Network Pharmacology-Based Exploration of the Therapeutic Mechanisms of Cordyceps cicadae in Renal Ischemia/Reperfusion.

BACKGROUND Cordyceps cicadae is beneficial in treating renal diseases, especially in inhibiting renal ischemia/reperfusion injury (IRI). The aim of this study was to systematically analyze and predict the potential mechanism of Cordyceps cicadae in renal IRI therapy using network pharmacology. MATERIAL AND METHODS Cordycepin, adenosine, and cordycepic acid are the 3 major medicinal ingredients in Cordyceps cicadae. Based on network pharmacology, the 3D structure of the 3 compounds were obtained, and then the common targets between these compounds and renal IRI were analyzed and determined. We used the ingredient-target (I-T), protein-protein interaction (PPI) networks, the enrichment analysis of Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) to find the possible pharmacological mechanism of Cordyceps cicadae in treating renal IRI. RESULTS Through target fishing and analysis, the 3 active ingredients of Cordyceps cicadae shared 81 target genes with renal IRI. I-T network showed that adenosine had the highest degree, and 5 genes were associated with the 3 active ingredients. PPI network analysis showed that ALB, GAPDH, CASP3, MAPK1, FN1, and IL-10 play a pivotal role. The enrichment analysis of GO and KEGG showed that Cordyceps cicadae can treat renal IRI through MAPK, cAMP, PPAR, Rap1, and HIF-1 signaling pathways. CONCLUSIONS Cordyceps cicadae exerts its therapeutic effect on renal IRI via multiple targets and pathways. Nevertheless, further experimentation is needed to verify this. The method of network pharmacology provides an effective method of determining the comprehensive action mechanism of Traditional Chinese Medicine (TCM).

Brassica rapa L. (Tibetan turnip) prevents sleep-deprivation induced cognitive deficits via the inhibition of neuroinflammation and mitochondrial depolarization.

Brassica rapa L., an edible, feeding and medicinal plant cultivated on the Tibetan plateau with altitudes above 3800 m, has several pharmacological effects. However, its therapeutic effects against memory impairment and central fatigue have yet to be conclusively established. In this study, the Y-maze and Morris water maze tasks revealed that Brassica rapa L. aqueous extract (BE) significantly ameliorated cognitive deficits of sleep deprivation (SD)-treated mice. Moreover, BE treatment partially alleviated SD-induced reductions in the levels of peripheral energy metabolism, and significantly decreased inflammatory factor levels in serum and hippocampus. In addition, BE treatment significantly relieved central fatigue and stabilized the excitability as well as activities of neurons by regulating the levels of hypothalamus tryptophan metabolites and striatum neurotransmitters. The neuroprotective effects of BE were also confirmed using glutamate-treated HT22 cells, whereby BE pretreatment significantly attenuated intracellular ROS production and mitochondrial depolarization via adenosine 5'-monophosphate activated protein kinase/peroxisome proliferators-activated receptors (AMPK/PPAR-γ) signaling pathways. Thus, BE might probably prevent SD-induced learning and memory deficits by inhibiting neuroinflammation and restoring mitochondrial energy metabolism in the hippocampus. These findings imply that BE is a potential complementary therapy for those suffering from deficient sleep or neurometabolic disorders, although this needs verification by prospective clinical studies.

High-dose adenosine versus saline-induced cardioplegic arrest in coronary artery bypass grafting: A randomized double-blind clinical feasibility trial.

BACKGROUND AND OBJECTIVE: In this clinical trial, we evaluated if a short-acting nucleoside, adenosine, as a high-dose bolus injection with blood cardioplegia induces faster arrest and provides better myocardial performance in patients after bypass surgery for coronary artery disease. METHODS: Forty-three patients scheduled for elective or urgent coronary artery bypass grafting were prospectively recruited in two-arm 1:1 randomized parallel groups to either receive 20 mg of adenosine (in 21 patients) or saline (in 22 patients) into the aortic root during the first potassium-enriched blood cardioplegia infusion. The main outcomes of the study were ventricular myocardial performance measured with cardiac index, right ventricular stroke work index, and left ventricular stroke work index at predefined time points and time to asystole after a single bolus injection of adenosine. Conventional myocardial biomarkers were compared between the two groups at predefined time points as secondary endpoints. Electrocardiographic data and other ad hoc clinical outcomes were compared between the groups. RESULTS: Compared with saline, adenosine reduced the time to asystole (68 (95% confidence interval (95% CI) = 37-100) versus 150 (95% CI = 100-210) seconds, p = 0.005). With myocardial performance, the results were inconclusive, since right ventricular stroke work index recovered better in the adenosine group (p = 0.008), but there were no significant overall differences in cardiac index and left ventricular stroke work index between the groups. Only the post-cardiopulmonary bypass cardiac index was better in the adenosine group (2.3 (95% CI = 2.2-2.5) versus 2.1 (95% CI = 1.9-2.2) L/min/m2, p = 0.016). There were no significant differences between the groups in cardiac biomarker values. CONCLUSIONS: A high dose adenosine bolus at the beginning of the first cardioplegia infusion resulted in significantly faster asystole in coronary artery bypass grafting patients but enhanced only partially the ventricular performance.EudraCT number: 2014-001382-26. https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-001382-26/FI.

A3 adenosine receptor allosteric modulator CF602 reverses erectile dysfunction in a diabetic rat model.

Adenosine plays a major role in erection by binding to its receptors and activating pathways resulting in increased arterial blood flow and intracavernosal pressure (ICP). CF602, an allosteric modulator of the A3 adenosine receptor (A3AR), increases the binding affinity of the endogenous adenosine to the receptor. We examined the effect of CF602 on resolving erectile dysfunction (ED) in a diabetic ED rat model (streptozotocin-induced diabetic rats that were screened for ED using the apomorphine test). ED was assessed by measuring ICP and main arterial pressure (MAP) during electrostimulation of the cavernosal nerve. A single dose of CF602 or placebo was applied either topically (100 µl from a 100 nM or 500 nM solution) or orally (100, 200 or 500 µg/kg) prior to erectile function assessment. A significant dose-dependent improvement in the ICP:MAP ratio without a change in MAP was recorded with the topical and oral CF602 treatments. A significant increase in smooth muscle:collagen ratio, vascular endothelial growth factor and endothelial nitric oxide synthase was also observed in both administration modes. In conclusion, topical and oral treatment with CF602 significantly improved erectile function, supporting its further evaluation as a treatment for ED.

Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern.

We assessed the in vitro antiviral activity of remdesivir and its parent nucleoside GS-441524, molnupiravir and its parent nucleoside EIDD-1931 and the viral protease inhibitor nirmatrelvir against the ancestral SARS-CoV2 strain and the five variants of concern including Omicron. VeroE6-GFP cells were pre-treated overnight with serial dilutions of the compounds before infection. The GFP signal was determined by high-content imaging on day 4 post-infection. All molecules have equipotent antiviral activity against the ancestral virus and the VOCs Alpha, Beta, Gamma, Delta and Omicron. These findings are in line with the observation that the target proteins of these antivirals (respectively the viral RNA dependent RNA polymerase and the viral main protease Mpro) are highly conserved.

Supraventricular tachydysrhythmias in the emergency department.

Diagnosing and treating supraventricular tachycardias is routine in emergency medicine, and new strategies can improve efficiency and outcomes. This review provides an overview of supraventricular tachycardias, their pathophysiology, differential diagnosis, and electrocardiographic features. Clinical evidence guiding contemporary practice is determined largely by multiple observational studies, with few randomized controlled trials. Current prehospital and emergency department management strategies beyond the use of adenosine and calcium channel blockers are addressed. Diagnostic and therapeutic recommendations are provided, based on the best available evidence.

COA-Cl prevented TGF-ß1-induced CTGF expression by Akt dephosphorylation in normal human dermal fibroblasts, and it attenuated skin fibrosis in mice models of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs. Although transforming growth factor (TGF)-ß1-induced connective tissue growth factor (CTGF/CCN2) expression has been presented in SSc fibrosis, the therapeutic potential of targeting CTGF in SSc has not been fully explored. COA-Cl is a novel nucleic acid analog, which is reported to have pleiotropic beneficial biologic effects. OBJECTIVE: We examine the effects of COA-Cl on TGF-ß1-induced CTGF expression in normal human dermal fibroblast (NHDF). We also examined the effects of COA-Cl on CTGF expression in a mouse SSc model of angiotensin II (Ang II)-induced skin fibrosis. METHODS: NHDF was cultured for in vitro experiments. For in vivo experiments, C57BL/6J mice were treated with Ang II for 14 days by subcutaneous osmotic pump. Quantitative real-time polymerase chain reaction, western blot analysis, immunohistochemical staining and immunofluorescence staining were performed to examine the expression levels of CTGF and phosphorylation levels of Smad2/3, ERK1/2 and Akt. RESULTS: COA-Cl attenuated the TGF-ß1-induced expression of both CTGF mRNA and protein in NHDF. Although COA-Cl did not alter the TGF-ß1-induced phosphorylation of Smad2/3 or ERK1/2, it reduced the TGF-ß1-induced phosphorylation levels of Akt in NHDF. Notably, COA-Cl dephosphorylated the Akt of lysates of TGF-ß1-treated NHDF. COA-Cl reduced the levels of CTGF mRNA, CTGF protein, dermal thickness, collagen content and Akt phosphorylation in the skin of mice SSc model. CONCLUSION: These results imply that the inhibition of TGF-ß1-induced CTGF expression by COA-Cl may be a therapeutic approach for SSc.

An integrated metabolomic strategy for the characterization of the effects of Chinese yam and its three active components on septic cardiomyopathy.

Chinese yam (CY), used as both a traditional Chinese medicine and a nutritious food, is an excellent candidate for treating septic cardiomyopathy (SCM). Adenosine, arbutin and allantoin are the major active components in the aqueous extract of CY. The aim of the present study was to interpret the roles of CY, adenosine, arbutin and allantoin in SCM treatment. Firstly, significant physiological indexes were examined to assess the model and treatment effects of CY, adenosine, arbutin and allantoin. Then, a metabolomic approach was utilized to reveal the metabolic disorders in SCM concerning the intervention of CY/adenosine/arbutin/allantoin. The integrated results demonstrated that adenosine, arbutin and allantoin are responsible for the efficacy of CY on SCM treatment by regulating amino acid, arachidonic acid, sphingolipid, glycerophospholipid and glycol metabolism. Moreover, adenosine and/or arbutin could be used as a substitute for CY in treating SCM, and allantoin efficacy was slightly weaker. This integrated metabolomic approach performed excellently in understanding the herbal function and the roles of its components.

Guidelines for the diagnosis and treatment of male-pattern and female-pattern hair loss, 2017 version.

Male-pattern hair loss (MPHL, androgenetic alopecia) is a slowly progressive form of alopecia which begins after puberty. In 2010, we published the first Japanese edition of guidelines for the diagnosis and treatment of MPHL. It achieved the original goal of providing physicians and patients in Japan with evidence-based information for choosing efficacious and safe therapy for MPHL. Subsequently, new therapeutic drugs and treatment methods have been developed, and women's perception of MPHL has undergone change and the term "female-pattern hair loss (FPHL)" is becoming more common internationally. Thus, here we report a revised version of the 2010 guidelines aimed at both MPHL and FPHL. In these guidelines, finasteride 1 mg daily, dutasteride 0.5 mg daily and topical 5% minoxidil twice daily for MPHL, and topical 1% minoxidil twice daily for FPHL, are recommended as the first-line treatments. Self-hair transplantation, irradiation by light-emitting diodes and low-level lasers, and topical application of adenosine for MPHL are recommended, whereas prosthetic hair transplantation and oral administration of minoxidil should not be performed. Oral administration of finasteride or dutasteride are contraindicated for FPHL. In addition, we have evaluated the effectiveness of topical application of carpronium chloride, t-flavanone, cytopurine, pentadecane and ketoconazole, and wearing a wig. Unapproved topical application of bimatoprost and latanoprost, and emerging hair regeneration treatments have also been addressed. We believe that the revised guidelines will improve further the diagnostic and treatment standards for MPHL add FPHL in Japan.

Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2A receptor-induced SDF-1/CXCR4/PI3K/AKT signaling.

BACKGROUND: Baicalin, an important flavonoid in Scutellaria baicalensis Georgi extracts, exerts a variety of pharmacological effects. In this study, we explored the effects of baicalin on chronic hypoxia-induced pulmonary arterial hypertension (PAH) and investigated the mechanism underlying these effects. Moreover, we examined whether the inflammatory response was mediated by the A2A receptor (A2AR) and stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-induced phosphatidyl inositol-3-kinase (PI3K) signaling in vivo. METHODS: We established a hypoxia-induced pulmonary hypertension (HPH) mouse model by subjecting wild-type (WT) and A2AR knockout (A2AR-/-) animals to chronic hypoxia, and we examined the effects of a 4-week treatment with baicalin or the A2AR agonist CGS21680 in these animals. Invasive hemodynamic parameters, the right ventricular hypertrophy index, pulmonary congestion, the pulmonary arterial remodeling index, blood gas parameters, A2AR expression, and the expression of SDF-1/CXCR4/PI3K/protein kinase B (PKB; AKT) signaling components were measured. RESULTS: Compared with WT mice, A2AR-/- mice exhibited increased right ventricular systolic pressure (RVSP), right ventricle-to-left ventricle plus septum [RV/(LV + S)] ratio, RV weight-to-body weight (RV/BW) ratio, and lung wet weight-to-body weight (Lung/BW) ratio in the absence of an altered mean carotid arterial pressure (mCAP). These changes were accompanied by increases in pulmonary artery wall area and thickness and reductions in arterial oxygen pressure (PaO2) and hydrogen ion concentration (pH). In the HPH model, A2AR-/- mice displayed increased CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression compared with WT mice. Treating WT and A2AR-/- HPH mice with baicalin or CGS21680 attenuated the hypoxia-induced increases in RVSP, RV/(LV + S) and Lung/BW, as well as pulmonary arterial remodeling. Additionally, baicalin or CGS21680 alone could reverse the hypoxia-induced increases in CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression. Moreover, baicalin improved the hypoxemia induced by 4 weeks of hypoxia. Finally, we found that A2AR levels in WT lung tissue were enhanced by hypoxia and that baicalin up-regulated A2AR expression in WT hypoxic mice. CONCLUSIONS: Baicalin exerts protective effects against clinical HPH, which are partly mediated through enhanced A2AR activity and down-regulated SDF-1/CXCR4-induced PI3K/AKT signaling. Therefore, the A2AR may be a promising target for baicalin in treating HPH.

Effects of Dual-Dose Clopidogrel, Clopidogrel Combined with Tongxinluo Capsule, and Ticagrelor on Patients with Coronary Heart Disease and CYP2C19*2 Gene Mutation After Percutaneous Coronary Interventions (PCI).

BACKGROUND In recent years, genetic factors have attracted research interest as important predisposing factors for cardiovascular susceptibility. This study aimed to investigate the influences of dual-dose clopidogrel, clopidogrel combined with tongxinluo, and ticagrelor on the platelet activity and MACE events of patients with CYP2C19*2 gene function deficiency and poor clopidogrel response after PCI. MATERIAL AND METHODS We selected 458 patients with coronary heart disease undergoing PCI, and the genotype of CYP2C19*2 was detected by TaqMan real-time PCR. We finally enrolled 212 patients and divided them into 4 groups: a standard anti-platelet group of 46 patients, a clopidogrel double-dose group of 50 cases, a clopidogrel combined with tongxinluo group of 59 cases, and a ticagrelor group of 57. The platelet inhibition rate was detected by TEG. We analyzed and compared differences in platelet activity and the occurrence of MACE events in these 4 groups at different follow-up times. RESULTS The results showed that inhibition of platelet aggregation was better in the double-dose clopidogrel group, the clopidogrel combined with tongxinluo group, and the ticagrelor group than in the regular-dose clopidogrel group, and ticagrelor was the best. We also found that the total incidence of MACE was much lower in the double-dose clopidogrel group, the clopidogrel combined with tongxinluo group, and the ticagrelor group, while the incidence of hemorrhage in the ticagrelor group was higher. CONCLUSIONS Adjusting the dose or combining with other drugs improves the efficacy of anti-platelet therapy and reduces the incidence of ischemic events after PCI.

Endovascular occlusion of pial arteriovenous macrofistulae, using pCANvas1 and adenosine-induced asystole to control nBCA injection.

Background In large-caliber pial macrofistulae (pMF), the combination of high blood flow velocity and large efferent artery diameter makes control over the endovascular vessel occlusion difficult and may result in the inadvertent venous passage of occlusive devices or embolic agents. Case descriptions Patient 1: A 27-year-old man presented with headache and ataxia. An infratentorial pMF supplied by both superior cerebellar arteries with venous ectasia was found. The first treatment attempt using balloons and coils failed since the position of either device could not be controlled because of a distal diameter of the feeding artery of 8 mm. In a second session a pCANvas1 (phenox) was deployed at the level of the arteriovenous connection and adenosine-induced asystole allowed the controlled injection of nBCA/Lipiodol with partial occlusion of the pMF. A remaining arteriovenous shunt was occluded under asystole in a third session. The procedures were well tolerated, the patient returned to normal and DSA confirmed the occlusion of the fistula. Patient 2: A 13-year-old boy with hereditary hemorrhagic teleangiectasia presented with an intracerebral hemorrhage from an aneurysm of the left MCA. Twelve weeks after the aneurysm treatment a feeding MCA branch (diameter 4.5 mm) of a right frontal pMF was catheterized. The macrofistula was occluded by deployment of a pCANvas1, followed by the injection of nBCAl/Lipiodol under adenosine-induced asystole. Conclusion pCANvas1 and adenosine-induced asystole allow a controlled injection of nBCA/Lipiodol for the endovascular occlusion of high-flow pMF without venous passage of the embolic agent.

Comparative Effectiveness and Safety Analysis of Dual Antiplatelet Therapies Within an Integrated Delivery System.

BACKGROUND: Dual antiplatelet therapy is a mainstay of care for percutaneous coronary intervention (PCI) patients; however, uncertainty exists in real-world practice about comparative effectiveness and safety outcomes. OBJECTIVE: To evaluate outcomes of different oral P2Y12 inhibitors in PCI patients. METHODS: We retrospectively studied patients treated between July 1, 2010, and December 31, 2013. Patients received clopidogrel, prasugrel, ticagrelor, or more than 1 antiplatelet (switch) during PCI. Outcomes were evaluated for major adverse cardiovascular events (MACE) and bleeding at 1 year. Propensity score matching with Cox proportional hazards analysis was used to determine predictors of MACE and bleeding. RESULTS: A total of 8127 patients were included: clopidogrel (n = 6872), prasugrel (n = 605), ticagrelor (n = 181), and switch (n = 469). Treatment with prasugrel was associated with the lowest risk of MACE using multivariate regression (odds ratio [OR] = 0.57; 95% CI = 0.36-0.92; P = 0.02). In the propensity score-matched analysis, only the prasugrel group was associated with a lower risk of MACE compared with the clopidogrel group. Clopidogrel was associated with the lowest risk of major bleeding using multivariate regression (OR = 0.64; 95% CI = 0.42-0.98; P = 0.042). Both ticagrelor (hazard ratio [HR] = 2.00; 95% CI = 1.11-3.59) and the switch groups (HR = 1.65; 95% CI = 1.09-2.50) were associated with a greater risk of major bleeding compared with clopidogrel. However, no differences were found in the propensity score-matched analysis. CONCLUSIONS: Dual antiplatelet therapies differed in both MACE and bleeds in a real-world setting of PCI. Prasugrel was associated with fewer MACE, whereas clopidogrel had fewer major bleeding events.

Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial.

BACKGROUND: Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months. METHODS: In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395. FINDINGS: Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239-354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1·09 [95% CI 0·80-1·50]; p=0·5840). INTERPRETATION: A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach. FUNDING: Janssen Research & Development and Bayer AG.

Functional, Metabolic, and Dynamic Mitochondrial Changes in the Rat Cirrhosis-Hepatocellular Carcinoma Model and the Protective Effect of IFC-305.

Background: Mitochondrion is an important metabolic and energetic organelle that regulates several cellular processes. Mitochondrial dysfunction has been related to liver diseases including hepatocellular carcinoma. As a result, the energetic demand is not properly supplied and mitochondrial morphologic changes have been observed, resulting in an altered metabolism. We previously demonstrated the chemopreventive effect of the hepatoprotector IFC-305. Aim: In this work we aimed to evaluate the functional, metabolic, and dynamic mitochondrial alterations in the sequential model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats and the possible beneficial effect of IFC-305. Methods: Experimental groups of rats were formed to induce cirrhosis-hepatocellular carcinoma and to assess the IFC-305 effect during cancer development and progression through the evaluation of functional, metabolic, and dynamic mitochondrial parameters. Results: In this experimental model, dysfunctional mitochondria were observed and suspension of the diethylnitrosamine treatment was not enough to restore them. Administration of IFC-305 maintained and restored the mitochondrial function and regulated parameters implicated in metabolism as well as the mitochondrial dynamics modified by diethylnitrosamine intoxication. Conclusion: This study supports IFC-305 as a potential hepatocellular carcinoma treatment or as an adjuvant in chemotherapy.

BET 2: Ice water immersion, other vagal manoeuvres or adenosine for SVT in children.

A short cut review was carried out to establish whether a vagal manoeuvre was better than or as good as adenosine at safely terminating supraventricular tachycardia in children. Forty unique papers were found in Medline and Embase using the reported searches, of which five were relevant. A hand search of the forty unique citations identified a further nine relevant papers. Thus, 14 papers presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that the evidence on the management of SVT in children is made up of poor-quality retrospective cohort studies or case series. This best evidence shows that ice water to the face appears to be a safe, quick, effective and non-invasive treatment for paediatric SVT. Adenosine also appears safe and effective, but is more invasive. Valsalva and carotid sinus massage are less effective.

CYP2C19 LOF and GOF-Guided Antiplatelet Therapy in Patients with Acute Coronary Syndrome: A Cost-Effectiveness Analysis.

PURPOSE: This study aimed to examine the cost-effectiveness of CYP2C19 loss-of-function and gain-of-function allele guided (LOF/GOF-guided) antiplatelet therapy in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS: A life-long decision-analytic model was designed to simulate outcomes of three strategies: universal clopidogrel (75 mg daily), universal alternative P2Y12 inhibitor (prasugrel 10 mg daily or ticagrelor 90 mg twice daily), and LOF/GOF-guided therapy (LOF/GOF allele carriers receiving alternative P2Y12 inhibitor, wild-type patients receiving clopidogrel). Model outcomes included clinical event rates, quality-adjusted life-years (QALYs) gained and direct medical costs from perspective of US healthcare provider. RESULTS: Base-case analysis found nonfatal myocardial infarction (5.62%) and stent thrombosis (1.2%) to be the lowest in universal alternative P2Y12 inhibitor arm, whereas nonfatal stroke (0.72%), cardiovascular death (2.42%), and major bleeding (2.73%) were lowest in LOF/GOF-guided group. LOF/GOF-guided arm gained the highest QALYs (7.5301 QALYs) at lowest life-long cost (USD 76,450). One-way sensitivity analysis showed base-case results were subject to the hazard ratio of cardiovascular death in carriers versus non-carriers of LOF allele and hazard ratio of cardiovascular death in non-carriers of LOF allele versus general patients. In probabilistic sensitivity analysis of 10,000 Monte Carlo simulations, LOF/GOF-guided therapy, universal alternative P2Y12 inhibitor, and universal clopidogrel were the preferred strategy (willingness-to-pay threshold = 50,000 USD/QALY) in 99.07%, 0.04%, and 0.89% of time, respectively. CONCLUSIONS: Using both CYP2C19 GOF and LOF alleles to select antiplatelet therapy appears to be the preferred antiplatelet strategy over universal clopidogrel and universal alternative P2Y12 inhibitor therapy for ACS patients with PCI.

Clinical Features and Sites of Ablation for Patients With Incessant Supraventricular Tachycardia From Concealed Nodofascicular and Nodoventricular Tachycardias.

OBJECTIVES: This study sought to describe the clinical features and sites of successful ablation for incessant nodofascicular (NF) and nodoventricular (NV) tachycardias. BACKGROUND: Incessant supraventricular tachycardias have been associated with tachycardia-induced cardiomyopathies and have been previously attributed to permanent junctional reciprocating tachycardias, atrial tachycardias, and atrioventricular nodal re-entrant tachycardias. Incessant concealed NF and NV tachycardias have not been described previously. METHODS: Three cases of incessant concealed NF and NV re-entrant tachycardias were identified from 2 centers. RESULTS: The authors describe 3 cases with incessant supraventricular tachycardia resulting from NV (2 cases) and NF (1 case) pathways. Atrioventricular nodal re-entrant tachycardia was excluded by His synchronous premature ventricular complexes that either delayed or terminated the tachycardia. Ventricular pacing showed constant and progressive fusion in cases 1 and 3. In 2 cases, there was spontaneous initiation with a 1:2 response (cases 1 and 3); the presence of retrograde longitudinal dissociation or marked decremental pathway conduction in cases 1 and 3 sustains these tachycardias. The NV pathway was successfully ablated in the slow pathway region in case 3 and at the right bundle branch in case 1. The NF pathway was successfully ablated within the proximal coronary sinus in case 2. CONCLUSIONS: This is the first report of incessant supraventricular tachycardia using concealed NF or NV pathways. These tachycardias demonstrated spontaneous initiation from sinus rhythm with a 1:2 response and retrograde longitudinal dissociation or marked decremental pathway conduction. Successful ablation was achieved at either right-sided sites or within the coronary sinus.

Vitamin D levels and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor.

BACKGROUND: Suboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCIs). However, very few are known so far on the predictors of high-residual platelet reactivity (HRPR) despite antiplatelet strategies. Increasing attention has been paid in the last years to the role of vitamin D in atherothrombosis. Therefore, the aim of our study was to evaluate the impact of vitamin D levels on platelet function in patients treated with dual antiplatelet therapy (DAPT). Patients treated with DAPT (ASA and clopidogrel or ticagrelor) after a recent acute coronary syndrome (ACS) or elective PCI were scheduled for platelet function assessment at 30-90 days post-discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate®-Roche Diagnostics AG), HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values ≥417 AU*min (for ADP-antagonists). Fasting samples were obtained for main chemistry parameters and vitamin D level assessment. Our population is represented by 503 patients, who were divided according to vitamin D quartiles (≤9.1; 9.2-14.4; 14.5-21.7; >21.7 ng/ml). Lower vitamin D levels related with age (p = 0.04), diabetic status (p = 0.05), and previous coronary surgery (p = 0.007), therapy with beta-blockers and statins (p = 0.01 and p = 0.02). Vitamin D inversely related to the levels of total cholesterol (p = 0.01), triglycerides (p < 0.001), hemoglobin (p = 0.05), and HbA1c (p < 0.001). Significantly higher platelet reactivity was observed after platelet stimulation with ADP (p = 0.01), but not with other platelet activators. The prevalence of HRPR for ASA was low (1.2%) and not conditioned by Vitamin D levels (adjusted OR[95%CI] = 1.56[0.71-3.5], p = 0.27). HRPR with ADP-antagonists was observed in 26% of patients, and the rate increased with lower vitamin D quartiles (37.3% vs 22.2% vs 24.4% vs 20.2%, p = 0.005, adjusted OR[95%CI] = 1.23[1.02-1.49], p = 0.04). An absolute increase in HRPR with lower vitamin D levels was similarly observed among patients receiving ticagrelor (adjusted OR[95% CI] = 1.40[0.95-2.06], p = 0.08), and those on clopidogrel (adjusted OR[95%CI] = 1.31[0.99-1.75], p = 0.06). Thus, lower vitamin D levels are associated with higher platelet reactivity and impaired effectiveness of ADP-antagonists, while not influencing the effectiveness of ASA. Future studies will tell whether vitamin D supplementation can reduce platelet reactivity, overcoming the phenomenon of resistance to antiplatelet agents.

Novel Oral Therapies for Psoriasis and Psoriatic Arthritis.

Several classes of new oral therapy are in use or in development for the treatment of psoriasis. Despite the high efficacy of biologics, new oral therapies remain important as patients generally prefer this mode of administration and they offer an alternative risk-benefit profile. In this review, we discuss the novel modes of action of these drugs, including modulation of cellular pathways involving diverse targets such as Janus kinase, phosphodiesterase 4, sphingosine 1-phosphate, A3 adenosine receptor and rho-associated kinase 2. We review the available evidence around licensed drugs (apremilast) and drugs that are advanced (tofacitinib) or early (ponesimod, baricitinib, peficitinib, INCB039110, CF101, KD025) in the development pipeline. The key limitations of these oral therapies are their modest efficacy profile (apremilast, ponesimod) and the limitations of their safety profile (tofacitinib, ponesimod), while the evidence for the early pipeline drugs are at phase II level only. Potential niches of current unmet needs include apremilast for patients with concomitant psoriatic arthritis, as combination treatments with biologic therapies, and/or for patients in whom multiple biologic therapies have failed due to immunogenicity and secondary inefficacy. The present knowledge gap regarding these novel drugs includes the need for longer clinical trials or observational studies to evaluate safety, and randomised phase III trials for the early pipeline drugs. We conclude that further research and data are necessary to conclusively establish the role of these agents in the current psoriasis treatment paradigm.