Acute isometric and dynamic exercise do not alter cerebral sympathetic nerve activity in healthy humans.

The impact of physiological stressors on cerebral sympathetic nervous activity (SNA) remains controversial. We hypothesized that cerebral noradrenaline (NA) spillover, an index of cerebral SNA, would not change during both submaximal isometric handgrip (HG) exercise followed by a post-exercise circulatory occlusion (PECO), and supine dynamic cycling exercise. Twelve healthy participants (5 females) underwent simultaneous blood sampling from the right radial artery and right internal jugular vein. Right internal jugular vein blood flow was measured using Duplex ultrasound, and tritiated NA was infused through the participants' right superficial forearm vein. Heart rate was recorded via electrocardiogram and blood pressure was monitored using the right radial artery. Total NA spillover increased during HG (P = 0.049), PECO (P = 0.006), and moderate cycling exercise (P = 0.03) compared to rest. Cerebral NA spillover remained unchanged during isometric HG exercise (P = 0.36), PECO after the isometric HG exercise (P = 0.45), and during moderate cycling exercise (P = 0.94) compared to rest. These results indicate that transient increases in blood pressure during acute exercise involving both small and large muscle mass do not engage cerebral SNA in healthy humans. Our findings suggest that cerebral SNA may be non-obligatory for exercise-related cerebrovascular adjustments.

Ozanimod Therapy in Patients With COVID-19 Requiring Oxygen Support: A Randomized Open-Label Pilot Trial.

BACKGROUND: Sphingosine-1-phosphate receptor ligands (SRLs) dampen immunopathologic damages in models of viral pneumonia. RESEARCH QUESTION: Is it feasible to administer an SRL therapy, here ozanimod (OZA), to acutely ill patients infected with SARS-CoV-2? STUDY DESIGN AND METHODS: The prospective randomized open-label COVID-19 Ozanimod Intervention (COZI) pilot trial was conducted in three Canadian hospitals. Patients admitted for COVID-19 requiring oxygen were eligible. Randomization was stratified for risk factors of poor outcome and oxygen needs at inclusion. Participants were allocated to standard of care or to standard of care plus OZA. OZA (oral, once daily, incremental dosage) was administered for a maximum of 14 days. Primary end point investigated for size effect and variance over time was the assessment of safety and efficacy, evaluated by the daily score on the World Health Organization-adapted six-point ordinal scale for clinical improvement analyzed under the intention-to-treat principle. RESULTS: Twenty-three patients were randomized to the standard of care arm, and 20 were randomized to the OZA arm from September 2020 to February 2022. Evaluation of efficacy showed nonsignificant reductions of median (interquartile range) duration of respiratory support (6 [3-10] vs 9 [4-12] days; P = .34), median duration of hospitalization (9 [6-12] vs 10 [6-18] days; P = .20), and median time to clinical improvement (4 [3-7] vs 7 [3-11] days; P = .12) for OZA compared with standard of care, respectively. Heart rate was significantly lower with OZA (65 [ 63-67] vs 71 [69-72] beats/min; P < .0001). However, QT and PR intervals were not affected. No severe adverse drug reaction was reported. INTERPRETATION: To our knowledge, SRL utility in severe pneumonia has never been tested in patients. This study shows for the first time that this new pharmacologic agent may safely be administered to patients hospitalized for viral pneumonia, with potential clinical benefits. Bradycardia was frequent but well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04405102; URL: www. CLINICALTRIALS: gov.

Tacrolimus Dose-Conversion Ratios Based on Switching of Formulations for Patients with Solid Organ Transplants.

BACKGROUND: Tacrolimus may be administered during hospitalization as an IV formulation or oral suspension. However, literature suggesting appropriate ratios for conversion from these formulations to capsules is limited. OBJECTIVE: To evaluate conversion ratios after a switch in formulation of tacrolimus for solid-organ transplant recipients. METHODS: This single-centre observational longitudinal study involved hospitalized patients who underwent a switch in formulation of tacrolimus according to 1 of 3 possible scenarios: IV to oral suspension, IV to capsule, or oral suspension to capsule. Data were collected from the earliest accessible electronic file (January 2009) to January 1, 2019. Conversion ratios were calculated for each of the 3 groups using data for blood concentrations and doses before and after the switch. The calculated ratios were then compared with recommended conversion ratios: 1:5 (i.e., 1 mg of IV tacrolimus is converted to 5 mg of oral tacrolimus, expressed as "5") for either of the switches involving an IV formulation and 1:1 (i.e., same amount, expressed as "1") for the switch from oral formulation to capsules. RESULTS: For the group who underwent switching from the IV formulation to oral suspension, the mean calculated conversion ratio was 3.04, which was significantly different from the recommended ratio of 5. For the group who underwent switching from the IV formulation to capsules, the calculated conversion ratio was 5.18, which was not significantly different from the recommended ratio of 5. For the group who underwent switching from oral suspension to capsules, the calculated conversion ratio was 1.17, which was not significantly different from the recommended ratio of 1. CONCLUSION: In this small retrospective study of tacrolimus therapy, the calculated conversion ratio was significantly different from the recommended ratio for patients who were switched from IV administration to oral suspension, but not for those switched from IV administration or oral suspension to capsules. Therapeutic drug monitoring therefore appears indispensable, regardless of conversion ratios.

CONTEXTE: Le tacrolimus peut être administré par IV ou sous forme de suspension orale pendant une hospitalisation. Cependant, il existe peu de documents qui proposent des ratios appropriés pour convertir ces formulations en capsules. OBJECTIF: Évaluer les ratios de conversion après un changement de formulation du tacrolimus pour les bénéficiaires de greffes d'organes solides. MÉTHODES: Cette étude observationnelle longitudinale unicentrique impliquait des patients hospitalisés, pour qui la formulation de tacrolimus changeait en fonction de chacun des trois scénarios possibles: passage de l'administration par IV à la suspension orale, passage de l'administration par IV aux capsules ou passage de l'administration par suspension aux capsules. Le recueil des données a été effectué à partir du plus ancien dossier électronique accessible (janvier 2009) jusqu'au 1er janvier 2019. Les ratios de conversion ont été calculés pour chacun des trois groupes à l'aide de données pour les concentrations de sang et des doses avant et après le changement. Les ratios calculés ont ensuite été comparés avec les ratios de conversion recommandés: 1:5 (c.-à-d., 1 mg de tacrolimus administré par IV est converti en 5 mg de tacrolimus par voie orale, conversion exprimée par le nombre « 5 ¼) pour chacun des changements impliquant une formulation IV et 1:1 (c.-à-d. même quantité, conversion exprimée par le nombre « 1 ¼) pour le passage de la formulation orale aux capsules. RÉSULTATS: Dans le groupe dont l'administration par IV est passée à une suspension orale, le ratio de conversion moyen calculé était de 3,04, ce qui était significativement différent par rapport au ratio recommandé de 5. Pour le groupe dont l'administration par IV est passée à des capsules, le ratio de conversion moyen calculé était de 5,18, ce qui n'était pas significativement différent par rapport au ratio recommandé de 5. Pour le groupe dont l'administration est passée de la suspension orale aux capsules, le ratio de conversion moyen calculé était de 1,17, ce qui n'était pas significativement différent par rapport au ratio recommandé de 1. CONCLUSION: Dans cette petite étude rétrospective de la thérapie à l'aide du tacrolimus, le ratio de conversion calculé était significativement différent du ratio recommandé pour les patients qui passaient d'une administration IV à une suspension orale, mais pas pour ceux qui passaient d'une administration par IV ou d'une suspension orale à des capsules. La surveillance thérapeutique des médicaments semble donc indispensable, quels que soient les ratios de conversion.

Complex drug interactions in an HIV-seropositive heart transplant recipient.

Highly active antiretroviral therapy has led to greater life expectancy for human immun-deficiency virus (HIV)-positive patients. This was a report of 11 years of follow-up of an HIV-seropositive patient who underwent heart transplantation in 2006, with emphasis on the management challenges of complex drug interactions over time.

Effects of chronic sildenafil use on pulmonary hemodynamics and clinical outcomes in heart transplantation.

BACKGROUND: Elevated pulmonary vascular resistance (PVR) in heart transplant (HT) candidates is associated with poor survival after HT. This study assessed the effect of peri-operative sildenafil administration on pulmonary hemodynamics and clinical outcomes in patients with advanced heart failure who were considered high-risk for HT because of elevated PVR and transpulmonary gradient (TPG). METHODS: The study included 119 consecutive patients who underwent HT between 2004 and 2011. Fifteen patients (Group A) had severe pulmonary hypertension (PH), defined as mean pulmonary pressure (MPAP)>25 mm Hg and PVR>2.5 Wood units (WU), and/or TPG>12 mm Hg after vasodilator test or the continuous administration of inotropics drugs, and 104 patients (Group B) were without severe PH. Group A received sildenafil therapy. Pulmonary hemodynamics were evaluated before HT with and without sildenafil therapy. Right catheterization was performed early after HT with sildenafil therapy and late after HT without sildenafil. Survival after HT was compared between the groups. RESULTS: The sildenafil dosage was 109±42 mg/day during 163±116 days before HT. After sildenafil therapy MPAP, PVR, and TPG decreased from 43.9±12.5 to 33.4±5.8 mm Hg, 5.0±1.1 to 3.0±1.6 WU, and 17.3±3.2 to 10.2±4.1 mm Hg, respectively (p<.01). All patients underwent successful HT. Sildenafil dosage was 140±70 mg/day for 43±45 days after HT. There were no differences in PVR and TPG with sildenafil therapy early after HT and without sildenafil 6 months after HT. Survival after HT was similar between the groups. CONCLUSION: Sildenafil therapy before and after HT in patients with severe PH is associated with improved pulmonary hemodynamics and successful HT, without an increase in post-HT mortality.