Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers.

BACKGROUND: Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. RESULTS: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P\u3c0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site. CONCLUSIONS: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.)

The reliability and validity of the persian version of sinonasal outcome test 22 (Snot22) questionnaires

Background: The quality of life (QOL) is an important indicator for disease-severity classification and outcome measurement in obtaining treatment sinonasal diseases. The sinonasal outcome test 22 (SNOT 22) questionnaire has been introduced as the best specific sinonasal instrument for QOL measurement. Objectives: To prepare a valid and reliable Persian language version of SNOT 22 questionnaire. Patients and Methods: After forward and backward translation of the original version of SNOT 22 questionnaire from English to Persian, a group of patients with nasal septal deviation who need septal surgery and another group of healthy volunteers answered the Persian version of the questionnaire. The responsiveness rate, validity (Pearson correlations and differential validity) and reliability (internal consistency and test-retest reliability) of the 22 items of the questionnaire was calculated. P value < 0.05 was considered significant. Results: Thirty adults with nasal septal deviation need surgical correction and 30 healthy volunteers were included (mean age 30.4 ± 7.1 vs. 33 ± 6.7, P value = 0.148). The questionnaire was introduced to subjects two times with a two-week-period gap. Total responsiveness rate for 22 items was more than 97%. The total Cronbach's Alfa coefficient was 0.898 (ranging 0.890-0.903). The Pearson correlations were 0.85 and 0.96 for patients and healthy volunteers, respectively. The mean total score were 25.6 ± 13.3 (range 6-52) and 7.6 ± 9.1 (range 0-45) in patients and healthy volunteers, respectively (P < 0.0001). The subscales scores were also significantly different between two groups. Conclusions: The Persian version of SNOT 22 questionnaire is a valid and reliable instrument for accessing sinonasal diseases in Persianspeaking people

Long-term impact of fecal transplantation in healthy volunteers

Fecal microbiota transplantation (FMT) has been recently approved by FDA for the treatment of refractory recurrent clostridial colitis (rCDI). Success of FTM in treatment of rCDI led to a number of studies investigating the effectiveness of its application in the other gastrointestinal diseases. However, in the majority of studies the effects of FMT were evaluated on the patients with initially altered microbiota. The aim of our study was to estimate effects of FMT on the gut microbiota composition in healthy volunteers and to monitor its long-term outcomes.Peer ReviewedPostprint (published version

The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers.

Nanocrystal budesonide (nanobudesonide) is a suspension for nebulization in patients with steroid-responsive pulmonary diseases such as asthma. The pharmacokinetics and safety of the product were compared to those of Pulmicort Respules. Sixteen healthy volunteers were administered nanobudesonide 0.5 and 1.0 mg, Pulmicort Respules 0.5 mg, and placebo in a four-way, randomized crossover design. All nebulized formulations were well tolerated, with no evidence of bronchospasm. Nebulization times were significantly shorter for nanobudesonide compared to Pulmicort Respules. Because of a low oral bioavailability, plasma concentration of budesonide is a good marker of lung-delivered dose. The pharmacokinetics of nanobudesonide 0.5 and 1.0 mg were approximately dose proportional with respect to Cmax, AUC(0-t), and AUC(0-infinity). Nanobudesonide 0.5 mg and Pulmicort Respules 0.5 mg exhibited similar AUCs, suggesting a similar extent of pulmonary absorption. A higher Cmax was noted with nanobudesonide 0.5 mg, and the tmax was significantly different, suggesting a more rapid rate of drug delivery of nanobudesonide 0.5 mg than Pulmicort Respules. In conclusion, nebulized nanobudesonide 0.5 mg was safe in healthy volunteers, with a similar extent of absorption as Pulmicort Respules

Value of superb microvascular imaging ultrasonography in the diagnosis of carpal tunnel syndrome: Compared with color Doppler and power Doppler.

The aim of this study was to compare the value of superb microvascular imaging (SMI) in carpal tunnel syndrome (CTS) with that of color Doppler ultrasonography (CDUS) and power Doppler ultrasonography (PDUS).Fifty patients with symptomatic CTS and 25 healthy volunteers were enrolled. The cross-sectional area (CSA), CDUS score, PDUS score, and SMI score of the median nerve (MN) at the carpal tunnel were recorded. The value of different ultrasonography (US) diagnostic strategies was calculated.The blood flow display ratio in the MN of the healthy volunteers had no statistical difference between CDUS, PDUS, and SMI (20%, 32%, and 48%, respectively, P \u3e.05). The blood flow display ratio for SMI in patients was significantly higher than that of CDUS and PDUS (90%, 52%, and 60%, respectively,

Blood Protein Binding of Cyclosporine in Transplant Patients

The objective of this study was to compare the binding of cyclosporine to blood proteins between four healthy subjects and five liver and eight renal transplant patients. Fresh heparinized blood was obtained, to which sufficient quantities of tritium-labelled cyclosporine and unlabelled cyclosporine were added to blood samples or red blood cell (RBC) suspensions. Concentrations of cyclosporine in whole blood, plasma, RBC suspension, and phosphate buffer were estimated by liquid scintigraphy. The blood:plasma ratio of cyclosporine in transplant patients was significantly lower (P < .05) than that in healthy volunteers. The RBC:buffer ratio, a measure of affinity of RBCs for cyclosporine, was highest in those with liver transplants and lowest in those with kidney transplants. The unbound fraction of cyclosporine in plasma was less in transplant patients than in healthy volunteers. The results of this study indicate that there are differences in blood protein binding of cyclosporine between transplant patients that may contribute to the differences in the pharmacokinetics and pharmacodynamics of this drug

Plasma from Volunteers Breathing Helium Reduces Hypoxia-Induced Cell Damage in Human Endothelial Cells-Mechanisms of Remote Protection Against Hypoxia by Helium.

PurposeRemote ischemic preconditioning protects peripheral organs against prolonged ischemia/reperfusion injury via circulating protective factors. Preconditioning with helium protected healthy volunteers against postischemic endothelial dysfunction. We investigated whether plasma from helium-treated volunteers can protect human umbilical vein endothelial cells (HUVECs) against hypoxia in vitro through release of circulating of factors.MethodsHealthy male volunteers inhaled heliox (79% helium, 21% oxygen) or air for 30 min. Plasma was collected at baseline, directly after inhalation, 6 h and 24 h after start of the experiment. HUVECs were incubated with either 5% or 10% of the plasma for 1 or 2 h and subjected to enzymatically induced hypoxia. Cell damage was measured by LDH content. Furthermore, caveolin 1 (Cav-1), hypoxia-inducible factor (HIF1α), extracellular signal-regulated kinase (ERK)1/2, signal transducer and activator of transcription (STAT3) and endothelial nitric oxide synthase (eNOS) were determined.ResultsPrehypoxic exposure to 10% plasma obtained 6 h after helium inhalation decreased hypoxia-induced cell damage in HUVEC. Cav-1 knockdown in HUVEC abolished this effect.ConclusionsPlasma of healthy volunteers breathing helium protects HUVEC against hypoxic cell damage, possibly involving circulating Cav-1

Neuropsychopharmacology of appetite in healthy volunteers

This thesis aimed to develop an Experimental Medicine Model for the assessment of the potential efficacy and psychiatric safety of novel anti-obesity drugs. Chapter 1 provides a general introduction. In Chapter 2, a Universal Eating Monitor (UEM) detected the satiety enhancing effects of an appetite suppressant drug (meta-chlorophenylpiperazine – mCPP) and the P1vital® Oxford Emotional Test Battery (ETB) suggested an absence of psychiatric side-effects. In Chapter 3, UEM measures of eating behaviour were similar whether or not the participants were aware of the UEM. Chapter 4 presents two studies providing evidence that 1) repeated use of the ETB is feasible and 2) performance on the ETB is not affected by satiety. In Chapter 5, functional magnetic resonance imaging (fMRI) was used to identify a profile of natural satiety. In Chapter 6, mCPP reduced brain activity to high calorie food images. It also reduced consumption of a palatable cookie snack but not a pasta meal. Analysis of individual differences to the drug showed that brain activity predicted anorectic response. Chapter 7 concludes that the Experimental Medicine Model may be valuable for the development of efficacious and safe appetite suppressant drugs, providing data to inform go/no go decisions in early phase clinical trials

Transcutaneous vagus nerve stimulation does not affect verbal memory performance in healthy volunteers

Introduction: Invasive vagus nerve stimulation (VNS) improves word recognition memory in patients with epilepsy. Recent studies with transcutaneous VNS (tVNS) have also shown positive effects on various subdomains of cognitive functioning in healthy volunteers. In this randomized, controlled, crossover study, we investigated the effect of tVNS on a word recognition memory paradigm in healthy volunteers to further investigate the potential of tVNS in the treatment of cognitive disorders. Methods: We included 41 healthy participants aged between 18 and 30 years (young age group) and 24 healthy participants aged between 45 and 80 years (older age group). Each participant completed a word recognition memory paradigm during three different conditions: true tVNS, sham, and control. During true tVNS, stimulation was delivered at the cymba conchae. Sham stimulation was delivered by stimulating the earlobe. In the control condition, no stimulation was given. In each condition, participants were asked to remember highlighted words from three test paragraphs. Accuracy scores were calculated for immediate recall after each test paragraph and for delayed recognition at the end of the paradigm. We hypothesized that highlighted words from paragraphs in the true tVNS condition would be more accurately recalled and/or recognized compared to highlighted words from paragraphs in the sham or control condition. Results: In this randomized study, tVNS did not affect the accuracy scores for immediate recall or delayed recognition in both age groups. The younger group showed significantly higher accuracy scores than the older group. The accuracy scores improved over time, and the most recently learned words were better recognized. Participants rated true tVNS as significantly more painful; however, pain was not found to affect accuracy scores. Conclusion: In this study, tVNS did not affect verbal memory performance in healthy volunteers. Our results could not replicate the positive effects of invasive VNS on word recognition memory in epilepsy patients. Future research with the aim of improving cognitive function should focus on the rational identification of optimized and individualized stimulation settings primarily in patients with cognitive deficits