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Journal of Education & Teaching in... Jan 2024Emergency medicine residents and medical students on emergency medicine rotation.
AUDIENCE
Emergency medicine residents and medical students on emergency medicine rotation.
BACKGROUND
Calcium channel blocker (CCB) overdoses can be severe with potentially serious adverse outcomes. CCBs work by blocking the calcium channels on smooth and cardiac muscle tissue. At low dose ranges, dihydropyridine CCBs (such as nifedipine, amlodipine, and nicardipine) block the L-type calcium receptors in the peripheral vasculature, whereas non-dihydropyridine CCBs (such as: verapamil and diltiazem) affect the L-type calcium receptors in the myocardium.1 Because of this distinction, dihydropyridine CCB toxicity manifests as arterial vasodilation and non-dihydropyridine CCB toxicity is associated with cardiac manifestations such as bradycardia and negative inotropy.2 It is important to note that in high concentrations (such as in overdoses), CCBs lose specificity for their specific receptors and can show all the manifestations of toxicity such as bradycardia, peripheral vasodilation, and hypotension. Patients can develop both vasoplegic shock from peripheral vasodilation and cardiogenic shock. This is a high acuity low occurrence case with infrequently used but specific treatments, and thus this case provides educational value.
EDUCATIONAL OBJECTIVES
At the end of this oral board session, examinees will: (1) demonstrate ability to evaluate a patient with undifferentiated shock with bradycardia and discuss the differential diagnosis, (2) recognize the signs and symptoms of calcium channel blocker overdose, (3) demonstrate ability to manage treatment of a patient with calcium channel overdose.
EDUCATIONAL METHODS
This oral board case followed the standard American Board of Emergency Medicine-style case in a tertiary care hospital with access to all specialists and resources needed. This case was tested using 12 resident volunteers ranging from PGY 1-2 in an ACGME (Accreditation Council for Graduate Medical Education) accredited emergency medicine residency program.
RESEARCH METHODS
Immediate feedback was solicited both from the learners and from the evaluators following the debriefing session. Residents were asked to evaluate the educational value of the case using a 1-5 Likert scale (5 being excellent). Evaluators were asked to score the residents using the ACGME core competencies with a scale of 1-8, 1-4 being unacceptable and 5-8 being acceptable.
RESULTS
Seven PGY1 residents and five PGY2 residents, thus twelve residents in total, completed the case. The average score was 5.10/8. Three residents missed zero critical actions. The most common critical action missed was consulting cardiology or cardiothoracic surgery for circulatory support options. Many residents failed to recognize that the patient did not have a perfusing blood pressure at the beginning of the case and did not start CPR. Although most residents recognized the patient's hemodynamic collapse was from a calcium channel blocker overdose, most did not know the treatment for this beyond atropine and intravenous fluids.The learners rated the educational value of the case as 4.9/5. Seven residents reported that the case definitely increased their medical knowledge; five residents reported that it somewhat increased their medical knowledge. All residents rated the case as helpful in preparing to manage this medical condition.
DISCUSSION
The educational content from this case was effective. This is a high acuity low occurrence case that has unique treatments that are not commonly used. This makes this case excellent for practice and discussion. We learned during implementation that this case has a high degree of difficulty compared to other cases, and junior learners will need more prompting. It is also important for the proctor to keep the case moving because there is a lot to cover in the allotted amount of time.
TOPICS
Calcium channel blocker overdose, toxicology.
PubMed: 38344049
DOI: 10.21980/J8CQ07 -
Channels (Austin, Tex.) Dec 2023Recent years have seen an outpouring of atomic or near atomic resolution structures of cyclic nucleotide-gated (CNG) channels, captured in closed, transition, pre-open,... (Review)
Review
Recent years have seen an outpouring of atomic or near atomic resolution structures of cyclic nucleotide-gated (CNG) channels, captured in closed, transition, pre-open, partially open, and fully open states. These structures provide unprecedented molecular insights into the activation, assembly, architecture, regulation, and channelopathy of CNG channels, as well as mechanistic explanations for CNG channel biophysical and pharmacological properties. This article summarizes recent advances in CNG channel structural biology, describes key structural features and elements, and illuminates a detailed conformational landscape of activation by cyclic nucleotides. The review also correlates structures with findings and properties delineated in functional studies, including nonselective monovalent cation selectivity, Ca permeation and block, block by L--diltiazem, location of the activation gate, lack of voltage-dependent gating, and modulation by lipids and calmodulin. A perspective on future research is also offered.
Topics: Humans; Cyclic Nucleotide-Gated Cation Channels; Channelopathies; Nucleotides, Cyclic; Calmodulin; Cyclic GMP
PubMed: 37905307
DOI: 10.1080/19336950.2023.2273165 -
The Mental Health Clinician Aug 2023Clozapine can be associated with significant side effects and tolerability issues. Hyperhidrosis occurs less commonly and is unanticipated by clinicians because of...
BACKGROUND
Clozapine can be associated with significant side effects and tolerability issues. Hyperhidrosis occurs less commonly and is unanticipated by clinicians because of clozapine's significant anticholinergic activity.
CASE REPORT
A 34-year-old female developed clozapine-induced nocturnal, generalized hyperhidrosis following initial titration to 400 mg/day. Dose reduction did not decrease the side effect. Treatment with an anticholinergic medication could not be initiated because of constipation. Treatment with a beta blocker resulted in worsening of asthma. Treatment with a calcium channel blocker, diltiazem CD 180 mg/day, resulted in a significant reduction in hyperhidrosis.
CONCLUSION
This case supports the use of calcium channel blockers to reduce clozapine-induced hyperhidrosis and offers an alternative to anticholinergic medications that may negatively impact clozapine tolerability.
PubMed: 37860588
DOI: 10.9740/mhc.2023.08.193 -
Clinical and Translational Science Dec 2023Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer....
Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro and may be susceptible to drug-drug interactions when co-administered with CYP3A inhibitors or inducers. The primary objective was to assess the impact of the strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P-gp inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy volunteers following a single 50-mg dose. A total of 32 participants were enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to infinity (AUC ) and maximum plasma concentration (C ) geometric mean for encorafenib increased by 183% and 68.4%, respectively, when co-administered with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2 L/h when coadministered with posaconazole, and plasma terminal half-life (t ) of encorafenib increased from 4.3 to 7.3 h. The AUC and C geometric mean for encorafenib increased by 83.0% and 44.7%, respectively, when co-administered with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 to 16.0 L/h when co-administered with diltiazem, and plasma t of encorafenib increased from 6.6 to 7.9 h. There were no deaths, serious adverse events (AEs), or patient discontinuations due to AEs in parts 1 or 2. The most frequently reported treatment-related AEs were erythema (n = 14; 88%) and headache (n = 11; 69%) in part 1 and headache (n = 7; 44%) in part 2. The results of this study indicate that co-administration of encorafenib with strong or moderate CYP3A4 inhibitors should be avoided.
Topics: Humans; Antineoplastic Agents; Colorectal Neoplasms; Cytochrome P-450 CYP3A Inhibitors; Diltiazem; Drug Interactions; Headache; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf
PubMed: 37837178
DOI: 10.1111/cts.13662 -
Europace : European Pacing,... Dec 2023Chronic obstructive pulmonary disease (COPD) may influence management and prognosis of atrial fibrillation (AF), but this relationship has been scarcely explored in...
AIMS
Chronic obstructive pulmonary disease (COPD) may influence management and prognosis of atrial fibrillation (AF), but this relationship has been scarcely explored in contemporary global cohorts. We aimed to investigate the association between AF and COPD, in relation to treatment patterns and major outcomes.
METHODS AND RESULTS
From the prospective, global GLORIA-AF registry, we analysed factors associated with COPD diagnosis, as well as treatment patterns and risk of major outcomes in relation to COPD. The primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACEs). A total of 36 263 patients (mean age 70.1 ± 10.5 years, 45.2% females) were included; 2,261 (6.2%) had COPD. The prevalence of COPD was lower in Asia and higher in North America. Age, female sex, smoking, body mass index, and cardiovascular comorbidities were associated with the presence of COPD. Chronic obstructive pulmonary disease was associated with higher use of oral anticoagulant (OAC) [adjusted odds ratio (aOR) and 95% confidence interval (CI): 1.29 (1.13-1.47)] and higher OAC discontinuation [adjusted hazard ratio (aHR) and 95% CI: 1.12 (1.01-1.25)]. Chronic obstructive pulmonary disease was associated with less use of beta-blocker [aOR (95% CI): 0.79 (0.72-0.87)], amiodarone and propafenone, and higher use of digoxin and verapamil/diltiazem. Patients with COPD had a higher hazard of primary composite outcome [aHR (95% CI): 1.78 (1.58-2.00)]; no interaction was observed regarding beta-blocker use. Chronic obstructive pulmonary disease was also associated with all-cause death [aHR (95% CI): 2.01 (1.77-2.28)], MACEs [aHR (95% CI): 1.41 (1.18-1.68)], and major bleeding [aHR (95% CI): 1.48 (1.16-1.88)].
CONCLUSION
In AF patients, COPD was associated with differences in OAC treatment and use of other drugs; Patients with AF and COPD had worse outcomes, including higher mortality, MACE, and major bleeding.
Topics: Humans; Female; Middle Aged; Aged; Aged, 80 and over; Male; Atrial Fibrillation; Prospective Studies; Risk Factors; Pulmonary Disease, Chronic Obstructive; Hemorrhage; Anticoagulants; Registries; Stroke
PubMed: 38266129
DOI: 10.1093/europace/euae021 -
Genes & Diseases Jan 2024Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release... (Review)
Review
Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exosomes to reprogram the factors associated with the tumor microenvironment (TME) causing tumor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with receptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some patients show poor drug response. Exosomal PD-L1 plays a vital role in lowering the treatment response, showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the effect of cell surface PD-L1. To enhance therapeutic response, inhibition of exosomal PD-L1 is required. Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors. Immune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine, nifedipine, lercanidipine, diltiazem, and verapamil were also reported to suppress cellular PD-L1 expression. Therefore, to enhance the PD-1/PD-L1 blockage therapy response, the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consideration. In this review, we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.
PubMed: 37588227
DOI: 10.1016/j.gendis.2023.01.026 -
Hypertension in Pregnancy Dec 2024Preeclampsia (PE) is a pregnancy disorder that represents a major cause of maternal and perinatal morbidity and mortality. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Preeclampsia (PE) is a pregnancy disorder that represents a major cause of maternal and perinatal morbidity and mortality.
METHODS
This network meta-analysis was registered with PROSPERO. We searched the PubMed, ClinicalTrials.gov. and Embase databases for studies published from inception to the 31 of March 2023. RevMan5.3 software provided by the Cochrane Collaboration was used for direct meta-analysis (DMA) statistical analysis. Funnel maps, network meta-analysis (NMA), the surface under the cumulative ranking curve (SUCRA) to rank the different interventions and publication bias were generated by STATA 17.0 software.
RESULTS
We included eight randomized controlled trials (RCTs) involving a total of 1192 women with PE; two studies were of high quality and six were of moderate quality. Eight interventions were addressed in the NMA. In the DMA, we found that blood pressure in the Ketanserin group were significantly higher than those in the Nicardipine group. NMA showed that blood pressure in the Dihydralazine group was significantly higher than that in the Methyldopa, Labetalol, Nicardipine and Diltiazem groups. And the blood pressure in the Labetalol group was significantly lower than that in the Nicardipine group. SUCRA values showed that Diltiazem was more effective in lowering blood pressure than other drugs looked at in this study.
CONCLUSION
According to the eight RCTs included in this study, Diltiazem was the most effective in reducing blood pressure in PE patients; Labetalol and Nicardipine also had good effects. Diltiazem is preferred for the treatment of patients with severe PE and high blood pressure.
Topics: Pregnancy; Female; Humans; Antihypertensive Agents; Labetalol; Pre-Eclampsia; Diltiazem; Nicardipine; Network Meta-Analysis
PubMed: 38488570
DOI: 10.1080/10641955.2024.2329068