A case of recurring perioperative circulatory arrest: mind the autonomic nervous system.

We report the case of an elderly woman who developed recurring episodes of unexplained cardiocirculatory arrest. The index event appeared during surgery to fix a fracture of the ankle and consisted of bradypnea, hypotension and asystole, coherent with a Bezold-Jarisch-like cardioprotective reflex. Classical signs of acute myocardial infarction were absent. Yet, occlusion of the right coronary artery (RCA) was observed and successfully revascularized, whereupon circulatory arrests vanished. We discuss several differential diagnoses. Unexplainable circulatory failure, with sinus bradycardia and arterial hypotension, despite lack of ECG signs of ischemia or significant troponin levels, suggest the action of cardioprotective reflexes of the autonomic nervous system. Coronary artery disease is a common source. Attention to cardioprotective reflexes should be taken in the case of unexplained cardiac arrest without overt reasons. We recommend performing coronary angiography to exclude significant coronary stenosis.

Absorption, Distribution, Metabolism, and Excretion of Capmatinib (INC280) in Healthy Male Volunteers and In Vitro Aldehyde Oxidase Phenotyping of the Major Metabolite.

Capmatinib (INC280), a highly selective and potent inhibitor of the MET receptor tyrosine kinase, has demonstrated clinically meaningful efficacy and a manageable safety profile in patients with advanced non-small-cell lung cancer harboring MET exon 14-skipping mutations. We investigated the absorption, distribution, metabolism, and excretion of capmatinib in six healthy male volunteers after a single peroral dose of 600 mg 14C-labeled capmatinib. The mass balance, blood and plasma radioactivity, and plasma capmatinib concentrations were determined along with metabolite profiles in plasma, urine, and feces. The metabolite structures were elucidated using mass spectrometry and comparing with reference compounds. The parent compound accounted for most of the radioactivity in plasma (42.9% ± 2.9%). The extent of oral absorption was estimated to be 49.6%; the Cmax of capmatinib in plasma was reached at 2 hours (median time to reach Cmax). The apparent mean elimination half-life of capmatinib in plasma was 7.84 hours. Apparent distribution volume of capmatinib during the terminal phase was moderate-to-high (geometric mean 473 l). Metabolic reactions involved lactam formation, hydroxylation, N-dealkylation, formation of a carboxylic acid, hydrogenation, N-oxygenation, glucuronidation, and combinations thereof. M16, the most abundant metabolite in plasma, urine, and feces was formed by lactam formation. Absorbed capmatinib was eliminated mainly by metabolism and subsequent biliary/fecal and renal excretion. Excretion of radioactivity was complete after 7 days. CYP phenotyping demonstrated that CYP3A was the major cytochrome P450 enzyme subfamily involved in hepatic microsomal metabolism, and in vitro studies in hepatic cytosol indicated that M16 formation was mainly catalyzed by aldehyde oxidase. SIGNIFICANCE STATEMENT: The absorption, distribution, metabolism, and excretion of capmatinib revealed that capmatinib had substantial systemic availability after oral administration. It was also extensively metabolized and largely distributed to the peripheral tissue. Mean elimination half-life was 7.84 hours. The most abundant metabolite, M16, was formed by imidazo-triazinone formation catalyzed by cytosolic aldehyde oxidase. Correlation analysis, specific inhibition, and recombinant enzymes phenotyping demonstrated that CYP3A is the major enzyme subfamily involved in the hepatic microsomal metabolism of [14C]capmatinib.

[Position dependent dyspnea and cyanosis of the lips at the daily round - A case of Platypnea-Orthodeoxia Syndrome]. / Lageabhängige Dyspnoe und Lippenzyanose im Rahmen der täglichen Visite ­ Platypnoe-Orthodeoxie Syndrom.

HISTORY AND CLINICIAL FINDINGS: We elaborate a case of a 79-year-old patient who presented with position dependent shortness of breath and cyanosis of the lips at the daily round. INVESTIGATIONS: In supine position the patient's oxygen saturation was normal > 95 %, in upright position we noticed a reproducible decrease to 76-85 %. Echocardiographic examination revealed a patent foramen ovale (PFO) with spontaneous right-left shunt and additionally a thoracic aortic aneurysm. DIAGNOSIS: Due to a typical position dependent cyanosis, dyspnea and decreased oxygen saturation in combination with patent foramen ovale and aortic aneurysm, Platypnea-Orthodeoxia Syndrome was our suspected diagnosis. TREATMENT AND COURSE: After percutaneously occlusion of the foramen ovale the patient presented symptom-free und oxygen saturation remained stable in supine and upright positions. In the follow up examination a significant right-left shunt could no longer be found. CONCLUSION: The combination of position dependent shortness of breath and decreased oxygen saturation should lead to the diagnosis of Platypnea-Orthodeoxia Syndrome. The underlying reasons are diverse and not only of cardiologic origin.

Kendomycin Cytotoxicity against Bacterial, Fungal, and Mammalian Cells Is Due to Cation Chelation.

Kendomycin is a small-molecule natural product that has gained significant attention due to reported cytotoxicity against pathogenic bacteria and fungi as well as a number of cancer cell lines. Despite significant biomedical interest and attempts to reveal its mechanism of action, the cellular target of kendomycin remains disputed. Herein it is shown that kendomycin induces cellular responses indicative of cation stress comparable to the effects of established iron chelators. Furthermore, addition of excess iron and copper attenuated kendomycin cytotoxicity in bacteria, yeast, and mammalian cells. Finally, NMR analysis demonstrated a direct interaction with cations, corroborating a close link between the observed kendomycin polypharmacology across different species and modulation of iron and/or copper levels.

Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism.

Siponimod, a next-generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism, and excretion (ADME) of a single 10-mg oral dose of [14C]siponimod in four healthy men. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine, and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds. Unchanged siponimod accounted for 57% of the total plasma radioactivity (area under the concentration-time curve), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median Tmax: 4 hours) and moderate distribution (Vz/F: 291 l). Siponimod was mainly cleared through biotransformation, predominantly by oxidative metabolism. The mean apparent elimination half-life of siponimod in plasma was 56.6 hours. Siponimod was excreted mostly in feces in the form of oxidative metabolites. The excretion of radioactivity was close to complete after 13 days. Based on the metabolite patterns, a phase II metabolite (M3) formed by glucuronidation of hydroxylated siponimod was the main circulating metabolite in plasma. However, in subsequent mouse ADME and clinical pharmacokinetic studies, a long-lived nonpolar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. We further conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. The selective inhibitor and recombinant enzyme results identified cytochrome P450 2C9 (CYP2C9) as the predominant contributor to the human liver microsomal biotransformation of siponimod, with minor contributions from CYP3A4 and other cytochrome P450 enzymes.

[Heart Failure Despite Low BNP-Level: Paradoxon or Pathfinder? - - A Case of Pericarditis constrictiva]. / Herzinsuffizienz bei niedrigem BNP-Wert: Paradoxon oder Wegweiser?

HISTORY AND CLINICIAL FINDINGS: We elaborate a case of a 48-year old patient of indian descent who presented with shortness of breath, lower extremity edema and ascites in our emergency unit.One year beforehand tuberculous pleuritis was diagnosed and treated in accordance with guidelines. INVESTIGATIONS: CT-Scan of the heart revealed a pericardial thickening with calcifications. Echocardiographic examination and invasive pressure measurement did not provide any clear evidence of pericarditis constrictiva. Coronary artery disease was ruled out. In laboratory tests, the BNP-level was noticeably low despite severe cardiac decompensation. DIAGNOSIS: Due to a typically low BNP-level, pericarditis constrictiva was our suspected diagnosis TREATMENT AND COURSE: After an intraoperative diagnosis confirmation by our cardiosurgery colleagues, a complete pericardiectomy was performed. In the follow up, the patient presented symptom-free and with normal capacity. CONCLUSION: In case of incongruent findings, the BNP-level seems to be a useful additional diagnostic tool in the diagnosis of pericarditis constrictiva.

Point-by-point versus multisite electrode mapping in VT ablation: does freedom from VT recurrences depend on mapping catheter? An observational study.

PURPOSE: This study was conducted with the purpose of determining whether or not the potential technical advantages of multi-electrode mapping catheters in catheter ablation (CA) of ventricular tachycardia (VT) result in any relevant clinical benefit for VT patients. METHODS: A single-center VT study, having taken place from 2012 to 2014 using a standard 3.5-mm catheter (Thermocool SF® group 1) and from 2014 to 2016 using a 1-mm multi-electrode-mapping catheter (PentaRay® group 2), was conducted. The endpoint was the complete elimination of late potentials (LPs), local abnormal ventricular activities (LAVA), and VT non-inducibility. Follow-up consisted of device interrogation to monitor for VT recurrence. RESULTS: Out of 74 VT patients aged 64.5 ± 12.0 years (66 male [89.2%], 56 with ICM [75.7%], and 18 with NICM [24.3%)]), 48 patients (64.9%) were investigated in group 1 and 26 (35.1%) in group 2. Using the multi-point acquisition approach, a tendency to require less mapping time (group 1 65.2 ± 37.6 min, group 2 55.6 ± 34.4 min, p ns) was determined. During 12-month follow-up, 57 patients had freedom from VT recurrences (79.2%). The result was insignificant between the groups (38 patients (79.2%) in group 1 and 19 patients (73.1%) in group 2). CONCLUSIONS: In a single-center observational study, both conventional and high-density mapping approaches in VT patients are comparable in terms of procedure duration and outcome. Mapping time when using a multi-electrode catheter seems to have the tendency of being shorter. We should be encouraged to recruit more patients comparing the benefit of different catheter types.

Interconversion Rates between Conformational States as Rationale for the Membrane Permeability of Cyclosporines.

Cyclic peptides have regained interest as potential inhibitors of challenging targets but have often a low bioavailability. The natural product cyclosporine A (CsA) is the textbook exception. Despite its size and polar backbone, it is able to passively cross membranes. This ability is hypothesized to be due to a conformational change from the low-energy conformation in water to a "congruent" conformation that is populated both in water and inside the membrane. Here, we use a combination of NMR measurements and kinetic models based on molecular dynamics simulations to rationalize the difference in the membrane permeability of cyclosporine E (CsE) and CsA. The structure of CsE differs only in a backbone methylation, but its membrane permeability is one order of magnitude lower. The most striking difference is found in the interconversion rates between the conformational states favored in water and in chloroform, which are up to one order of magnitude slower for CsE compared to CsA.

Pulmonary vein potential mapping in atrial fibrillation with high density and standard spiral (lasso) catheters: A comparative study.

BACKGROUND: The dominant single-shot procedure for Pulmonary Vein Isolation (PVI) is the Cryoballoon Ablation (CBA) technique using a spiral catheter (Achieve™, AC) for mapping and monitoring purposes. We hypothesized that Basket Catheters, such as the High Density Mesh Mapper (HDMM), with its high-density mapping properties, could detect Pulmonary Vein Potentials (PVPs) that the octapolar AC would not be able to identify. METHODS: Twenty-four patients (average age 61.8±10 years) with either paroxysmal or persistent atrial fibrillation (AF) (Paroxysmal AF or Persistent AF) were enrolled in the study. While the patients were in sinus rhythm, all pulmonary veins (PVs) were prospectively mapped both prior and subsequent to CBA with a 32-pole HDMM and an 8-pole AC. PVPs were recorded using both catheters, and their location was allocated to one of four PV quadrants. Then, the quadrant findings of the mapping catheters were compared. RESULTS: Mapping using the HDMM allowed for more precise identification of PVPs both before and after CBA compared to AC mapping. We identified an average of 83.6±4.8 PVPs in all four PVs (this means 20.9±10.5 PVPs /per single PV per patient [HDMM], 14.5±1.3 PVPs/in all four PVs and 3.6±2.7 PVPs /per single PV per patient [AC]) before ablation, thereby leading to a significant difference in the identification of PVPs per PV quadrant. Of 384 PV quadrants/24 patients analyzed, the HDMM identified PVPs in 279 and AC in only 192 quadrants (P<0.05). CONCLUSION: High-density mapping with a Basket Catheter, such as the HDMM, detects PVPs that remain undetected when using the standard AC catheter in CBA procedures.

Comparison of 19F NMR and 14C Measurements for the Assessment of ADME of BYL719 (Alpelisib) in Humans.

The human mass balance study is the definitive study for the assessment of absorption, distribution, metabolism, and excretion (ADME) properties of a new chemical entity in humans. Traditionally this has been carried out by the administration of radiolabeled drug substances, typically 14C or occasionally 3H, as detection methods for these isotopes allow the absolute quantification of drug-related material (DRM) in blood, plasma, and excreta. Coupled with the use of analytical techniques such as liquid chromatography-mass spectrometry, a picture of the metabolic fate of a compound can be elucidated. In this study, we demonstrate the capabilities of 19F nuclear magnetic resonance (NMR) spectroscopy, applied as an alternative to radiolabeling, for the determination of mass balance and for metabolite profiling of an orally administered fluorinated drug. To demonstrate the capabilities of NMR, the study was conducted on remaining samples from a 14C human mass balance study conducted on Alpelisib (BYL719), a compound in late stage development at Novartis for the treatment of solid tumors. Quantitative 14C data were used to cross-validate the data obtained by NMR. The data show that, using 19F NMR, comparable data can be obtained for key human ADME endpoints including mass balance, total DRM determination in plasma and metabolite profiling and identification in plasma and excreta. Potential scenarios where NMR could be employed as an alternative to radiolabeling for the conduct of an early human ADME study are discussed.

Impact of High-Intensity-NIV on the heart in stable COPD: a randomised cross-over pilot study.

BACKGROUND: Although high-intensity non-invasive ventilation has been shown to improve outcomes in stable COPD, it may adversely affect cardiac performance. Therefore, the aims of the present pilot study were to compare cardiac and pulmonary effects of 6 weeks of low-intensity non-invasive ventilation and 6 weeks of high-intensity non-invasive ventilation in stable COPD patients. METHODS: In a randomised crossover pilot feasibility study, the change in cardiac output after 6 weeks of each NIV mode compared to baseline was assessed with echocardiography in 14 severe stable COPD patients. Furthermore, CO during NIV, gas exchange, lung function, and health-related quality of life were investigated. RESULTS: Three patients dropped out: two deteriorated on low-intensity non-invasive ventilation, and one presented with decompensated heart failure while on high-intensity non-invasive ventilation. Eleven patients were included in the analysis. In general, cardiac output and NTproBNP did not change, although individual effects were noticed, depending on the pressures applied and/or the co-existence of heart failure. High-intensity non-invasive ventilation tended to be more effective in improving gas exchange, but both modes improved lung function and the health-related quality of life. CONCLUSIONS: Long-term non-invasive ventilation with adequate pressure to improve gas exchange and health-related quality of life did not have an overall adverse effect on cardiac performance. Nevertheless, in patients with pre-existing heart failure, the application of very high inspiratory pressures might reduce cardiac output. TRIAL REGISTRATION: The trial was registered in the Deutsches Register Klinischer Studien (DRKS-ID: DRKS00007977 ).

Pneumocystis jirovecii-induced chronic interstitial lung disease in Waldenström's macroglobulinemia.

Infections with Pneumocystis jirovecii can result in asymptomatic colonization or induce life threatening clinical symptoms. However, there appears to be a 'gray area' between colonization and severe pneumonia that remains underestimated so far. We describe a case with chronic interstitial lung disease and chronic cough that was attributed to P. jirovecii. The patient's history of chronic cough, although very likely being fostered by the underlying Waldenström's macroglobulinemia and interstitial lung disease, was most likely caused by P. jirovecii infection. This gives raise to the hypothesis that P. jirovecii infections do not necessarily induce life threatening pneumonia. Consequently, serial testing is required in eligible patients with positive PCR results in order to discriminate between colonization, 'gray zone' infection, and beginning pneumonia.

Effect of patient's age on the profitability of inpatient cardiac catheterization: a contribution margin analysis of frequently performed procedures over a 5-year period.

BACKGROUND: Due to a continuing age shift in the German society hospital providers are concerned about the additional costs associated with the treatment of elderly patients. It is not clear if cardiac catheterization in aged patients leads to higher resource utilization and if DRG-revenues do compensate for this factor. METHODS: Procedure-related and administrative data of all patients who underwent cardiac catheterization at a tertiary heart center between 2007 and 2011 were collected and analyzed. Then a profitability analysis was performed by comparing the case related variable costs with the Diagnosis-related group (DRG) per case revenues. A particular emphasis was placed on a comparative analysis of identical clusters of procedures. RESULTS: The most frequently performed catheterization procedure (n = 1800) was associated with significantly higher material expenditure in very old patients (178 ± 48 €) than in old (171 ± 28; p = 0.001) and young patients (172 ± 39; p = 0.046). Furthermore, radiation time and the length of hospital stay were increased in very old patients (3.5 ± 3.8 min and 6.2 ± 4.8 days) compared to old (2.7 ± 2.8 min and 4.6 ± 3.8 days; p < 0.001) and young patients (2.5 ± 2.5 min and 4.5 ± 3.9 days; p < 0.001). Due to higher DRG revenues very old patients achieved higher absolute contribution margins (2065 ± 1033 €) than old (1804 ± 1902 €; p < 0.001) and young patients (1771 ± 902 €; p < 0.001). However, the contribution margins per day were significantly smaller (440 ± 226 €) than those in old (488 ± 234 €; p = 0.001) and young patients (484 ± 206 €; p = 0.001). CONCLUSIONS: Catheterization of very old patients is related to lower contribution margins per day despite higher material and time expenditures. Since efforts to reduce the length of hospital stay of these patients are limited, this may result in a competitive disadvantage of hospitals which are more affected by the demographic change.

High-Density Mapping in Ventricular Tachycardia Ablation: A PentaRay® Study.

BACKGROUND: High-density mapping of ventricular tachycardia (VT) with PentaRay® (Biosense-Webster) provides high resolution with discrimination of local abnormal electrograms and slow conducting channels. We evaluate the feasibility of PentaRay® to characterize the anatomical substrate and assume an influence of the outcome despite limitations. METHODS: Over a 24-month period, 26 endocardial and four epicardial maps were obtained of 26 VT patients (18 ischemic cardiomyopathy (ICM, 69.2%) and 8 non-ischemic cardiomyopathy (NICM, 30.8%), age 65 ± 9 years). Catheter ablation (CA) was performed with the aim of transecting the isthmus. The endpoint was non-inducibility of any VT. Manual review of the maps was performed and focused on evaluating scarring, bipolar electrograms, and procedure times. RESULTS: In 55.6 ± 34.4 min, 1,085.9 ± 726.2 points were created. The mean ablation time was 50.8 ± 30.1 min. The endpoint was achieved in 12 patients (46.2%). The mean dense scar area and the mean patchy scar area were 49.4 ± 51.8 cm2 (range 0 - 190 cm2) and 14.7 ± 14.9 cm2 (range 0 - 110 cm2), respectively. Analyzing the learning curve, we found a tendency in decreasing procedure times. During the course of follow-up treatment averaging a 14-month period, device interrogation showed that 17 patients (65.4%) had remained free of any arrhythmia recurrence. CONCLUSION: The high-density maps with PentaRay® were safely created in a short period of time. Our manual review of the maps reveals limitations of current annotation criteria; nevertheless, medium-term outcomes were encouraging. Further prospective studies are required to validate our findings in a larger cohort of patients.

Is it time to rebalance the case mix? A portfolio analysis of direct catheterization laboratory costs over a 5-year period.

BACKGROUND: Cardiac catheterization laboratories (CLL) have continued to function as profit centers for hospitals. Due to a high percentage of material and labor costs, they are natural targets for process improvement. Our study applied a contribution margin (CBM) concept to evaluate costs and cost dynamics over a 5-year period. METHODS: We retrospectively analyzed all procedures performed at a tertiary heart center between 2007 and 2011. Total variable costs, including labor time, material, and maintenance-expenses, were allocated at a global as well as a procedural level. CBM and CBM ratios were calculated by integration of individual DRG revenues. RESULTS: Annual case volume increased from 1288 to 1545. In parallel, overall profitability improved as indicated by a 2% increase in CBM ratio and a higher CBM generated per hour of CLL working time (4325 vs. 5892 €, p < 0.001). Coronary angiography generated higher average CBMs per hour than coronary or electrophysiological interventions (5831 vs. 3458 vs. 1495 €; p < 0.001). The latter are characterized by relatively high per case material expenditures. On a procedural level, DRG-specific trends as a steady improvement of examination time or an increase in material costs were detectable. CONCLUSIONS: The CBM concept allows a comprehensive analysis of CLL costs and cost dynamics. From a health service providers view, its range of application includes global profitability analysis, portfolio evaluation, and a detailed cost analysis of specific service lines. From a healthcare payers perspective, it may help to monitor hospital activities and to provide a solid data basis in cases where inappropriate developments are suspected. The calculation principle is simple which may increase user acceptance and thus the motivation of team members.

Metabolomic changes in CSF of migraine patients measured with 1H-NMR spectroscopy.

BACKGROUND: Migraine is a common episodic brain disorder. Treatment options and diagnosis are hampered by an incomplete understanding of disease pathophysiology and the lack of objective diagnostic markers. The aim of this study was to identify biochemical differences characteristic for different subtypes of migraine in cerebrospinal fluid (CSF) of migraine patients using an exploratory 1H-NMR-based metabolomics approach. METHODS: CSF was obtained, in between migraine attacks, via lumbar puncture from patients with hemiplegic migraine, migraine with aura, migraine without aura, and healthy controls. Metabolite concentrations were measured by quantitative 1H-NMR spectroscopy. Multivariate data analysis was used to find the optimal set of predictors, generalized linear models (GLM) were used to ascertain the differential significance of individual metabolites. RESULTS: In CSF samples from 18 patients with hemiplegic migraine, 38 with migraine with aura, 27 migraine without aura, and 43 healthy controls, nineteen metabolites were identified and quantified. Hemiplegic migraine patients could be discriminated from healthy controls using supervised multivariate modelling with 2-hydroxybutyrate and 2-hydroxyisovalerate as the most discriminant metabolites. Univariate GLM analysis showed 2-hydroxybutyrate to be lower in hemiplegic migraine compared with healthy controls; no significant differences were observed for other metabolites. It was not possible to discriminate migraine with and without aura from healthy controls based on their metabolic profile. CONCLUSIONS: Using an exploratory 1H-NMR metabolomics analysis we identified metabolites that were able to discriminate hemiplegic migraine patients from healthy controls. The lower levels of 2-hydroxybutyrate found in patients with hemiplegic migraine could indicate a dysregulation of the brain's energy metabolism. An experimental confirmation in vitro or in animal models will be required to confirm or discard this hypothesis. Migraine with and migraine without aura patients did not reveal a metabolic profile different from healthy controls.

Impact of Cryoballoon Ablation in Hypertrophic Cardiomyopathy-related Heart Failure due to Paroxysmal Atrial Fibrillation. A Comparative Case Series.

BACKGROUND: Atrial fibrillation (AF) represents a turning point in hypertrophic cardiomyopathy (HCM). Pulmonary Vein Isolation (PVI) with Radiofrequency Catheter Ablation (RFCA) is accepted to be successful in restoring sinus rhythm (SR) in HCM patients. The efficacy of cryoballoon (CB) therapy in HCM patients has not been studied so far. METHODS: 166 patients with AF underwent PVI with CB technology in our single center between 1/2012 and 12/2015. To evaluate the efficacy of the CB therapy in HCM patients, we compared their clinical outcome with those in "Non-HCM" AF patients in a 3 and 6 months follow-up. RESULTS: Out of 166 AF patients (65.7% paroxysmal AF, PAF), 4 patients had HCM and PAF (young males < 50 years). During the blanking period, 26 patients (15.8%) suffered from AF recurrence (11.0% PAF), including all HCM patients. The 6 months follow up of "Non-HCM" AF patients showed acceptable results (80% stable SR), whereas the HCM patients remained AF. IN CONCLUSION: Even if the CB provides advantages, the single device cannot be recommended in HCM patients because of early AF recurrences. Anyway, because of the specific hemodynamic changes in HCM patients with AF, ablation should be sought in an early state of its occurrence, then, however, preferably with RFCA.

Update on the cardiovascular profile of fingolimod in the therapy of relapsing-remitting multiple sclerosis (MS).

BACKGROUND: Fingolimod (FTY720) has been approved as the first oral representative of the class of sphingosine-1-phosphate (S1P) receptor modulators for the treatment of relapsing-remitting multiple sclerosis (MS). Besides inducing vaso-relaxation, fingolimod can also influence electrical conduction in the myocardium and vascular endothelium by having a transient negative chronotropic effect on the sinus node. METHODS: Cardiac safety and tolerability of fingolimod in the cardiac sense were reviewed by analysing the data collected from the FREEDOMS and TRANSFORMS studies -both relevant studies for marketing authorisation, from their extension studies, as well as the clinical data collected from a practice-related MS patient cohort with cardiovascular risk factors and corresponding co-medication (FIRST study). RESULTS: The safety analyses on file gave no indication of any increased cardiovascular risk. The 2-3mmHg increase in blood pressure observed after the first dose of fingolimod has no therapeutic consequences. The first dose of 0.5mg fingolimod resulted in an average decrease in heart rate of 7-8beats/min. The onset of effect occurred approximately 1-2h after the first dose and the nadir was reached after approximately 4-5h. This negative chronotropic effect returned to normal after internalisation of the S1P1 receptors on maintenance therapy. There were no indications that patients with cardiac risk factors required closer observation beyond the monitoring recommended by the EMA following the first dose of fingolimod. Case study observations from the routine clinical setting show that patients accept this method of monitoring, which they assess as being a positive aspect of attentive medical care and concern.