ABSTRACT Sonodynamic therapy (SDT) is an emerging site specific and minimally‐invasive modality for cancer treatment. Its efficacy heavily relies on the accumulation and retention of systemically‐administered sensitizing agents within tumor cells. Active molecular efflux via membrane transporters, such as the human ATP‐binding cassette (ABC) superfamily G member 2 (ABCG2) transporter, can pose a major challenge by reducing intracellular levels of sensitizers and hinder sonodynamic activity. In this study, the role of ABCG2 transporter in the retention of nanoparticulate hematoporphyrin was investigated using prostate cancer cells. The potential of lapatinib to improve cellular retention of the sensitizer via inhibition of ABCG2 and improve the efficacy of SDT was evaluated. The effect of hypoxia and neuroendocrine differentiation on ABCG2 activity and the role of lapatinib were examined. Results showed that hypoxia intensifies ABCG2 localization in the cytoplasmic membrane. There was no effect of lapatinib on the cellular accumulation of nanoparticulate hematoporphyrin during exposure of the cell systems to the sensitizer. Following sensitizer withdrawal, a sharp intracellular hematoporphyrin level decrease was observed within the first 2 h. Lapatinib significantly attenuated the reduction of intracellular sensitizer in hypoxia, during the first 8 h after withdrawal of the sensitizer. Lapatinib can extend the intracellular presence of the sonosensitizer, prolonging the therapeutic window for performing SDT. This outcome underlined the value of lapatinib for improving the sensitizer intracellular levels in hypoxic areas of the tumor mass, where sensitizer supply is expected to be low, due to the low vascularization levels.
ABSTRACT The pharmaceutical industry is a major employer of graduates from pharmacology BSc and MSc programs. Understanding its expectations of graduates is therefore important for pharmacology educators. To explore this, interviews were conducted with pharmaceutical industry employees to understand their views on graduate colleagues. Eight semi‐structured interviews were conducted with employees of the UK pharmaceutical sector, identified by convenience sampling. The transcripts of the interviews were coded, and the resulting 117 codes were used to generate three themes and nine sub‐themes. The first theme concerned how academia should prepare students for industry careers. The subthemes included what academia should focus on in their courses; differences identified by interviewees between industry and academia; educating students about the reality of careers in industry; and highlighting career options outside of academia via industrial placements. The second theme concerned the graduate attributes desired by industry, with the subthemes of knowledge, skills, behaviors and attitudes. Finally, the third theme concerned the behaviors and attributes students should develop to be successful in industry. These findings provide insight into graduate preparation for the workplace and may inform pharmacology program design. Exploring the views of employees in other career destinations of pharmacology graduates would be valuable. Limitations include convenience sampling, the limited number of participants, and the potential for interviewer bias.
ABSTRACT Pharmacokinetic (PK) studies require temporally precise measurements of drug concentrations in biological matrices, most commonly whole blood or plasma. However, repeated venous sampling may increase participant burden and complicate PK‐intensive study designs. Needle‐free blood collection devices that access peripheral intravenous (IV) catheters may provide an alternative approach to repeated venipuncture while maintaining sampling schedules and specimen quality. This pilot study evaluated the feasibility of integrating the PIVO Pro needle‐free blood collection device into a PK‐intensive human laboratory study of inhaled Δ 8 ‐tetrahydrocannabinol (Δ 8 ‐THC), Δ 9 ‐THC, and placebo. Participants completed a screening visit and three dosing visits conducted in a university research facility equipped with a full‐scale driving simulator. During each dosing visit, venous blood samples were collected at nine time points over approximately 8 h through an indwelling peripheral IV catheter using the PIVO device. All participants reported that study procedures, including blood collection, were acceptable. Approximately 40% of vascular access sites required replacement, most commonly within the first hour and typically associated with poor initial blood return. Despite slower flow compared with standard venipuncture, sampling was generally sufficient to maintain the PK sampling schedule. One mild adverse event related to vascular access (localized bruising) was observed. These findings demonstrate the operational feasibility of needle‐free blood collection through indwelling IV catheters in a PK‐intensive research protocol conducted outside a traditional clinical research unit. Further studies are warranted to compare analytical performance and access durability relative to conventional venous sampling approaches.
ABSTRACT Residual cardiovascular risk persists in patients with adequately controlled hypertension, driven partly by inflammation, oxidative stress and endothelial dysfunction. Chios mastic ( Pistacia lentiscus var. Chia ) has shown antihypertensive, antioxidant and vascular effects in experimental and clinical settings. This trial evaluated whether Chios mastic supplementation confers additional cardiovascular benefits in well‐controlled hypertensive individuals. In this double‐blind, randomized, placebo‐controlled trial, 106 adults with stable, well‐controlled hypertension and variable cardiovascular risk, based on SCORE2, received low‐dose Chios mastic (1500 mg/day), high‐dose Chios mastic (2800 mg/day) or placebo for 3 months. Primary endpoints were changes in 24‐h ambulatory systolic and diastolic blood pressure. Secondary endpoints included vascular function, oxidative stress and proteasome activity in peripheral blood mononuclear cells and red blood cells. Transcriptomic profiling was performed in a predefined high‐risk subgroup. Chios mastic supplementation was well tolerated, with high adherence confirmed by dose‐dependent increases in plasma masticadienonic and isomasticadienonic acids. No significant between‐group differences were observed in 24‐h systolic or diastolic blood pressure after the intervention. Oxidative stress markers and proteasome activity remained unchanged across groups. In high‐risk participants, mastic supplementation induced distinct transcriptomic changes, particularly in pathways related to endothelial junction organization and vascular integrity. Overall, in adults with well‐controlled hypertension and low baseline cardiovascular risk, Chios mastic supplementation did not lower blood pressure over 3 months, likely reflecting a ceiling effect. Transcriptomic findings suggest biologically meaningful vascular effects in individuals with higher residual cardiovascular risk, supporting future investigation in higher‐risk populations.
ABSTRACT Opioid receptor antagonists increase the plasma membrane density of μ‐opioid receptors (MOR) in vivo, thereby inducing “supersensitivity” to opioid agonists. This phenomenon increases the risk of overdose in patients that were being treated with naltrexone (Ntx), a popular MOR antagonist. Although there are many studies on the effects of ligands on the plasma membrane density of MORs, their effects on MOR trafficking from the endoplasmic reticulum (ER) via endoplasmic reticulum exit sites (ERES) have not been investigated. Using fluorescently tagged Sec24 to visualize ERES and a highly ER‐retained μ‐opioid receptor (MOR) point mutant, MOR[N190K], we measured ERES levels after incubation in various opioid receptor ligands. Data from sensitized emission Förster resonance energy transfer (FRET) show that MOR[N190K] interacts with Sec24D. We observe that Ntx, naloxone, morphine, and fentanyl increase the fraction of the cytoplasm occupied by ERES. In contrast, buprenorphine, methadone, and two allosteric modulators have no substantial effect on ERES levels. Mutating S375, an important phosphorylation site for MOR internalization, decreased morphine and fentanyl's pharmacological chaperoning abilities but did not affect Ntx's pharmacological chaperoning abilities. Ntx did not change intracellular cyclic adenosine monophosphate (cAMP) concentrations, so global trafficking is not expected to change. We also find that antagonist‐induced pharmacological chaperoning depends on retrotransport from the Golgi as brefeldin A (BFA) treatment prevented pharmacological chaperoning. These data reveal new understandings of how opioid ligands change MOR trafficking from the ER and can help us better understand the pathophysiology of opioid use disorder.
