Infusion In Healthy Volunteers Research Articles

Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial

The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin’s broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants’ task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = −2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values ≥ 4.21, p-values ≤ 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.

Phase I Pharmacokinetics Study of Drug for Infusion «Areplivir» (INN: Favipiravir) (LLC "PROMOMED RUS", Russia)

Introduction. The novel coronavirus infection COVID-19 (Coronavirus Disease 2019) is caused by an enveloped, positive-sense, single-stranded ribonucleic acid (RNA) virus SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2). Favipiravir is the antiviral drug recommended for etiotropic treatment of COVID-19. Parenteral therapy has advantages over the other routes of the drug administration: there are no interaction with food and digestive enzymes, may be used for patients with diseases of the digestive system and unconscious patients. For parenteral drug administration of favipiravir the drug "Areplivir" has been registered in Russia.Aim. The aim is pharmacokinetics study of drug "Areplivir", a lyophilisate for the preparation of a concentrate for the infusion solution (the manufacturer is JSC "Biokhimic", LLC "Promomed RUS" as registration certificate holder) by intravenous infusion in healthy volunteers in a phase I pharmacokinetics study.Materials and methods. The clinical and analytical phases of the pharmacokinetic study as well as pharmacokinetic analyses have been performed as part of a clinical trial of the drug "Areplivir" in different doses, a lyophilisate for the preparation of a concentrate for the infusion solution (LLC "Promomed RUS", Russia). Chromatographic separation and detection were carried out on a LC-2040C high-performance liquid chromatograph (Shimadzu Corporation, Japan) with a built-in UV detector, a low-pressure four-component gradient pump, a degasser, an autosampler, a column thermostat and a controller. The pharmacokinetic parameters were calculated with the Boomer pharmacokinetic analysis add-in for Microsoft Excel (Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA 92606, USA). Descriptive pharmacokinetic statistics were calculated with Microsoft Excel (Microsoft Corporation, USA). Correlation and Regression Analysis were conducted with IBM SPSS Statistics (version 23.0), IBM, USA.Results and discussion. For single dose administration of 400, 800, 1600 and 1800 mg in 4 cohorts of 5 volunteers pharmacokinetic parameters were calculated. For Cmax and an administered dose the strong correlation coefficient on the Chaddock scale (r = 0,98; p = 0,02; r – Pearson correlation coefficient; p – the reached significance value) and the determination coefficient (R2 = 0,96; F = 45,97; p = 0,02; R2 – determination coefficient; F – the actual value of the Fisher's criterion) were statistically significant. For AUC0-t and an administered dose the strong correlation coefficient on the Chaddock scale (r = 0,97; p = 0,03) and the determination coefficient (R2 = 0,94; F = 33,54; p = 0,03) were statistically significant. The obtained results show the linearity of Cmax and an administered dose and the linearity of AUC0-t and an administered dose (400–1800 mg).Conclusion. According to the concentrations of favipiravir from the analytical phase of the pharmacokinetic study the pharmacokinetic parameters were calculated, averaged pharmacokinetic profiles in linear and log-linear scales were plotted after single dose administrations of the drug "Areplivir" in different doses, a lyophilisate for the preparation of a concentrate for the infusion solution (LLC "Promomed RUS", Russia). The linearity of Cmax and a single administered dose and the linearity of AUC0-t and a single administered dose of the drug "Areplivir" have been demonstrated for doses of 400 to 1800 mg. The results justified the study of multiple dose administration of "AREPLIVIR" and the subsequent phases of clinical trials.

A Phase 1 randomized study on the safety and pharmacokinetics of OCS-05, a neuroprotective disease modifying treatment for Acute Optic Neuritis and Multiple Sclerosis

OCS-05 (aka BN201) is a peptidomimetic that binds to serum glucocorticoid kinase-2 (SGK2), displaying neuroprotective activity. The objective of this randomized, double-blind 2-part study was to test safety and pharmacokinetics of OCS-05 administered by intravenous (i.v.) infusion in healthy volunteers. Subjects (n = 48) were assigned to receive placebo (n = 12) or OCS-05 (n = 36). , Doses tested were 0.05, 0.2, 0.4, 0.8, 1.6, 2.4 and 3.2 mg/kg in the single ascending dose (SAD) part. In the multiple ascending dose (MAD) part, 2.4 and 3.0 mg/kg doses were administered with 2 h i.v. infusion for 5 consecutive days. Safety assessments included adverse events, blood tests, ECG, Holter monitoring, brain MRI and EEG. No serious adverse events were reported in the OCS-05 group (there was one serious adverse event in the placebo group). Adverse events reported in the MAD part were not clinically significant, and no changes on the ECG, EEG or brain MRI were observed. Single-dose (0.05–3.2 mg/kg) exposure (Cmax and AUC) increased in a dose-proportional manner. Steady state was reached by Day 4 and no accumulation was observed. Elimination half-life ranged from 3.35 to 8.23 h (SAD) and 8.63 to 12.2 h (MAD). Mean individual Cmax concentrations in the MAD part were well below the safety thresholds. OCS-05 administered as 2-h i.v. infusions of multiple doses up to 3.0 mg/Kg daily for up to 5 consecutive days was safe and well tolerated. Based on this safety profile, OCS-05 is currently being tested in a phase 2 trial in patient with acute optic neuritis (NCT04762017, date registration 21/02/2021).

Genetic and Physiological Effects of Insulin-Like Growth Factor-1 (IGF-1) on Human Urate Homeostasis.

Hyperinsulinemia induces hyperuricemia by activating net renal urate reabsorption in the renal proximal tubule. The basolateral reabsorptive urate transporter GLUT9a appears to be the dominant target for insulin. By contrast, IGF-1 infusion reduces serum urate (SU), through mechanisms unknown. Genetic variants of IGF1R associated with reduced SU have increased IGF-1R expression and interact with genes encoding the GLUT9 and ABCG2 urate transporters, in a sex-specific fashion, which controls the SU level. Activation of IGF-1/IGF-1R signaling in Xenopus oocytes modestly activates GLUT9a and inhibits insulin's stimulatory effect on the transporter, which also activates multiple secretory urate transporters-ABCG2, ABCC4, OAT1, and OAT3. The results collectively suggest that IGF-1 reduces SU by activating secretory urate transporters and inhibiting insulin's action on GLUT9a. Metabolic syndrome and hyperinsulinemia are associated with hyperuricemia. Insulin infusion in healthy volunteers elevates serum urate (SU) by activating net urate reabsorption in the renal proximal tubule, whereas IGF-1 infusion reduces SU by mechanisms unknown. Variation within the IGF1R gene also affects SU levels. Colocalization analyses of a SU genome-wide association studies signal at IGF1R and expression quantitative trait loci signals in cis using COLOC2, RT-PCR, Western blotting, and urate transport assays in transfected HEK 293T cells and in Xenopus laevis oocytes. Genetic association at IGF1R with SU is stronger in women and is mediated by control of IGF1R expression. Inheritance of the urate-lowering homozygous genotype at the SLC2A9 locus is associated with a differential effect of IGF1R genotype between men and women. IGF-1, through IGF-1R, stimulated urate uptake in human renal proximal tubule epithelial cells and transfected HEK 293T cells, through activation of IRS1, PI3/Akt, MEK/ERK, and p38 MAPK; urate uptake was inhibited in the presence of uricosuric drugs, specific inhibitors of protein tyrosine kinase, PI3 kinase (PI3K), ERK, and p38 MAPK. In X. laevis oocytes expressing ten individual urate transporters, IGF-1 through endogenous IGF-1R stimulated urate transport mediated by GLUT9, OAT1, OAT3, ABCG2, and ABCC4 and inhibited insulin's stimulatory action on GLUT9a and OAT3. IGF-1 significantly activated Akt and ERK. Specific inhibitors of PI3K, ERK, and PKC significantly affected IGF-1 stimulation of urate transport in oocytes. The combined results of infusion, genetics, and transport experiments suggest that IGF-1 reduces SU by activating urate secretory transporters and inhibiting insulin's action.

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

136 (PB126) - ALRN 6924 induces cell cycle arrest in bone marrow stem cells and hair follicles with dose-dependent degree and duration of effects after a single infusion in healthy volunteers

Background: ALRN-6924 is a cell-permeating, stabilized alpha-helical peptide that binds to endogenous p53 inhibitors MDMX and MDM2, thereby activating p53 and its transcriptional target p21 to cause cell cycle arrest (CCA). This effect is limited to cells with wild-type, functional p53. For cancer patients with tumors bearing mutated p53, ALRN-6924 treatment selectively induces CCA in normal cells, allowing chemotherapy to preferentially target p53-mutant cancer cells that are actively cycling. Materials and methods: A Phase 1 study in heathy volunteers is being conducted to evaluate ALRN-6924 pharmacokinetics (PK) and pharmacodynamics (PD). In Part 1 (37 subjects; Voors-Pette et al, ESMO 2021) it was shown that a 1-hour intravenous (IV) ALRN-6924 infusion was safe, well tolerated, and transiently upregulates p21 in human bone marrow (BM) cells with minimal signal for apoptosis. In Part 2, we aim to directly measure dose-dependent CCA in the BM as well as in hair follicles (HFs) in female subjects across a range of doses by 1-hour IV infusion and 3-minute bolus IV injection. ALRN-6924 was administered as a single IV infusion or bolus injection at 0 (placebo), 0.3, 0.6, or 0.9 mg/kg to cohorts of 3 to 5 subjects. Subjects were evaluated for safety and tolerability. Plasma and serum samples were obtained to determine PK and levels of macrophage inhibitory cytokine-1 (MIC-1), a biomarker of p53 activation. BM was sampled 12 hours post-dose to directly measure CCA by flow cytometry in CD34+, lineage-negative BM stem cells. Occipital scalp skin was sampled by 2 mm punch biopsy for p21 immunohistochemistry in HFs. Results: As of June 20, 2022, 42 subjects (ages 18–59; 100% female) were enrolled and evaluated in Part 2. Subjects experienced only mild, transient adverse events (AEs), with nausea/vomiting as the most frequent related AEs. The degree and duration of serum MIC-1 elevation was dose-dependent. At 12 hours post-dose, the proportion of cycling BM stem cells was significantly reduced at all dose levels, while blinded pathology review suggested ALRN-6924-dependent p21 induction in anagen-phase HFs. Safety profiles, PK and PD were similar for both bolus and infusion. Conclusions: ALRN-6924 shows a favorable safety profile for use as a chemoprotection agent. CCA measured in BM supports prevention of chemotherapy-induced neutropenia, thrombocytopenia, and anemia, while HF results support chemoprotection for alopecia. Administration by IV bolus may simplify dosing vs. the current 1-hr infusion clinical regimen. The dose-dependent degree and duration of effects support development of a universal treatment schedule for broad use across cancer indications and types of chemotherapy. Conflict of interest: Ownership: Manuel Aivado, Vojislav Vukovic, and Allen Annis are employees and shareholders of Aileron Therapeutics Advisory Board: Ulrich Steidl is a member of the Scientific Advisory Board of Aileron Therapeutics Other Substantive Relationships: Britta Will and Kevin Randall are consultants to Aileron Therapeutics

The Engineered Antibiotic Peptide PLG0206 Eliminates Biofilms and Is a Potential Treatment for Periprosthetic Joint Infections.

Antimicrobial peptides (AMPs) have recently gained attention for their potential to treat diseases related to bacterial and viral infections, as many traditional antimicrobial drugs have reduced efficacy in treating these infections due to the increased prevalence of drug-resistant pathogens. PLG0206, an engineered cationic antibiotic peptide that is 24 residues long, has been designed to address some limitations of other natural AMPs, such as toxicity and limited activity due to pH and ion concentrations. Nonclinical studies have shown that PLG0206 is highly selective for targeting bacterial cells and is not toxic to human blood cells. Antibiofilm experiments demonstrated that PLG0206 is effective at reducing both biotic and abiotic biofilm burdens following direct biofilm contact. PLG0206 has rapid and broad-spectrum activity against both Gram-positive and Gram-negative bacteria that are implicated as etiologic agents in periprosthetic joint infections, including multidrug-resistant ESKAPE pathogens and colistin-resistant isolates. A recent first-in-human study demonstrated that PLG0206 is well tolerated and safe as an intravenous infusion in healthy volunteers. Studies are planned to determine the efficacy of PLG0206 in patients for the treatment of periprosthetic joint infections. This review summarizes the chemistry, pharmacology, and microbiology of PLG0206 and explores its current preclinical, clinical, and regulatory status.

Foslevodopa/foscarbidopa subcutaneous infusion maintains equivalent levodopa exposure to Levodopa-Carbidopa Intestinal Gel delivered to the jejunum

Levodopa-Carbidopa Intestinal Gel (LCIG) 16-h infusion offers superior symptomatic control than oral levodopa/carbidopa in patients with advanced Parkinson's disease (aPD); however, it requires percutaneous endoscopic gastrostomy tube placement. Foslevodopa/foscarbidopa is an investigational drug being developed for treatment of aPD providing 24-h therapeutic levels of levodopa following subcutaneous (SC) delivery. We characterize levodopa pharmacokinetics (PK) following foslevodopa/foscarbidopa SC infusion and LCIG jejunal infusion in healthy volunteers.

Pharmacokinetic Properties of S-oxiracetam After Single and Multiple Intravenous Infusions in Healthy Volunteers.

As a chiral drug, oxiracetam (ORT) can exist in two different isomeric forms: S-oxiracetam (S-ORT) and R-oxiracetam (R-ORT). S-ORT has emerged as a promising nootropic drug with the potential to treat brain injury and the resulting loss of neural function, memory and mental impairment as assessed by studies in various animal models. However, limited data are available on the pharmacokinetics of S-ORT in humans, so the present study was designed to evaluate the safety and pharmacokinetic profile of S-ORT in healthy volunteers. In part 1, subjects were intravenously administered single ascending dose (2.0, 4.0 and 8.0 g) S-ORT. In part 2, subjects were treated at a single intravenous infusion dose of 3.0 g S-ORT or 6.0 g racemic ORT using a two-sequence, two-period crossover design. In part 3, subjects were intravenously injected with 4.0 g S-ORT once a day for 7 days. Blood and urine samples were collected to evaluate the pharmacokinetic parameters and urine excretion rate. The safety profile of the drug was also evaluated throughout the study. Fifty-two subjects (30 in part 1, 12 in part 2, 10 in part 3) completed the study; only one subject displayed a mild adverse event, which possibly was treatment related, and no serious adverse event occurred. In part 1 for a single dose of 2.0, 4.0 and 8.0 g, the maximum concentration (Cmax) values were 111.28±18.99, 230.76±29.16 and 352.67±42.94 μg/ml, respectively; the values of area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable concentration (AUC0-t) were 267.09±59.66, 524.50 ±72.87 and 822.68±95.21 μg·h/ml, respectively; the AUC from 0 h to infinity (AUC0-∞) values were 274.72±61.65, 536.06±78.13 and 832.07±96.91 μg·h/ml, respectively. The urine excretion rate of the unchanged drug was approximately 60%. After consecutive administration of S-ORT for 7 days, the accumulation index was 1.05±0.08. The plasma drug concentration-time curves for both S-ORT and R-oxiracetam (R-ORT) were almost identical. S-ORT was well tolerated, and no serious adverse events occurred in 2.0, 4.0 and 8.0 g in single- and 4.0 g in multiple-dose studies. S-ORT showed dose linearity with increasing doses and no drug accumulation after 7 days of continuous administration was observed.

The aptamer BT200 effectively inhibits von Willebrand factor (VWF) dependent platelet function after stimulated VWF release by desmopressin or endotoxin

Von Willebrand factor (VWF) plays a major role in arterial thrombosis. Antiplatelet drugs induce only a moderate relative risk reduction after atherothrombosis, and their inhibitory effects are compromised under high shear rates when VWF levels are increased. Therefore, we investigated the ex vivo effects of a third-generation anti-VWF aptamer (BT200) before/after stimulated VWF release. We studied the concentration-effect curves BT200 had on VWF activity, platelet plug formation under high shear rates (PFA), and ristocetin-induced platelet aggregation (Multiplate) before and after desmopressin or endotoxin infusions in healthy volunteers. VWF levels increased > 2.5-fold after desmopressin or endotoxin infusion (p < 0.001) and both agents elevated circulating VWF activity. At baseline, 0.51 µg/ml BT200 reduced VWF activity to 20% of normal, but 2.5-fold higher BT200 levels were required after desmopressin administration (p < 0.001). Similarly, twofold higher BT200 concentrations were needed after endotoxin infusion compared to baseline (p < 0.011). BT200 levels of 0.49 µg/ml prolonged collagen-ADP closure times to > 300 s at baseline, whereas 1.35 µg/ml BT200 were needed 2 h after desmopressin infusion. Similarly, twofold higher BT200 concentrations were necessary to inhibit ristocetin induced aggregation after desmopressin infusion compared to baseline (p < 0.001). Both stimuli elevated plasma VWF levels in a manner representative of thrombotic or pro-inflammatory conditions such as arterial thrombosis. Even under these conditions, BT200 potently inhibited VWF activity and VWF-dependent platelet function, but higher BT200 concentrations were required for comparable effects relative to the unstimulated state.

Dose-dependent immunomodulatory effect of intravenous allogeneic umbilical cord-derived mesenchymal stromal cells (Cytopeutics CLV-100) infusion in healthy volunteers

Background & Aim Background Mesenchymal stromal cells (MSCs) express growth factors and other cytokines that stimulate repair and control the immune response. MSCs are also immunoprivileged with low risk of rejection. Umbilical cord derived MSC (UCMSCs) are particularly attractive as off-the-shelf allogeneic treatment in emergency medical conditions. Objective We aim to determine the safety and feasibility of intravenous allogeneic infusion of UCMSCs (CLV-100) by Cytopeutics® (Selangor, Malaysia) in healthy volunteers, and to determine the effective dose at which an immunomodulatory effect is observed. Methods, Results & Conclusion Methodology Umbilical cord samples were collected after delivery of full-term, healthy babies with written consent from both parents. All 3 generations (newborn, parents and grandparents) were screened for genetic mutations, infections, cancers and other inherited diseases. Samples were transferred to a certified Good Manufacturing Practice laboratory for processing. Subjects were infused with either low dose (LD, 65 million cells) or high dose (HD, 130 million cells) of CLV-100 followed up for 6 months. We measured cytokines level using ELISA including the acute phase reactant high-sensitivity C-reactive protein (hs-CRP), anti-inflammatory cytokines interleukin 1 receptor antigen (IL-1RA) and interleukin 10 (IL-10), and the pro-inflammatory cytokine Tumor Necrosis Factor-Alpha (TNF-α). The study was approved by the National Medical Research and Ethics Committee (MREC). Results 11 healthy subjects (LD, n=5; HD, n=6; mean age of 55±13 years) were recruited. All subjects tolerated the CLV-100 infusion well with no adverse reaction throughout the study. While there was no change in vital parameters and routine blood tests, there was a transient rise in hs-CRP at Day 3 post infusion (1.2±1.5 vs. 4.5±3.9 mg/L; p=0.03) which resolved at Day 7. The anti-inflammatory IL-1RA was significantly elevated in HD patients at 1 month post infusion (436±128 vs. 615±148 pg/mL; p=0.028). At 6 months, HD group had significantly higher levels of anti-inflammatory markers IL1-RA (705±160 vs. 306±36 pg/mL; p=0.02) and IL-10 (321±27 vs. 251±28 pg/mL; p=0.02); and lower levels of pro-inflammatory marker TNF-α (74±23 vs. 115±15 pg/mL; p=0.038) compared to LD group. Conclusion Allogeneic UCMSCs CLV-100 infusion is safe and well-tolerated in low and high doses. Anti-inflammatory effect is observed with high dose infusion.

Hemodynamic Effects of Intravenous, High-Dose Lipid Emulsion With and Without Metoprolol Infusion in Healthy Volunteers: A Randomized Clinical Trial.

In a double-blinded, randomized, crossover trial, we investigated the hemodynamic effects of high-dose intravenous lipid emulsion (ILE) with/without metoprolol. Ten healthy volunteers each completed 4 trial days (placebo+ILE; metoprolol+placebo; metoprolol+ILE; placebo+placebo) in random order. Metoprolol was administered as an initial bolus (10mg), followed by an infusion (50mg) from 5 to 30minutes. ILE was administered as a bolus at 12.5minutes (2.5mL/kg), followed by a 15-minute infusion (0.25mL/kg per minute). On metoprolol+ILE days (compared with metoprolol+placebo) after 120 minutes, mean heart rates were significantly higher (difference, 5.5 beats per minute (bpm); 95% confidence interval (CI), 3.0-8.1 bpm; P<0.001), and average relative cardiac output was higher (difference, 10 percentage points; 95% CI, 5-15 percentage points; P<0.001). The hemodynamic effect of ILE developed gradually. ILE had no effect on plasma metoprolol or major adverse events. In conclusion, high-dose ILE has relatively marginal and delayed hemodynamic effects that may have limited clinical relevance in the short-term clinical toxicological setting.

Pharmacokinetics and pharmacodynamics of dexmedetomidine-induced vasoconstriction in healthy volunteers.

Alpha-2 agonists are direct peripheral vasoconstrictors, which achieve these effects by activating vascular smooth muscle alpha-2 adrenoceptors. The impact of this response during dexmedetomidine infusion remains poorly quantified. Our goal was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD, vasoconstriction) effects of a computer-controlled dexmedetomidine infusion in healthy volunteers. After local ethics committee approval, we studied 10 healthy volunteers. To study the peripheral vasoconstrictive effect of dexmedetomidine without concurrent sympatholytic effects, sympathetic fibres were blocked with a brachial plexus block. Volunteers received a dexmedetomidine target-controlled infusion for 15min, to a target concentration of 0.3ng ml-1 . Arterial blood samples were collected during and for 60min after dexmedetomidine infusion for PK analysis. Peripheral vasoconstriction (PD) was assessed using finger photoelectric plethysmography. PK/PD analysis was carried out using nonlinear mixed-effect models. We found that the computer-controlled infusion pump delivered mean concentrations greater than 0.3ng ml-1 over the 15-min infusion duration. The peripheral vasoconstrictive effect correlated with dexmedetomidine plasma concentrations during and after the infusion. A three-compartment model provided a better fit to the data than a two-compartment model. We found that dexmedetomidine-induced vasoconstriction is concentration dependent over time. Dexmedetomidine PK were best estimated by a three-compartment model with allometric scaling. Our results may contribute to future modelling of dexmedetomidine-induced haemodynamic effects.

Volatile organic compounds in exhaled breath are independent of systemic inflammatory syndrome caused by intravenous lipopolysaccharide infusion in humans: results from an experiment in healthy volunteers

Systemic inflammatory response syndrome (SIRS) is observed during critical illness in most patients. It is defined by a clinical definition. The composition of volatile organic compounds (VOCs) in exhaled breath may change during SIRS and may thus serve as a diagnostic tool. We investigated whether exhaled breath VOCs can serve as biomarker for SIRS in a human model of endotoxemia. Eighteen healthy volunteers received 2 ng Eschericia coli lipopolysaccharide (LPS) kg−1 body weight intravenously. Venous blood and exhaled breath were collected before infusion of LPS and every 2 h thereafter, up to 8 h after infusion. The interleukin (IL)-6 concentration was measured in plasma. VOCs in the exhaled breath were measured by gas chromatography and mass spectrometry. A mixed effects model was fitted to examine the relation between the measured compounds in exhaled breath and time after LPS infusion or IL-6 levels in plasma. Partially-least squares discriminant analysis (PLS-DA) was used to investigate whether we could discriminate between samples collected before and after LPS infusion. The exhaled concentrations of 3-methyl-pentane, 4-methyl-pentanol, 1-hexanol, 2,4-dimethyl-heptane, decane and one unknown compound changed after LPS infusion. However, the false-discovery rate was 43% for the total set of 52 compounds that were present in all samples. Of these VOCs only the unknown compound was associated with systemic levels of IL-6. The PLS-DA algorithm resulted in a moderate discriminatory accuracy. SIRS induced by endotoxemia in human volunteers resulted in minor changes in exhaled VOCs. We therefore conclude that LPS infusion in healthy volunteers does not induce metabolic effects that can be detected through VOC analysis of the exhaled breath. This trial is registered at the Dutch Trial Register: NTR4455.

Development of an Optimized Pharmacokinetic Model of Dexmedetomidine Using Target-controlled Infusion in Healthy Volunteers.

Several pharmacokinetic models are available for dexmedetomidine, but these have been shown to underestimate plasma concentrations. Most were developed with data from patients during the postoperative phase and/or in intensive care, making them susceptible to errors due to drug interactions. The aim of this study is to improve on existing models using data from healthy volunteers. After local ethics committee approval, the authors recruited 18 volunteers, who received a dexmedetomidine target-controlled infusion with increasing target concentrations: 1, 2, 3, 4, 6, and 8 ng/ml, repeated in two sessions, at least 1 week apart. Each level was maintained for 30 min. If one of the predefined safety criteria was breached, the infusion was terminated and the recovery period began. Arterial blood samples were collected at preset times, and NONMEM (Icon plc, Ireland) was used for model development. The age, weight, and body mass index ranges of the 18 volunteers (9 male and 9 female) were 20 to 70 yr, 51 to 110 kg, and 20.6 to 29.3 kg/m, respectively. A three-compartment allometric model was developed, with the following estimated parameters for an individual of 70 kg: V1 = 1.78 l, V2 = 30.3 l, V3 = 52.0 l, CL = 0.686 l/min, Q2 = 2.98 l/min, and Q3 = 0.602 l/min. The predictive performance as calculated by the median absolute performance error and median performance error was better than that of existing models. Using target-controlled infusion in healthy volunteers, the pharmacokinetics of dexmedetomidine were best described by a three-compartment allometric model. Apart from weight, no other covariates were identified.

Dynamic cerebral autoregulation to induced blood pressure changes in human experimental and clinical sepsis.

Previous studies have demonstrated that dynamic cerebral autoregulation to spontaneous fluctuations in blood pressure is enhanced following lipopolysaccharide (LPS) infusion, a human experimental model of early sepsis, whereas by contrast it is impaired in patients with severe sepsis or septic shock. In this study, we hypothesized that this pattern of response would be identical during induced changes in blood pressure. Dynamic cerebral autoregulation was assessed in nine healthy volunteers and six septic patients. The healthy volunteers underwent a 4-h intravenous infusion of LPS (total dose: 2ngkg-1 ). Mean arterial blood pressure (MAP, arterial transducer) and middle cerebral artery blood flow velocity (MCAv, transcranial Doppler ultrasound) were recorded continuously during thigh-cuff deflation-induced changes in MAP for the determination of a modified rate of regulation (RoR). This was performed before and after LPS infusion in healthy volunteers, and within 72h following clinical diagnosis of sepsis in patients. In healthy volunteers, thigh-cuff deflation caused a MAP reduction of 16 (13-20) % at baseline and 18 (16-20) % after LPS, while the MAP reduction was 12 (11-13) % in patients (P<0·05 versus volunteers at baseline; P<0·01 versus volunteers after LPS). The corresponding RoR values increased from 0·46 (0·31-0·49) s-1 at baseline to 0·58 (0·36-0·74) s-1 after LPS (P<0·05) in healthy volunteers, whereas they were similar to values observed in patients [0·43 (0·36-0·52) s-1 ; P=0·91 versus baseline; P=0·14 versus LPS]. While our findings support the concept that dynamic cerebral autoregulation is enhanced during the very early stages of sepsis, they remain inconclusive with regard to more advanced stages of disease, because thigh-cuff deflation failed to induce sufficient MAP reductions in patients.

Effect of the Melatonin on Morning Blood Pressure Surge and Norepinephrine Endovenous Infusion in Healthy Volunteers

Melatonin, the pineal gland hormone, has been considered as a central hypotension factor. However their roles in the regulation of the human blood pressure and its possible use as antihyper-tensive drug have not been fully determined. The objective of this trial was to determine the effect of melatonin on blood pressure morning increase and a peripheral vasoconstriction challenge in healthy volunteers. Twelve healthy male volunteers were included in a prospective, comparative, randomized, crossover trial in which changes on blood pressure (BP) and heart rate (HR) after the first morning orthostatism and endovenous norepinephrine (NE) infusion were measured one hour after the administration of placebo (PL) or 10 mg of melatonin in double blind conditions. Melatonin blunted the effects of the first orthostatism on BP and HR. Melatonin also reduces the pressor effect of NA. One concludes that melatonin has central and peripheral hypotensive effects that support a potential role of this hormone in cardiovascular therapeutics.

Chronic administration of ketamine mimics the perturbed sense of body ownership associated with schizophrenia.

Subanaesthetic ketamine infusion in healthy volunteers induces experiences redolent of early psychosis, including changes in the experience of one's own body. It is not clear, however, whether repeated self-administration of ketamine has a sustained effect on body representation that is comparable to that found during acute administration. We sought to establish whether chronic ketamine use resulted in disturbances to sense of body ownership. Following on from our work on the effects of acute ketamine infusion, we used the rubber hand illusion (RHI) to experimentally manipulate the sense of body ownership in chronic ketamine users, compared to healthy controls. Chronic ketamine users experienced the RHI more strongly and reported more body-image aberrations, even though they had not recently taken the drug. These findings suggest that the chronic ketamine model for psychosis models more long-lasting changes in sense of ownership, perhaps more akin to schizophrenia.

A cortical source localization analysis of resting EEG data after remifentanil infusion

ObjectiveTo explore changes in current source density locations after remifentanil infusion in healthy volunteers using source localization of the electroencephalography (EEG). MethodsEEG data was collected from 21 males using a 62-electrode system. Additionally, cognitive performance was evaluated by a continuous reaction time paradigm, and pain scores were obtained for experimental bone and heat stimuli. Data were recorded before and during treatment with remifentanil and placebo. Source localization was performed by sLORETA at delta (1–3.9Hz), theta (4–7.9Hz), alpha (8–12Hz), beta1 (12.1–18Hz), and beta2 (18.1–30Hz) frequency bands. ResultsPre-treatment recordings demonstrated reproducible source characteristics. The alterations (i.e., pre- versus post-treatment) due to remifentanil were significantly and robustly different from placebo infusions. The results indicated that neurons in several brain areas including inferior frontal gyrus and insula at frontal lobe oscillated more strongly after remifentanil infusion compared to placebo. Furthermore, the source activity at delta band was correlated with continuous reaction time index. ConclusionsThese results indicate that alterations in brain oscillations during remifentanil are mostly localized to frontal, fronto-temporal and fronto-central lobes and related to cognitive function. SignificanceThe approach offers the potential to be used for understanding the underlying mechanism of action of remifentanil on brain activity.

Tumour necrosis factor‐alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers

Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumour necrosis factor-alpha (TNF-α). Although TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown. We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to oral and intravenous glucose loads in a crossover study design with ten healthy male volunteers (mean age 24 years, mean body mass index 23.7 kg/m(2) ). The study consisted of four study days: days 1 and 2, 6-h infusion of saline; days 3 and 4, 6-h infusion of TNF-α; days 1 and 3, 4-h oral glucose tolerance test; and days 2 and 4, 4-h corresponding intravenous isoglycaemic glucose tolerance test. Glucose tolerance tests were initiated after 2 h of saline/TNF-α infusion. Plasma concentrations of TNF-α, interleukin 6, glucose, incretin hormones, and cortisol, and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Prehepatic insulin secretion rates were calculated. TNF-α infusion induced symptoms of systemic inflammation; increased plasma levels of cortisol, TNF-α, and interleukin 6; and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged. In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect.