management of pharmaceutical waste, and contributes to the currently limited evidence within this area.

Alzheimer’s disease (AD) is a neurodegenerative disorder that primarily manifests itself by progressive memory loss and cognitive decline, thus significantly affecting memory functions and quality of life. The canonical amyloid-β hypothesis, while significant, has faced setbacks, highlighting the need to adopt a broader perspective considering the intricate interplay of diverse pathological pathways for effective AD treatments. Sex differences in AD offer valuable insights into a better understanding of its pathophysiology. Fluctuation of the levels of ovarian sex hormones during perimenopause is associated with changes in glucose metabolism, as a possible window of opportunity to further understand the roles of sex steroid hormones and their associated receptors in the pathophysiology of AD. We review these dimensions, emphasizing the potential of estrogen receptors (ER) to reveal mitochondrial functions in the search for further research and therapeutic strategies for AD pharmacotherapy. Understanding and addressing the intricate interactions of mitochondrial dysfunction and estrogen receptors potentially pave the way for more effective approaches to AD therapy.

MM is an incurable cancer in the bone marrow. The treatment of MM has developed significantly during the last 20 years, which has resulted in increased survival. Daratumumab is the first CD38 antibody approved for treatment of MM. It has improved the treatment of MM even further. This is an evaluation of the modes of action of daratumumab and a description of the development of resistance with focus on inhibitory checkpoint receptors on CD8+ T-cells, complement activation and extracellular vesicles.

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different compositions of microparticle formulations called LIQ865. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modeling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for bupivacaine clearance at higher doses. Bupivacaine clearance and the transit rate constant describing the slow absorption process both decreased with increasing doses following a power function with a shared covariate effect of dose on the two parameters. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine, and the biphasic absorption seen for several local anesthetics.

Dementia is an umbrella term for a broad group of age-associated neurodegenerative diseases. It is estimated that dementia affects 50 million people worldwide and that Alzheimer’s disease (AD) is responsible for up to 75% of cases. Small extracellular senile plaques composed of filamentous aggregates of amyloid β (Aβ) protein tend to bind to neuronal receptors, affecting cholinergic, serotonergic, dopaminergic, and noradrenergic neurotransmission, leading to neuroinflammation, among other pathophysiologic processes, and subsequent neuronal death, followed by dementia. The amyloid cascade hypothesis points to a pathological process in the cleavage of the amyloid precursor protein (APP), resulting in pathological Aβ. There is a close relationship between the pathologies that lead to dementia and depression. It is estimated that depression is prevalent in up to 90% of individuals diagnosed with Parkinson’s disease, with varying severity, and in 20 to 30% of cases of Alzheimer’s disease. The hypothalamic pituitary adrenal (HPA) axis is the great intermediary between the pathophysiological mechanisms in neurodegenerative diseases and depression. This review discusses the role of Aβ protein in the pathophysiological mechanisms of dementia and depression, considering the HPA axis, neuroinflammation, oxidative stress, signaling pathways, and neurotransmission.

Transient receptor potential vanilloid type-1 (TRPV1) channels play key roles in chronic pain conditions and are modulated by different inflammatory mediators to elicit heat sensitisation. Bradykinin is a 9-amino acid peptide chain that promotes inflammation. The aim of present study is to investigate how bradykinin and prostaglandin receptors (EP3 and EP4) modulate the sensitisation of TRPV1-mediated responses. Calcium imaging studies of rat dorsal root ganglion (DRG) neurons were employed to investigate the desensitizing responses of TRPV1 ion channels by capsaicin, and the re-sensitization of TRPV1 by bradykinin, then to explore the role EP3 and EP4 receptors in mediating these bradykinin-dependent effects. Immunocytochemistry was used to study the co-expression and distribution of EP4, TRPV1, COX-1 and B2 in rat DRG neurons. Desensitization was seen upon repeated capsaicin application, we show that bradykinin-mediated sensitization of capsaicin-evoked calcium responses in rat DRG neurons occurs is dependent on COX-1 activity, and utilises a pathway that invovles EP4 but not EP3 receptors. The present study provides evidence for a novel signalling pathway through which bradykinin can regulate the TRPV1 ion channel function via the EP4 but not EP3 receptors and provides the anatomical basis for this regulation

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by elevated pulmonary pressure, right ventricular failure (RVF) and ultimately death. Aggressive treatment of RVF is considered the most important therapeutic strategy. In this study, betaine injection was prepared and characterized by various techniques. The therapeutic efficacy of gavage (I.G.), nebulized inhalation (Inh.) and intravenous (I.V.) injections was evaluated comprehensively in terms of pharmacokinetics, tissue distribution and pharmacodynamics using three different methods of administration. The results of pharmacokinetic demonstrated that Inh. betaine injection significantly prolonged the half-life of the drug, increased its internal circulation time and increased Inh. administration significantly improved the pharmacokinetics of betaine compared to I.G. and I.V. administration. Combined with biodistribution experiments verified that betaine formulation could accumulate in lung tissue via Inh. The results of pharmacodynamic further confirmed that right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP) and right ventricular hypertrophy index (RVHI) were increased in the model group and that betaine prepared by Inh. was able to suppress this increase to levels similar to those observed in the control group. Consequently, Inh. administration would be a promising strategy for the treatment of PAH-induced RVF.

ChatGPT: First Glance from a Perspective of Clinical PharmacologyAuthors: Julie Rudbech Krumborg1,2, Nicolaj Mikkelsen1,2, Per Damkier1,2, Zandra Nymand Ennis1,2, Daniel Pilsgaard Henriksen1,2, Mads Lillevang-Johansen1,2, Sidsel Arnspang Pedersen1,2, Troels K Bergmann1,31. Department of Clinical Pharmacology, Odense University Hospital, Denmark2. Department of Clinical Research, Faculty of Health Science, University of Southern Denmark, Denmark3. Department of Regional Health Research, University of Southern Denmark, Esbjerg, DenmarkCorresponding author: Julie Rudbech Krumborg: Julie.Rudbech.Krumborg@rsyd.dkKeywords : Artificial intelligence, Clinical Pharmacology, Drug Information Services, evidence-based medicine, Medical WritingConflict of interest statement: The authors state no conflicts of interest

Background: Serotonin syndrome is a potentially life-threatening syndrome with manifestations spanning from mild adverse effects to life-threatening toxicity. The syndrome is caused by overstimulation of serotonin receptors by serotonergic drugs. Since the use of serotonergic drugs is increasing, primarily due to the widespread use of selective serotonin reuptake inhibitors, cases of serotonin syndrome have likely seen a parallel increase. The true incidence of serotonin syndrome remains unknown due to its diffuse clinical presentation. Objectives: This review aims to provide a clinically focused overview of serotonin syndrome, covering its pathophysiology, epidemiology, clinical manifestations, diagnostic criteria, differential diagnosis, and treatment as well as classifying serotonergic drugs and their mechanism of action. The pharmacological context is emphasized, as it is crucial for detection and management of serotonin syndrome. Methods: Focused review based on a literature search using the PubMed database. Findings and conclusion: Serotonin syndrome can occur through therapeutic use or overdose of a single serotonergic drug, or as a drug interaction between two or more serotonergic drugs. Central clinical features consist of neuromuscular excitation, autonomic dysfunction and altered mental status, occurring in a patient undergoing new or altered serotonergic therapy. Early clinically recognition and treatment are crucial to prevent significant morbidity.

A document by Nagham Ailabouni. Click on the document to view its contents.

Interventions to promote deprescribing are an important focus of research. Key decisions for such interventions are whether to target one or multiple medicines, and whether the intervention scope is deprescribing, or also extends to other aspects of medicines optimisation. This article reflects on how these decisions impact on developing interventions and measuring outcomes. Many behavioural strategies are common to deprescribing and medicines optimisation, however operationalisation may differ. Aspects to consider include the burden of multiple simple interventions versus one complex intervention, the extent to which the approach to deprescribing can be specified as part of the intervention, and variability in how the intervention is delivered across patients and providers. Outcomes should be selected based on the intervention target and scope and the audience for whom evidence is being produced. These may include medication changes, and process outcomes to assess intervention delivery. Targeting single medications may allow for a focus on specific clinical or symptom-related outcomes, rather than more general outcomes such as adverse drug reactions. Cost-related outcomes are also important to inform implementation decisions, and modelling approaches may be more feasible for interventions targeting single medications.

Background: A quasi-experimental study investigated a pharmacist-led intervention aimed at deprescribing among patients with type 2 diabetes at risk of hypoglycaemia. Objective: To evaluate the process of implementing the intervention in primary care in order to understand variations in implementation and outcomes. Methods: Mixed-methods study based on the Grant-framework, with 10 domains, including recruitment of patients, delivery of the intervention, and response of pharmacists and patients. Data collected were: administrative logs, semi-structured observations of patient consultations (n=8), interviews with pharmacists (n=16), and patient-reported experience measure (PREM) questionnaires (n=66; response 73%). Results: Ninety patients from 14 pharmacies were included. Although the selection of patients based on high hypoglycaemia-risk was considered useful, pharmacists experienced barriers to proposing deprescribing in patients with recent medication changes, patients without current health problems or hypoglycaemic events, and patients treated in secondary care. The consultation aid and deprescribing tool provided were evaluated positively by the pharmacists. The majority of patients were satisfied with the service and information that the pharmacists provided. Conclusion: Pharmacists and patients were positive about the intervention. Both groups valued the consultation on deprescribing, supported by tools. To optimise the effect, improvements can be made to patient selection and local agreements on proactive deprescribing.

Title: Developing and testing complex behaviour change interventions to support proactive deprescribingRunning title: Behaviour change and deprescribing