Defining and unpacking the core concepts of pharmacology: A global initiative.

BACKGROUND AND PURPOSE: Development of core concepts in disciplines such as biochemistry, microbiology and physiology have transformed teaching. They provide the foundation for the development of teaching resources for global educators, as well as valid and reliable approaches to assessment. An international research consensus recently identified 25 core concepts of pharmacology. The current study aimed to define and unpack these concepts. EXPERIMENTAL APPROACH: A two-phase, iterative approach, involving 60 international pharmacology education experts, was used. The first phase involved drafting definitions for core concepts and identifying key sub-concepts via a series of online meetings and asynchronous work. These were refined in the second phase, through a 2-day hybrid workshop followed by a further series of online meetings and asynchronous work. KEY RESULTS: The project produced consensus definitions for a final list of 24 core concepts and 103 sub-concepts of pharmacology. The iterative, discursive methodology resulted in modification of concepts from the original study, including change of 'drug-receptor interaction' to 'drug-target interaction' and the change of the core concept 'agonists and antagonists' to sub-concepts of drug-target interaction. CONCLUSIONS AND IMPLICATIONS: Definitions and sub-concepts of 24 core concepts provide an evidence-based foundation for pharmacology curricula development and evaluation. The next steps for this project include the development of a concept inventory to assess acquisition of concepts, as well as the development of case studies and educational resources to support teaching by the global pharmacology community, and student learning of the most critical and fundamental concepts of the discipline.

Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories.

Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond 'know' towards 'know how to'. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented.

Role of nuclear factor kappa-B in TNF-induced cytoprotection.

Ischaemic heart disease (IHD) is a leading cause of death worldwide. Understanding prosurvival signalling pathways that protect against ischaemia-reperfusion injury (IRI) may assist in the development of novel cardioprotective strategies against IHD. In this regard, the transcription factor, nuclear factor kappa-B (NFκB) is activated by tumour necrosis factor (TNF), but its role in TNF-induced cytoprotection is unknown. Therefore, to investigate the role of NFκB in TNF-induced cytoprotection, C2C12 cells were pretreated with TNF (0.5 ng/ml) in the presence and absence of an NFκB inhibitor, pyrrolidine derivative of dithiocarbamate (PDTC; 100 µM). Cells were subjected to simulated IRI and treated with PDTC, either during TNF exposure or at reperfusion. Phosphorylation of IkB was measured after the TNF stimulus. Cytoprotection by TNF in cells subjected to IRI (cell viability: 43.7 ± 8.1% in control vs 70.6 ± 6.1% with TNF, p < 0.001) was abrogated by co-administration of PDTC (40.6 ± 1.9%, p < 0.001 vs TNF) but not by exposure to PDTC at reperfusion (70.7 ± 1.7%). Cytosolic IkB phosphorylation [1.5 ± 0.2 arbitrary units (AU) for TNF vs 1.0 ± 0.0 for untreated, p < 0.01]) was increased after TNF exposure and this increase was abolished by co-administration with PDTC (0.8 ± 0.3 AU, p < 0 01 vs TNF). Our data suggest that NFκB acts as a key component in TNF-induced cytoprotection. These findings may pave the way for the development of novel therapeutic drugs that target TNF/NFκB signalling to protect against IHD.

Identifying the core concepts of pharmacology education: A global initiative.

BACKGROUND AND PURPOSE: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. EXPERIMENTAL APPROACH: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. KEY RESULTS: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. CONCLUSION AND IMPLICATIONS: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.

Ethanolamine: A Potential Promoiety with Additional Effects on the Brain.

Ethanolamine is a bioactive molecule found in several cells, including those in the central nervous system (CNS). In the brain, ethanolamine and ethanolamine-related molecules have emerged as prodrug moieties that can promote drug movement across the blood-brain barrier. This improvement in the ability to target drugs to the brain may also mean that in the process, ethanolamine concentrations in the brain are increased enough for ethanolamine to exert its own neurological actions. Ethanolamine and its associated products have various positive functions ranging from cell signaling to molecular storage, and alterations in their levels have been linked to neurodegenerative conditions such as Alzheimer's disease. This mini-review focuses on the effects of ethanolamine on the CNS and highlights the possible implications of these effects for drug design.

Cardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat heart.

Fingolimod (FTY720) inhibits Ca2+-permeable, Mg2+-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca2+ paradox (CP) - induced myocardial damage has not been evaluated. We studied the effect of FTY720 on CP-induced myocardial damage and used other TRPM7 channel inhibitors nordihydroguaiaretic acid (NDGA) and Mg2+ to test if any effect of FTY720 was via TRPM7 inhibition. Langendorff-perfused Wistar rat hearts were treated with FTY720 or NDGA and subjected to a CP protocol consisting of Ca2+ depletion followed by Ca2+ repletion. Hearts of rats pre-treated with MgSO4 were also subjected to CP. Hemodynamic parameters were measured using an intraventricular balloon, and myocardial infarct size was quantified using triphenyltetrazolium chloride stain. TRPM7 proteins in ventricular tissue were detected using immunoblot analysis. FTY720, but not NDGA, decreased CP-induced infarct size. Both FTY720 and NDGA minimized the CP-induced elevation of left ventricular end-diastolic pressure, but only FTY720 ultimately improved ventricular developed pressure. Mg2+ pre-treatment had no effect on CP-induced infarct size, nor hemodynamic parameters during CP, nor the level of TRPM7 protein expression in ventricular tissue. Overall, FTY720 attenuated CP-induced myocardial damage, with potential therapeutic implications on Ca2+-mediated cardiotoxicity; however, the cardioprotective mechanism of FTY720 seems to be unrelated to TRPM7 channel modulation.

The effect of sphingosine-1-phosphate on the endothelial glycocalyx during ischemia-reperfusion injury in the isolated rat heart.

OBJECTIVE: Sphingosine-1-phosphate is a natural metabolite that is cardioprotective, but its effects on endothelial glycocalyx damage during ischemia-reperfusion are unknown. Therefore, we investigated the effect of sphingosine-1-phosphate on the endothelial glycocalyx during ischemia-reperfusion. METHODS: Isolated hearts from Wistar rats were perfused on a Langendorff system with Krebs-Henseleit buffer and pretreated with sphingosine-1-phosphate (10 nmol/L) before ischemia-reperfusion. Infarct size was measured by triphenyl tetrazolium chloride staining (n ≥ 6 per group). Cardiac edema was assessed by calculating total water content (n = 7 per group) and histologically quantifying the interstitial compartment (n ≥ 3 per group). The post-ischemic coronary release of syndecan-1 was quantified using ELISA. Syndecan-1 immunostaining intensity was assessed in perfusion-fixed hearts (n ≥ 3 per group). RESULTS: Pretreatment with sphingosine-1-phosphate decreased infarct size in isolated hearts subjected to ischemia-reperfusion (P = .01 vs ischemia-reperfusion). However, sphingosine-1-phosphate had no effect on syndecan-1 levels in the coronary effluent or on the intensity of the syndecan-1 immunostaining signal in cardiac tissue. Heart total water content was not significantly different between control and ischemic groups but was significantly decreased in hearts treated with sphingosine-1-phosphate alone. CONCLUSION: These results suggest that sphingosine-1-phosphate-induced cardioprotection against ischemia-reperfusion injury is not mediated by the maintenance of syndecan-1 in the endothelial glycocalyx.

Cardioprotective and Anti-arrhythmic Effects of Magnesium Pretreatment Against Ischaemia/Reperfusion Injury in Isoprenaline-Induced Hypertrophic Rat Heart.

The effects of magnesium (Mg2+) on ischaemic complications of pathological cardiac hypertrophy are unclear. In this study, we investigated effects of Mg2+ pretreatment on ischaemia/reperfusion (I/R) injury in isoprenaline (ISO)-induced hypertrophic hearts. Wistar rats were treated for 7 days with different combinations of ISO (1.25 mg/kg) subcutaneously, MgSO4 (270 mg/kg) intraperitoneally, or vehicle (saline). On the eighth day, hearts were either subjected to regional I/R during Langendorff perfusion or histologically stained with haematoxylin and eosin and Masson's trichrome. Haemodynamic and electrocardiographic parameters were recorded using the PowerLab data-acquisition system. Infarcts were identified by triphenyltetrazolium chloride staining. Plasma Mg2+ was measured using photometric assays. Mg2+ pretreatment significantly decreased I/R-induced infarct size (p = 0.001) and the overall arrhythmia score (p < 0.001) of I/R-induced ventricular ectopics, ventricular tachycardia, and ventricular fibrillation in hypertrophic hearts, but not non-hypertrophied hearts. Mg2+ also improved post-I/R left ventricular developed pressure in hypertrophic hearts. However, Mg2+ did not reverse the ISO-induced myocyte thickening and interstitial fibrosis or increases in heart weight. Plasma Mg2+ was not different among treatment groups. These results suggest that Mg2+ pretreatment may protect against I/R-induced injury and malignant arrhythmias in hypertrophic hearts, possibly via mechanisms unrelated to long-lasting changes in plasma Mg2+ or prevention of structural changes such as fibrosis.

Beneficial Effects of Magnesium Treatment on Heart Rate Variability and Cardiac Ventricular Function in Diabetic Rats.

BACKGROUND: Diabetes mellitus induces life-threatening cardiovascular complications such as cardiac autonomic neuropathy and ventricular dysfunction and is associated with hypomagnesemia. In this study, we investigated the short-term effects of magnesium (Mg2+) treatment on streptozotocin (STZ)-induced diabetic cardiac complications. METHODS: Adult Wistar rats were treated once with STZ (50 mg/kg, intraperitoneally [ip]) or vehicle (citrate) and then daily for 7 days with MgSO4 (270 mg/kg, ip) or saline. On the eighth day, in vivo tail-pulse plethysmography was recorded for heart rate variability (HRV) analysis, and ex vivo Langendorff-based left ventricular (LV) pressure-volume parameters were measured using an intraventricular balloon. Measurements of plasma lipid and Mg2+ levels as well as blood glucose and cardiac tissue Mg2+ levels were also performed. RESULTS: Treatment with Mg2+ prevented diabetes-induced alterations in the standard deviation of the averages of normal-to-normal (NN) intervals (SDANN), root mean square differences of successive NN intervals (RMSSD), heart rate, and low-frequency (LF) power-high-frequency (HF) power ratio. In addition, Mg2+ restored orthostatic stress-induced changes in SDANN, RMSSD, and LF-HF ratio in diabetic rats. In isolated hearts, Mg2+ reversed the diabetes-induced decrease in LV end-diastolic elastance and the right shift of end-diastolic equilibrium volume intercept, without altering LV-developed pressure or end-systolic elastance. However, Mg2+ did not prevent the elevation in blood glucose, total cholesterol, and triglycerides or the decrease in high-density lipoprotein cholesterol in diabetes. Plasma- or cardiac tissue Mg2+ was not different among the treatment groups. CONCLUSION: These results suggest that Mg2+ treatment may attenuate diabetes-induced reduction in HRV and improve LV diastolic distensibility, without preventing hyperglycemia and dyslipidemia. Thus, Mg2+ may have a modulatory role in the early stages of diabetic cardiovascular complications.

First-year medical students' naïve beliefs about respiratory physiology.

The present study explored the nature and frequency of physiology naïve beliefs by investigating novices' understanding of the respiratory system. Previous studies have shown considerable misconceptions related to physiology but focused mostly on specific physiological processes of normal respiration. Little is known about novices' broader understanding of breathing in a clinical context. Our study hypothesized that naïve beliefs could hamper participants' ability to understand the interrelatedness of respiratory structures and functions related to breathing during a clinical complication. The study entailed both quantitative and qualitative foci. A two-tier test was designed and administered to 211 first-year medical students. Participants were asked to choose the correct answer out of a set of four options and to substantiate their choices. Questions were purposefully left open to elicit a wide range of responses. Statistical analysis (SPSS) was done to evaluate the frequency of naïve beliefs. Thematic analysis was used to determine themes within the raw data. The majority of participants selected incorrect answers in the multiple-choice question part of the questionnaire. Results from the thematic analysis yielded a considerable range of naïve beliefs about gas exchange, foundational physics, airflow, anatomic structures, and breathing pathways. An awareness of the existence of such naive beliefs in respiratory physiology will allow educators to address them in their teaching and thereby prevent naïve beliefs transforming into misconceptions.

Lack of cardioprotection by single-dose magnesium prophylaxis on isoprenaline-induced myocardial infarction in adult Wistar rats.

AIM: Magnesium (Mg(2+)) is effective in treating cardiovascular disorders such as arrhythmias and pre-eclampsia, but its role during myocardial infarction (MI) remains uncertain. In this study, we investigated the effects of Mg(2+)pre-treatment on isoprenaline (ISO) -induced MI in vivo. METHODS: Rats divided into four groups were each pre-treated with either MgSO4 (270 mg/kg intraperitoneally) or an equivalent volume of physiological saline, prior to the ISO (67 mg/kg subcutaneously) or saline treatments. One day post-treatment, the electrocardiogram and left ventricular blood pressures were recorded. Infarcts were determined using 2,3,5-triphenyltetrazolium chloride staining, and serum markers of lipid peroxidation were measured with spectrophotometric assays. RESULTS: Mg(2+) pre-treatment neither altered the ISO-induced infarct size compared with ISO treatment alone (p > 0.05), nor reversed the low-voltage electrocardiogram or the prominent Q waves induced by ISO, despite a trend to decreased Q waves. Similarly, Mg(2+) did not prevent the ISO-induced decrease in peak left ventricular blood pressure or the decrease in minimal rate of pressure change. Mg(2+) did not reverse the ISO-induced gain in heart weight or loss of body weight. Neither ISO nor Mg(2+) altered the concentrations of lipid peroxidation markers 24 hours post MI induction. CONCLUSION: Although Mg(2+) had no detrimental effects on electrical or haemodynamic activity in ISO-induced MI, the lack of infarct prevention may detract from its utility in MI therapy.

Cardiac preconditioning with sphingosine-1-phosphate requires activation of signal transducer and activator of transcription-3.

AIM: Sphingosine-1-phosphate (S1P) is a cardioprotective agent. Signal transducer and activator of transcription 3 (STAT-3) is a key mediator of many cardioprotective agents. We aimed to explore whether STAT-3 is a key mediator in S1P-induced preconditioning. METHODS: Langendorff-perfused hearts from Wistar rats and wild-type or cardiomyocyte-specific STAT-3 knockout mice were pre-treated with S1P (10 nmol/l), with or without the STAT-3 pathway inhibitor AG490, before an ischaemia-reperfusion insult. Triphenyltetrazolium chloride and Evans blue staining were used for the determination of infarct size. Western blot analysis was carried out on the S1P pre-treated hearts for detection of cytosolic, nuclear and mitochondrial phosphorylated and total STAT-3 proteins. RESULTS: Pre-treatment with S1P decreased the infarct size in isolated rat (5 ± 3% vs control 26 ± 8%, p < 0.01) and wild-type mouse hearts (13 ± 1% vs control 33 ± 3%, p < 0.05). This protective effect was abolished in the rat hearts pre-treated with AG490 (30 ± 10%, p = ns vs control) and in the hearts from STAT-3 knockout mice (35 ± 4% vs control 30 ± 3%, p = ns). Levels of phosphorylated STAT-3 were significantly increased in both the nuclear (p < 0.05 vs control) and mitochondrial (p < 0.05 vs control) fractions in the S1P pre-treated hearts, but remained unchanged in the cytosolic fraction (p = ns vs control). CONCLUSION: These novel results demonstrate that pharmacological preconditioning with S1P in the isolated heart is mediated by activation of mitochondrial and nuclear STAT-3, therefore suggesting that S1P may be a novel therapeutic target to modulate mitochondrial and nuclear function in cardiovascular disease in order to protect the heart against ischaemia-reperfusion.

Oleanolic acid: a novel cardioprotective agent that blunts hyperglycemia-induced contractile dysfunction.

Diabetes constitutes a major health challenge. Since cardiovascular complications are common in diabetic patients this will further increase the overall burden of disease. Furthermore, stress-induced hyperglycemia in non-diabetic patients with acute myocardial infarction is associated with higher in-hospital mortality. Previous studies implicate oxidative stress, excessive flux through the hexosamine biosynthetic pathway (HBP) and a dysfunctional ubiquitin-proteasome system (UPS) as potential mediators of this process. Since oleanolic acid (OA; a clove extract) possesses antioxidant properties, we hypothesized that it attenuates acute and chronic hyperglycemia-mediated pathophysiologic molecular events (oxidative stress, apoptosis, HBP, UPS) and thereby improves contractile function in response to ischemia-reperfusion. We employed several experimental systems: 1) H9c2 cardiac myoblasts were exposed to 33 mM glucose for 48 hr vs. controls (5 mM glucose); and subsequently treated with two OA doses (20 and 50 µM) for 6 and 24 hr, respectively; 2) Isolated rat hearts were perfused ex vivo with Krebs-Henseleit buffer containing 33 mM glucose vs. controls (11 mM glucose) for 60 min, followed by 20 min global ischemia and 60 min reperfusion ± OA treatment; 3) In vivo coronary ligations were performed on streptozotocin treated rats ± OA administration during reperfusion; and 4) Effects of long-term OA treatment (2 weeks) on heart function was assessed in streptozotocin-treated rats. Our data demonstrate that OA treatment blunted high glucose-induced oxidative stress and apoptosis in heart cells. OA therapy also resulted in cardioprotection, i.e. for ex vivo and in vivo rat hearts exposed to ischemia-reperfusion under hyperglycemic conditions. In parallel, we found decreased oxidative stress, apoptosis, HBP flux and proteasomal activity following ischemia-reperfusion. Long-term OA treatment also improved heart function in streptozotocin-diabetic rats. These findings are promising since it may eventually result in novel therapeutic interventions to treat acute hyperglycemia (in non-diabetic patients) and diabetic patients with associated cardiovascular complications.