Response In Healthy Volunteers Research Articles

Savory Cracker Development for Blood Glucose Control and Management: Glycogen Storage Diseases.

The blood glucose response of savory slow energy-release crackers (GLY-HYP) were evaluated in volunteers carrying glycogen storage diseases (GSDs), Types I (Ia) and IV. The crackers have been shown previously to provide a "flat" slow glucose response in healthy volunteers, for up to 4 h. On average for the mixed-sex volunteer group aged 53 to 70 for Type I, the blood glucose concentration increased from baseline to a maximum of 9.5 mmol/L at 60 min and remained above baseline for up to 210 min; overall, above 5 mmol/L for 4 h. In common with healthy individuals, a relatively flat blood glucose response was recorded. For Type IV, mixed-sex patients aged between 55 and 72, the blood glucose concentration reached maximum of 10.2 mmol/L at 45 min and then stayed above baseline for 150 min. Again, overall, above 5 mmol/L for 4 h. Altogether, these data indicate that these crackers would provide a valuable contribution to the nutritional needs of people of different age groups with GSDs (Clinical Registration Number: HRC10032021).

Cerebral Blood Flow Assessed with Phase-contrast Magnetic Resonance Imaging during Blood Pressure Changes with Noradrenaline and Labetalol: A Trial in Healthy Volunteers.

Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on mean arterial pressure (MAP) as a surrogate, even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase-contrast magnetic resonance imaging to characterize blood flow responses in healthy volunteers to commonly used pharmacologic agents that increase or decrease arterial blood pressure. Eighteen healthy volunteers aged 30 to 50 yr were investigated with phase-contrast magnetic resonance imaging. Intra-arterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase-contrast magnetic resonance imaging and defined as the sum of flow in the internal carotid arteries and vertebral arteries. Cardiac output (CO) was defined as the flow in the ascending aorta. Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg-1 · h-1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03). In healthy, awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. These data do not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

A double-blind, randomised, placebo-controlled parallel study to investigate the effect of sex and dietary nitrate on COVID-19 vaccine-induced vascular dysfunction in healthy men and women: protocol of the DiNOVasc-COVID-19 study

BackgroundCardiovascular events, driven by endothelial dysfunction, are a recognised complication of COVID-19. SARS-CoV-2 infections remain a persistent concern globally, and an understanding of the mechanisms causing endothelial dysfunction, particularly the role of inflammation, nitric oxide, and whether sex differences exist in this response, is lacking. We have previously demonstrated important sex differences in the inflammatory response and its impact on endothelial function and separately that the ingestion of inorganic nitrate can protect the endothelium against this dysfunction. In this study, we will investigate whether sex or a dietary inorganic nitrate intervention modulates endothelial function and inflammatory responses after the COVID-19 vaccine.MethodsDiNOVasc-COVID-19 is a double-blind, randomised, single-centre, placebo-controlled clinical trial. A total of 98 healthy volunteers (49 males and 49 females) will be recruited. Participants will be randomised into 1 of 2 sub-studies: part A or part B. Part A will investigate the effects of sex on vascular and inflammatory responses to the COVID-19 vaccine. Part B will investigate the effects of sex and dietary inorganic nitrate on vascular and inflammatory responses to the COVID-19 vaccine. In part B, participants will be randomised to receive 3 days of either nitrate-containing beetroot juice (intervention) or nitrate-deplete beetroot juice (placebo). The primary outcome for both sub-studies is a comparison of the change in flow-mediated dilatation (FMD) from baseline after COVID-19 vaccination. The study has a power of > 80% to assess the primary endpoint. Secondary endpoints include change from baseline in inflammatory and leukocyte counts and in pulse wave analysis (PWA) and pulse wave velocity (PWV) following the COVID-19 vaccination.DiscussionThis study aims to evaluate whether sex or dietary influences endothelial function and inflammatory responses in healthy volunteers after receiving the COVID-19 vaccine.Trial registrationClinicalTrials.gov NCT04889274. Registered on 5 May 2023. The study was approved by the South Central – Oxford C Research Ethics Committee (21/SC/0154).

Evaluation of single-strain Prevotella histicola on KLH-driven immune responses in healthy volunteers: A randomized controlled trial with EDP1815

IntroductionEDP1815 is a single-strain of Prevotella histicola with preclinical immunomodulatory properties. The aim of this study was to evaluate pharmacodynamic effects of EDP1815 on the immune response following immunization with keyhole limpet hemocyanin (KLH) and dermal rechallenge. MethodsThirty-two healthy subjects (median 30, range 18–59 years) were randomized over two cohorts to EDP1815 or placebo (12:4). Both cohorts received 8.0 × 1011 total cells daily for 28 days, reconstituted in 10 (A formulation) or 5 (B formulation) capsules. KLH-specific antibodies and circulating regulatory T cells were evaluated. Skin response after rechallenge was assessed with imaging. Immune cell subsets from blister exudates were assessed in the B cohort only. Ex vivo phytohemagglutinin and lipopolysaccharide whole blood challenges were performed to evaluate cytokine release. Gastrointestinal tract persistence, prevalence, and colonization of EDP1815 were assessed by fecal qPCR and microbiome assays. Data were analyzed using repeated measures analysis of covariances. ResultsThere was a trend toward a treatment effect on the KLH-induced skin rechallenge response (CIELab a* estimated difference (ED) −1.50 arbitrary unit (AU), 95% CI −3.47–0.47 AU, P = .13, and average redness ED −0.14 AU, 95% CI −0.31–0.03 AU, P = .10 in B cohort) and, to a lesser extent, on the humoral KLH response. No notable EDP1815 effects were observed on gut persistence, microbiome, and other safety parameters. ConclusionBased on our findings and the clinical benefit observed in the phase 2 study in psoriasis, further investigation of the immunomodulatory effects and potential clinical benefit of EDP1815 is warranted.

HBV001: Phase I study evaluating the safety and immunogenicity of the therapeutic vaccine ChAdOx1-HBV

Background & AimsMillions of people worldwide are infected chronically with HBV, which results in significant morbidity and mortality. Therapeutic vaccination is a strategy that aims to induce functional cure by restoring cellular immunity to HBV. Previously we have shown the candidate HBV immunotherapeutic vaccine ChAdOx1-HBV, encoding all major HBV antigens and a genetic adjuvant (shark invariant chain), is highly immunogenic in mice. MethodsHere we report the results of HBV001, a first-in-human, phase I, non-randomised, dose-escalation trial of ChAdOx1-HBV assessed in healthy volunteers and patients with chronic HBV (CHB). ResultsVaccination with a single dose of ChAdOx1-HBV was safe and well tolerated in both healthy and CHB cohorts. Vaccination induced high magnitude HBV-specific T cell responses against all major HBV antigens (core, polymerase, and surface) in healthy volunteers. Responses were detected but lower in patients with CHB. T cells generated by vaccination were cross-reactive between HBV C and D genotypes. ConclusionsChAdOx1-HBV is safe and immunogenic in healthy volunteers and patients with CHB. In further studies, ChAdOx1-HBV will be used in combination with other therapeutic strategies with an aim to overcome the attenuated immunogenicity in patients with CHB. Impact and implicationsTherapeutic vaccine ChAdOx1-HBV, a novel treatment for chronic hepatitis B infection (CHB), has been shown to be immunogenic in preclinical studies. In HBV001, a first-in-human phase I study, we show vaccination with ChAdOx1-HBV is safe and generates high magnitude T cell responses in healthy volunteers and lower levels of responses in patients with CHB. This is an important first step in the development of ChAdOx1-HBV as part of a wider therapeutic strategy to induce hepatitis B functional cure, and is of great interest to patients CHB and clinicians treating the condition. Clinical Trials RegistrationThis study is registered at ClinicalTrials.gov (NCT04297917).

A metabolomic analysis of sensitivity and specificity of 23 previously proposed biomarkers for renal transporter-mediated drug-drug interactions.

Endogenous biomarkers are discussed as tools for detection of drug-drug interactions mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2-K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intrastudy comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of ten previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with four inhibitors of transport proteins [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N-oxide were both sensitive and specific (median log2-fold changes -1.18 in estimated renal elimination and -0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2-fold changes -3.77 and -2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE- and OAT-mediated drug-drug interactions.

A KETOGENIC DIET REDUCES TISSUE SODIUM CONTENT: AN EXPLORATORY STUDY

Objective: Hypertension and diabetes are a substantial global public health problem. The prevalence of these diseases will further increase in the near future, leading to increased health and socioeconomic costs. Hence efficient therapeutic approaches are urgently needed. It has been previously shown that nutritional approaches including a very-low carbohydrate, or a ketogenic diet potentially decrease body weight, blood pressure and glucose levels in patients with type 2 diabetes along with an overall significant reduction in their pill burden. However, the detailed physiological mechanisms underlying the observed induction and maintenance of diabetes remission remain largely unknown. Previous studies have shown that the skin could be a buffer system for sodium and that skin sodium content could be both a pathogenic cause and a marker of hypertension and salt sensitivity. Since a nutritionally created metabolic milieu such as nutritional ketosis can lower blood pressure, we hypothesize that this dietary approach also reduces tissue sodium content. Design and method: By using 7-T 23Na MRI technique, we performed an exploratory study and analyzed skin and muscle sodium concentration before, and after a 6-week ketogenic diet in three healthy probands. Nutritional ketosis was verified by frequent check of blood ketone (beta-hydroxybutyrate; BOHB) levels greater than 0.3 mmol/L. Results: Preliminary data of our planned exploratory study (in patients with chronic kidney disease and type 2 diabetes mellitus and healthy probands) demonstrated that compared to baseline 6 weeks of ketogenic diet decreased tissue sodium content in the skin (16.6 ± 2.1 vs. 12.6 ± 2.1 mmol/L), in the medial gastrocnemius muscle (20.5 ± 0.9 vs. 16.7 ± 0.7 mmol/L), in the lateral gastrocnemius muscle (19.7 ± 1.0 vs. 16.0 ± 1.0 mmol/L) and in the soleus muscle (13.1 ± 0.8 vs. 11.5 ± 0.5 mmol/L). Conclusions: Our results indicate a massive reduction of tissue sodium concentration in healthy volunteers in response to a ketogenic diet which might be associated with the observed clinical benefits and be implicated in the anti-hypertensive effects of this powerful dietary intervention. Findings of this study could have an impact on future treatment strategies of various chronic diseases.

Novel capsaicin cough endpoints effectively discriminate between healthy controls and patients with refractory chronic cough

RationaleChronic cough is a common problem, substantially affecting quality of life. Effective treatments and diagnostic clinical tools for refractory chronic cough are lacking which remains a diagnosis of exclusion. ObjectivesTo investigate capsaicin evoked cough responses in healthy volunteers and refractory chronic cough patients and assess the discriminatory ability of novel endpoints. MethodsDose-response capsaicin cough challenges were performed, and receiver operating characteristic curves constructed to evaluate the discriminatory value of novel endpoints; Emax (maximum number of coughs evoked by any capsaicin concentration) and ED50 (capsaicin concentration evoking at least half of Emax). Measurements and main resultsNinety-three healthy volunteers (median age 39yrs(IQR; 29–52), 47 females) and 51 refractory chronic cough patients (59yrs(53–67), 31 females) were studied. Emax was significantly higher in the patient group compared to healthy volunteers (p < 0.001) and ED50 was significantly lower (p = 0.001). Both parameters were influenced by gender; females had a higher Emax (p = 0.009) and more sensitive ED50 (p < 0.001) but there were no correlations with other patient demographics. There was a significant relationship between Emax and cough frequency in the patient group (p < 0.001). Emax effectively discriminated between the groups (AUC = 0.83, 95% CI; 0.75–0.90, p < 0.001) independently of ED50 which was less favourable (AUC = 0.66, 95% CI; 0.57–0.76, p = 0.002). Emax and ED50 were shown to be repeatable, and the dose-response method well tolerated. ConclusionNovel capsaicin dose-response endpoints effectively discriminate between healthy controls and refractory chronic cough patients, which may better represent pathophysiological mechanisms and show promise for development as a tool to identify patients with cough hyper-excitability. Clinical trial registrationwww.isrctn.com; ISRCTN23684347.

Short-term transcutaneous trigeminal nerve stimulation does not affect visual oddball task and paired-click paradigm ERP responses in healthy volunteers

Recent research suggests that transcutaneous trigeminal nerve stimulation (TNS) may positively affect cognitive function. However, no clear-cut evidence is available yet, since the majority of it derives from clinical studies, and the few data on healthy subjects show inconsistent results. In this study, we report the effects of short-term TNS on event-related potentials (ERP) recorded during the administration of a simple visual oddball task and a paired-click paradigm, both considered useful for studying brain information processing functions. Thirty-two healthy subjects underwent EEG recording before and after 20min of sham- or real-TNS, delivered bilaterally to the infraorbital nerve. The amplitude and latency of P200 and P300 waves in the simple visual oddball task and P50, N100 and P200 waves in the paired-click paradigm were measured before and after treatment. Our results show that short-term TNS did not alter any of the ERP parameters measured, suggesting that in healthy subjects, short-term TNS may not affect brain processes involved in cognitive functions such as pre-attentional processes, early allocation of attention and immediate memory. The perspective of having an effective, non-pharmacological, non-invasive, and safe treatment option for cognitive decline is particularly appealing; therefore, more research on the positive effects on cognition of TNS is definitely needed.

037 Bermekimab, Anti-Interleukin-1α Antibody, Inhibits Skin Injury Induced Response in Healthy Volunteers

Interleukin-1 alpha (IL-1α) is constitutively expressed in epithelial cells located at barrier sites, such as skin, lung, and gut. Upon cellular death, injury or infection, IL-1α is released. Serum levels of IL-1α are largely undetectable in healthy volunteers (HV), or atopic dermatitis (AD) and hidradenitis suppurativa (HS) patients, while levels in the skin, especially in the epidermis and exudates from HS tunnels, are highly concentrated. Bermekimab (BMK) is a first-in-class fully human anti-IL-1α monoclonal antibody that has been tested in Phase-2A AD and HS studies.

Persistent but atypical germinal center reaction among 3rd SARS-CoV-2 vaccination after rituximab exposure.

BackgroundDurable vaccine-mediated immunity relies on the generation of long-lived plasma cells and memory B cells (MBCs), differentiating upon germinal center (GC) reactions. SARS-CoV-2 mRNA vaccination induces a strong GC response in healthy volunteers (HC), but limited data is available about response longevity upon rituximab treatment.MethodsWe evaluated humoral and cellular responses upon 3rd vaccination in seven patients with rheumatoid arthritis (RA) who initially mounted anti-spike SARS-CoV-2 IgG antibodies after primary 2x vaccination and got re-exposed to rituximab (RTX) 1-2 months after the second vaccination. Ten patients with RA on other therapies and ten HC represented the control groups. As control for known long-lived induced immunity, we analyzed humoral and cellular tetanus toxoid (TT) immune responses in steady-state.ResultsAfter 3rd vaccination, 5/7 seroconverted RTX patients revealed lower anti-SARS-CoV-2 IgG levels but similar neutralizing capacity compared with HC. Antibody levels after 3rd vaccination correlated with values after 2nd vaccination. Despite significant reduction of circulating total and antigen-specific B cells in RTX re-exposed patients, we observed the induction of IgG+ MBCs upon 3rd vaccination. Notably, only RTX treated patients revealed a high amount of IgA+ MBCs before and IgA+ plasmablasts after 3rd vaccination. IgA+ B cells were not part of the steady state TT+ B cell pool. TNF-secretion and generation of effector memory CD4 spike-specific T cells were significantly boosted upon 3rd vaccination.SummaryOn the basis of pre-existing affinity matured MBCs within primary immunisation, RTX re-exposed patients revealed a persistent but atypical GC immune response accompanied by boosted spike-specific memory CD4 T cells upon SARS-CoV-2 recall vaccination.

Effects of the PARP Inhibitor Olaparib on the Response of Human Peripheral Blood Leukocytes to Bacterial Challenge or Oxidative Stress.

Prior studies demonstrate the activation of poly-(ADP-ribose) polymerase 1 (PARP1) in various pathophysiological conditions, including sepsis. We have assessed the effect of olaparib, a clinically used PARP1 inhibitor, on the responses of human peripheral blood leukocytes (PBMCs) obtained from healthy volunteers in response to challenging with live bacteria, bacterial lipopolysaccharide (LPS), or oxidative stress (hydrogen peroxide, H2O2). The viability of PBMCs exposed to olaparib or to the earlier generation PARP inhibitor PJ-34 (0.1–1000 µM) was monitored using Annexin V and 7-aminoactinomycin D. To evaluate the effects of olaparib on the expression of PARP1 and its effects on protein PARylation, PBMCs were stimulated with Staphylococcus aureus with or without olaparib (1–10 μM). Changes in cellular levels of nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP), as well as changes in mitochondrial membrane potential (MMP), were measured in PBMCs exposed to H2O2. Bacterial killing was evaluated in PBMCs and polymorphonuclear leukocytes (PMNs) incubated with S. aureus. Cytokine production was measured in supernatants using a cytometric bead array. Reactive oxygen species (ROS), nitric oxide (NO) production, and phagocytic activity of monocytes and neutrophils were measured in whole blood. For ROS and NO production, samples were incubated with heat-killed S. aureus; phagocytic activity was assessed using killed Escherichia coli conjugated to FITC. Olaparib (0.1–100 µM) did not adversely affect lymphocyte viability. Olaparib also did not interfere with PARP1 expression but inhibits S. aureus-induced protein PARylation. In cells challenged with H2O2, olaparib prevented NAD+ and ATP depletion and attenuated mitochondrial membrane depolarization. LPS-induced production of TNF-α, MIP-1α, and IL-10 by PBMCs was also reduced by olaparib. Monocytes and neutrophils displayed significant increases in the production of ROS and NO after stimulation with S. aureus and phagocytic (E. coli) and microbicidal activity, and these responses were not suppressed by olaparib. We conclude that, at clinically relevant concentrations, olaparib exerts cytoprotective effects and modulates inflammatory cytokine production without exerting adverse effects on the cells’ ability to phagocytose or eradicate pathogens. The current data support the concept of repurposing olaparib as a potential experimental therapy for septic shock.

Participation of MAPK and PI3K in Regulation of Cytokine Secretion by Peripheral Blood Monocular Cells in Response to Escherichia coli LPS and rDer p 2 Combination.

Search for the effective approaches to treat acute inflammation caused by combination of allergens and infectious agents is an important task for public health worldwide. House dust mites Dermatophagoides pteronyssinus are the source of allergens of the Der p groups and of microbial compounds, in particular, lipopolysaccharides (LPS). LPS and Der p 2 induce secretion of pro-inflammatory cytokines via activation of kinases p38 MAPK, MEK1/2, and PI3K. Participation of these kinases in the regulation of cells response to combined exposure to LPS and Der p 2 has not been sufficiently studied. We studied the effects of kinases (p38 MAPK, MEK1/2, and PI3K) inhibition on secretion of cytokines (TNF, IL-8, and IL-6) by peripheral blood mononuclear cells (PBMC) of healthy volunteers in response to E. coli LPS and rDer p 2. Contribution of kinases to the regulation of cell response to different agents (rDer p 2 and/or LPS) was revealed. It was found that p38 MAPK plays a key role in the regulation of secretion TNF by PBMC in response to the combination of LPS and rDer p 2. MEK1/2-dependent signaling is the main pathway for the synthesis of TNF and IL-8 in response to LPS and rDer p 2. PI3K-dependent signaling negatively regulates TNF production during rDer p 2-induced cell activation, but is not involved in the response to the combination of LPS and rDer p 2. PI3K-dependent signaling in the regulation of PBMC cytokine synthesis is most pronounced in response to their activation by rDer p 2. Understanding the mechanisms of immune cell responses to combinations of inflammatory agents could facilitate the search for new intracellular targets for anti-inflammatory therapy.

Acute Effects of Split Pea-Enriched White Pan Bread on Postprandial Glycemic and Satiety Responses in Healthy Volunteers-A Randomized Crossover Trial.

Pulse consumption has been associated with reduced postprandial glucose response (PPGR) and improved satiety. The objective of this study was (i) to investigate the effects of fortifying white pan bread with split yellow pea (Pisum sativum L.) flour on PPGR and appetite-related sensations, and (ii) to determine whether Revtech heat processing of pea flour alters the postprandial effects. A randomized controlled crossover trial was performed with 24 healthy adults. Participants consumed 50 g available carbohydrate from bread containing 20% pea flour that was untreated (USYP), Revtech processed at 140 °C with no steam (RT0%), Revtech processed at 140 °C with 10% steam (RT10%), or a control bread with 100% white wheat flour (100%W). Blood samples were analyzed for glucose and plasma insulin at 0, 15, 30, 45, 60, 90, and 120 min post-meal. Appetite sensations and product acceptability were measured using visual analogue and 9-point hedonic scales. Results showed no significant difference in the postprandial glucose and insulin responses of different bread treatments. However, pea-containing variants resulted in 18% higher fullness and 16–18% lower hunger, desire to eat, and prospective food consumption ratings compared to 100% W. No differences in the aroma, flavor, color, and overall acceptability of different bread products were observed. This trial supports using pea flour as a value-added ingredient to improve the short-term appetite-related sensations of white pan bread without affecting the overall acceptability.

OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005.

The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti‐OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty‐four healthy male subjects (26.5 ± 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure‐response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (Tmax) ~ 4 hours, geometric mean terminal half‐life (t½) ~ 24 days). Cutaneous blood perfusion (estimated difference (ED) −13.4 arbitrary unit (AU), 95% confidence interval (CI) −23.0 AU to −3.8 AU) and erythema quantified as average redness (ED −0.23 AU, 95% CI −0.35 AU to −0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure‐response analysis displayed a statistically significant treatment effect on anti‐KLH antibody titers (IgG maximum effect (Emax) −0.58 AU, 95% CI −1.10 AU to −0.06 AU) and skin response (erythema Emax −0.20 AU, 95% CI −0.29 AU to −0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune‐mediated disorders.

Influence of tedizolid on the cytokine response to the endotoxin challenge in healthy volunteers: a cross-over trial.

Preclinical data suggested anti-inflammatory properties of tedizolid. To investigate the influence of tedizolid on the cytokine response to the human endotoxin challenge and the effect of endotoxaemia on the pharmacokinetics and protein binding of tedizolid. In this cross-over trial, 14 male healthy volunteers underwent two treatment periods: (A) 200 mg of tedizolid phosphate once daily for 6 days (3 days orally and 3 days intravenously), followed by an intravenous bolus of 2 ng/kg body weight of LPS on the last treatment day; and (B) intravenous bolus of LPS (2 ng/kg body weight) without concomitant tedizolid treatment. Participants underwent first period A or B, separated by at least 6 weeks. Plasma was sampled to assess cytokines and the pharmacokinetics of tedizolid. Following the endotoxin challenge, the peak plasma concentration (median [IQR]; 280 [155-502] versus 287 [132-541] pg/mL; P = 0.875) and AUC0-24 (979 [676-1319] versus 1000 [647-1632] pg·h/mL; P = 0.638) of interleukin-6 remained unchanged with and without concomitant tedizolid treatment. The peak concentration and AUC0-24 of TNF-α remained also unchanged with and without tedizolid (47 [31-61] versus 54 [27-69] pg/mL; P = 0.73 and 197 [163-268] versus 234 [146-280] pg·h/mL; P = 0.875, respectively). The total maximum concentration (mean ± SD; 2.94 ± 0.69 versus 2.96 ± 0.62 mg/L), total AUC0-24 (22.3 ± 3.8 versus 21.1 ± 3.6 mg·h/L) and protein binding (21.4% ± 1.7% versus 21.6% ± 1.9%) of tedizolid were similar with and without the endotoxin challenge. Tedizolid did not attenuate the LPS-induced cytokine response in healthy volunteers. Furthermore, endotoxaemia did not influence the plasma pharmacokinetics of tedizolid.

The Effect of Hyperbaric Oxygen Therapy on Markers of Oxidative Stress and the Immune Response in Healthy Volunteers.

Hyperbaric oxygen therapy (HBOT) consists of breathing 100% oxygen under increased ambient pressure. There are indications that HBOT induces oxidative stress and activates immune pathways. However, previous research on immunological effects of HBOT has mainly been established in in vitro experiments and selected patient populations, limiting generalizability and increasing the chances of confounding by comorbidities and specific patient-related factors. More insight into the immunological effects of HBOT would aid investigation and comprehension of potentially novel treatment applications. Therefore, in this study, we investigated the effects of three 110-min HBOT-sessions with 24-h intervals on immunological parameters in healthy, young, male volunteers. Blood samples were obtained before and after the first and third HBOT sessions. We assessed neutrophilic reactive oxygen species (ROS) production, systemic oxidative stress [plasma malondialdehyde (MDA) concentrations] as well as neutrophil phagocytic activity, plasma concentrations of tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, and IL-10, and production of TNF, IL-6, and IL-10 by leukocytes ex vivo stimulated with the Toll-like receptor (TLR) ligands lipopolysaccharide (TLR4) and Pam3Cys (TLR2). We observed decreased neutrophilic ROS production and phagocytosis following the second HBOT session, which persisted after the third session, but no alterations in MDA concentrations. Furthermore, plasma concentrations of the investigated cytokines were unaltered at all-time points, and ex vivo cytokine production was largely unaltered over time as well. These results indicate no induction of systemic oxidative stress or a systemic inflammatory response after repeated HBOT in healthy volunteers but may suggest exhaustion of ROS generation capacity and phagocytosis.

Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers.

AimsWhereas intravenous administration of Toll‐like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies.MethodsEighteen healthy male volunteers received 2 or 4 intradermal 5 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate.ResultsLPS elicited a visible response and returned to baseline at 48 hours. Erythema, perfusion and temperature were statistically significant (P < .0001) over a 24‐hour time course compared to saline. The protein response was dominated by an acute interleukin (IL)‐6, IL‐8 and tumour necrosis factor response followed by IL‐1β, IL‐10 and interferon‐γ. The cellular response consisted of an acute neutrophil influx followed by different monocyte subsets and dendritic cells.DiscussionIntradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well‐tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti‐inflammatory investigational compounds in proof of pharmacology studies.

Effects of Recombinant Human Angiotensin-Converting Enzyme 2 on Response to Acute Hypoxia and Exercise: A Randomised, Placebo-Controlled Study

IntroductionAngiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). Enhancing ACE2 activity using GSK2586881, a recombinant form of human ACE2, could be beneficial in diseases such as ARDS but may blunt the hypoxic pulmonary vasoconstriction (HPV) response and potentially impact systemic and tissue oxygenation. This study aimed to evaluate the effect of GSK2586881 0.8 mg/kg on HPV response in healthy adult volunteers during exercise under hypoxic conditions.MethodsIn this phase I, randomised, double-blind (sponsor open) study, GSK2586881 or placebo was administered as a single intravenous (IV) dose in a two-period crossover design. Treatment periods were separated by a washout period of 3–14 days. The primary endpoint was change from baseline in pulmonary artery systolic pressure (PASP) measured by echocardiography. Secondary endpoints included RAS peptides and oxygen saturation.ResultsSeventeen adults aged 18–40 years were randomised to treatment. There were no clinically relevant differences (defined as a reduction of ≥ 5 mmHg) in change from baseline in PASP between GSK2586881 and placebo. GSK2586881 was well tolerated, with no serious adverse events, no worsening of hypoxaemia and no evidence of immunogenicity. The study was terminated early after review of the data, which showed that the predefined success criteria had not been met. Following GSK2586881 administration, levels of the RAS peptide angiotensin II decreased while angiotensin (1-7) increased, as expected, indicating that GSK2586881 was pharmacologically active.ConclusionsA single IV dose of GSK2586881 0.8 mg/kg was well tolerated but did not impact the acute HPV response in healthy volunteers.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41030-021-00164-7.

Morphine Induces a Neuroimmune Response in Healthy Volunteers: Implications for Opioid Use Disorder

Preclinical studies indicate opioid administration evokes pro-inflammatory responses in both the periphery and brain. Opioid-induced pro-inflammatory responses influence both appetitive and dysphoric addiction processes and thus, may influence the development of opioid use disorder (OUD) and/or perpetuate continued opioid use among OUD patients. Herein, we investigated the neuroimmune effects of morphine administration using Positron Emission Tomography (PET) imaging with [11C]PBR28, a radiotracer that binds to the 18kDa translocator protein (TSPO), a marker sensitive to immune stimuli.