Effects on cerebral blood flow after single doses of the ß2 agonist, clenbuterol, in healthy volunteers and patients with mild cognitive impairment or Parkinson's disease.

AIMS: Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic transmission from the locus coeruleus. In pre-clinical models, ß-adrenoceptor (ß-AR) agonists increase cerebrocortical glucose metabolism, and may have therapeutic potential for neurodegenerative diseases. This study investigated the safety and effects on regional cerebral blood flow (rCBF) of the oral, brain-penetrant ß2-AR agonist, clenbuterol, in healthy volunteers (HV) and patients with mild cognitive impairment (MCI) or Parkinson's disease (PD). METHODS: This study evaluated the safety and effects on cerebral activity of the oral, brain-penetrant, ß2-AR agonist clenbuterol (20-160 µg) in healthy volunteers and patients with MCI or PD. Regional CBF, which is tightly coupled to glucose metabolism, was measured by arterial spin labelling MRI in 32 subjects (25 HV and 8 MCI or PD) across five cohorts. In some cohorts, low doses of nadolol (1-5 mg), a ß-AR antagonist with minimal brain penetration, were administered with clenbuterol to control peripheral ß2-AR responses. RESULTS: Significant, dose-dependent increases in rCBF were seen in multiple brain regions, including hippocampus, amygdala and thalamus, following the administration of clenbuterol to HVs (mean changes from baseline in hippocampal rCBF of -1.7%, 7.3%, 22.9%, 28.4% 3 h after 20, 40, 80 and 160 µg clenbuterol, respectively). In patients with MCI or PD, increases in rCBF following 80 µg clenbuterol were observed both without and with 5 mg nadolol (in hippocampus, 18.6%/13.7% without/with nadolol). Clenbuterol was safe and well-tolerated in all subjects; known side effects of ß2-agonists, including increased heart rate and tremor, were mild in intensity and were blocked by low-dose nadolol. CONCLUSIONS: The effects of clenbuterol on rCBF were evident both in the absence and presence of low-dose nadolol, suggesting central nervous system (CNS) involvement. Concomitant inhibition of the peripheral effects of clenbuterol by nadolol confirms that meaningful ß2-AR antagonism in the periphery was achieved without interrupting the central effects of clenbuterol on rCBF.

Functional Analysis of TRPA1, TRPM3, and TRPV1 Channels in Human Dermal Arteries and Their Role in Vascular Modulation.

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces "local" changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels' contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration-response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K+ channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms.

Vascular read-out for TRP channel functionality on distal peripheral nerve endings in healthy men.

BACKGROUND: Quantification of the vasodilation after topical application of capsaicin or cinnamaldehyde is often implemented to indirectly assess Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1) or Ankyrin 1 (TRPA1) functionality respectively. This method has been well-established on the human forearm. However, to enable TRP functionality assessments in distal peripheral neuropathy, the vascular response upon TRP activation on dorsal finger skin was characterized. METHODS: Two doses of cinnamaldehyde (3 % and 10 % v/v) and capsaicin (300 µg and 1000 µg) were topically applied (20 µL) on the skin of the mid three proximal phalanges in 17 healthy men. The dose-response, and inter-hand and inter-period reproducibility of the dermal blood flow (DBF) increase was assessed using Laser Speckle Contrast Imaging (LSCI) during 60 min post-application. Linear mixed models explored dose-driven differences, whereas the intra-class correlation coefficient (ICC) estimated the reproducibility of the vascular response. RESULTS: Both doses of cinnamaldehyde and capsaicin induced a robust, dose-dependent increase in DBF. The vascular response to cinnamaldehyde 10 % on finger skin, expressed as area under the curve, correlated well over time (ICC = 0.66) and excellently between hands (ICC = 0.87). Similarly, the response to capsaicin 1000 µg correlated moderately over time (ICC = 0.50) and well between hands (ICC = 0.73). CONCLUSION: The vascular response upon topical cinnamaldehyde and capsaicin application on finger skin is an alternative approach for measurements on forearm skin. Thereby, it is a promising vascular read-out to investigate the pathophysiology, and TRP involvement in particular, of specific peripheral neuropathic pain syndromes.

TRPA1 Antagonist LY3526318 Inhibits the Cinnamaldehyde-Evoked Dermal Blood Flow Increase: Translational Proof of Pharmacology.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.

Does etodolac affect TRPA1 functionality in vivo in human?

OBJECTIVES: In preclinical research, etodolac, a non-steroidal anti-inflammatory drug, affected transient receptor potential ankyrin 1 (TRPA1) activation. Yet, whether the in vitro interaction between etodolac and TRPA1 translates to altered TRPA1 functionality in vivo in human remains to be investigated. METHODS: A randomized, double-blinded, celecoxib-controlled study was conducted to assess the effect of etodolac on TRPA1-mediated dermal blood flow (DBF) changes on the forearm of 15 healthy, male volunteers aged between 18 and 45 years. Over four study visits, separated by at least five days wash-out, a single or four-fold dose of etodolac 200 mg or celecoxib 200 mg was administered orally. Two hours post-dose, TRPA1 functionality was evaluated by assessing cinnamaldehyde-induced DBF changes. DBF changes were quantified and expressed in Perfusion Units (PUs) using laser Doppler imaging during 60 min post-cinnamaldehyde application. The corresponding area under the curve (AUC0-60min) was calculated as summary measure. Statistical analysis was performed using Linear mixed models with post-hoc Dunnett. RESULTS: Neither the single dose of etodolac nor celecoxib inhibited the cinnamaldehyde-induced DBF changes compared to no treatment (AUC0-60min ± SEM of 17,751 ± 1,514 PUs*min and 17,532 ± 1,706 PUs*min vs. 19,274 ± 1,031 PUs*min, respectively, both p=1.00). Similarly, also a four-fold dose of both compounds failed to inhibit the cinnamaldehyde-induced DBF changes (19,235 ± 1,260 PUs*min and 19,367 ± 1,085 PUs*min vs. 19,274 ± 1,031 PUs*min, respectively, both p=1.00). CONCLUSIONS: Etodolac did not affect the cinnamaldehyde-induced DBF changes, suggesting that it does not alter TRPA1 functionality in vivo in human.

Histamine Skin Prick Tests: From Established Diagnostic Technique to Advanced Experimental Biomarker.

INTRODUCTION: Skin prick tests have a long history as diagnostic and pharmacodynamic biomarker. Besides visual assessments of the wheal and flare, objective blood flow measurements using laser Doppler imaging (LDI) and laser speckle contrast imaging (LSCI) have been reported. In light of these advancements, an up-to-date characterization of the histamine-evoked response is worthwhile. METHODS: A single-centre study was completed in healthy males. Two parameters were addressed: (1) dermal blood flow (DBF) within a 7.65-mm ring encircling the skin prick site (DBFring), and (2) surface area of the flare (AREAflare). First, the dose response was assessed using placebo (0.9% sodium chloride) or histamine (histamine dihydrochloride 1, 3, or 10 mg/mL) skin pricks on the volar surface of subjects' (n = 12) forearm. The DBFring was measured by LDI, and the AREAflare by LDI and by ruler. Secondly, the inter-arm and inter-period reproducibility of the DBFring and AREAflare, as evoked by histamine (10 mg/mL) and measured by LDI and LSCI, was examined (n = 14). Lastly, the effect of aprepitant (125 mg), ketotifen (1 mg), and a single (5 mg) and fourfold (20 mg) dose of desloratadine and levocetirizine on the histamine-induced (10 mg/mL) DBFring and AREAflare was evaluated with LSCI (n = 13 or 12). RESULTS: All three histamine doses induced a time-dependent vasodilation. Ruler recordings did not conclusively correlate with LDI assessments of the AREAflare. The DBFring and AREAflare were reasonably reproducible when measured by using LDI or LSCI, with negligible bias between arms and study periods and poor to moderate within-subject reproducibility (0.23 ≤ ICC ≤ 0.71). While the fourfold dose of desloratadine (p = 0.0041) and the single and fourfold dose of levocetirizine (p < 0.0001) managed to reduce the AREAflare, only the fourfold dose of levocetirizine (p = 0.0052) reduced the DBFring. CONCLUSION: Caution is warranted when translating years of clinical experience with histamine skin prick tests to objective recordings of the associated changes in skin perfusion. Ruler and LDI assessments of the AREAflare do not consistently correlate, and the reproducibility and histamine dependency of the measurements are not obvious. While 10 mg/mL histamine may be a good choice for qualitative diagnostic evaluations, a lower dose may be better suited to use as a quantitative biomarker.

Pharmacokinetics of Oral Rebaudioside A in Patients with Type 2 Diabetes Mellitus and Its Effects on Glucose Homeostasis: A Placebo-Controlled Crossover Trial.

BACKGROUND AND OBJECTIVES: Rebaudioside A, a steviol glycoside, is deglycosylated by intestinal microflora prior to the absorption of steviol and conjugation to steviol glucuronide. While glucose-lowering properties are observed for rebaudioside A in mice, they have been attributed to the metabolites steviol and steviol glucuronide. We aimed to characterize the pharmacokinetic and pharmacodynamic properties of rebaudioside A and its metabolites in patients with early-onset type 2 diabetes mellitus (T2DM). METHODS: This randomized, placebo-controlled, open-label, two-way crossover trial was performed in subjects with T2DM on metformin or no therapy at the University Hospitals Leuven, Belgium. Following oral rebaudioside A (3 g), plasma concentrations of rebaudioside A, steviol and steviol glucuronide were determined. The effect on glucose homeostasis was examined by an oral glucose tolerance test (OGTT) performed 19 h following rebaudioside A administration, i.e. the presumed time of maximal steviol and steviol glucuronide concentrations. The primary pharmacodynamic endpoint was the difference in area under the blood glucose concentration-time curve during the first 2 h of the OGTT (AUCGlucose(0-2h)) for rebaudioside A vs. placebo. RESULTS: In total, 30 subjects [63.5 (57.8-69.0) years of age, 86.7% male] completed the trial. Rebaudioside A was detected as early as 1 h after administration in nearly all subjects. As expected, steviol and steviol glucuronide reached their maximal concentrations at 19.5 h following rebaudioside A administration. Rebaudioside A did not lower the AUCGlucose(0-2h) compared to placebo (- 0.7 (95% CI - 22.3; 20.9) h·mg/dL, P = 0.95). Insulin and C-peptide concentrations were also comparable between both conditions (P > 0.05). CONCLUSION: Rebaudioside A is readily absorbed after oral administration and metabolized to steviol and steviol glucuronide. However, no effect on glucose nor insulin or C-peptide excursion was observed during the OGTT at the time of maximal metabolite concentrations. Thus, no antidiabetic properties of rebaudioside A could be observed in patients with T2DM after single oral use. CLINICAL TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT03510624).

First-in-human development of a pharmacodynamic biomarker for PAC1 receptor antagonists using intradermal injections of maxadilan.

Maxadilan, a potent vasodilator peptide, selectively activates the PAC1 receptor, a promising target for migraine therapy. Therefore, maxadilan has been suggested as a tool to study the pharmacodynamics (PDs) of PAC1 receptor antagonists. The objectives of this first-in-human study were to: (1) determine the safety, tolerability, dose response, and time course of the dermal blood flow (DBF) changes after intradermal (i.d.) injections of maxadilan in the human forearm, and (2) assess the inter-arm and inter-period reproducibility of this response. This was a single-center, open-label study in healthy subjects, comprising three parts: (1) dose-response (n = 25), (2) response duration (n = 10), and (3) reproducibility (n = 15). DBF measurements were performed using laser Doppler imaging (LDI) up to 60 min postinjection, or up to 5 days for the response duration assessments. To assess reproducibility, the intraclass correlation coefficient (ICC) and sample sizes were calculated. The i.d. maxadilan (0.001, 0.01, 0.1, 0.9, 3, and 10 ng) produced a well-tolerated, dose-dependent increase in DBF, with a half-maximal effective concentration fitted at 0.0098 ng. The DBF response to 0.9 ng maxadilan was quantifiable with LDI up to 72 h postinjection. The inter-period reproducibility of the DBF response was better upon 0.9 ng (ICC > 0.6) compared to 0.01 ng (ICC < 0.4) maxadilan. However, irrespective of the study design or maxadilan dose, a sample size of 11 subjects is sufficient to detect a 30% difference in DBF response with 80% power. In conclusion, intradermal maxadilan provides a safe, well-tolerated, and reproducible PD biomarker for PAC1 receptor antagonists in vivo in humans.

The PET tracer [11C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease.

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

Doppler ultrasound to assess the pharmacodynamic effects of splanchnic vasoactive compounds.

AIMS: In search of noninvasive biomarkers to assess the pharmacodynamic effects of portal pressure-lowering drugs, the reproducibility of flow measurements in the superior mesenteric artery was evaluated using Doppler ultrasound. METHODS: A reproducibility study was conducted in 15 healthy male volunteers (18-50 y). Eight ultrasound measurements were performed for each subject: 2 observers each conducted 2 measurements during 2 separate visits. The following flow parameters were captured: peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), volume flow (VF) and vessel diameter. Reproducibility was assessed by the intraclass correlation coefficient. RESULTS: Results are presented as intraclass correlation coefficient [95% confidence interval]. The flow parameters PSV, EDV, PI and VF correlated excellently within observer during visit 1 (0.888 [0.748-0.953], 0.910 [0.793-0.962], 0.844 [0.656-0.933] and 0.916 [0.857-0.951], respectively) and visit 2 (0.925 [0.829-0.968], 0.942 [0.863-0.976], 0.883 [0.719-0.954] and 0.915 [0.855-0.951], respectively). Measurements conducted during 2 separate visits by 1 observer correlated well to excellently for PSV, EDV, PI and VF (0.756 [0.552-0.875], 0.836 [0.694-0.916], 0.807 [0.631-0.904] and 0.839 [0.783-0.882], respectively). Measurements conducted by 2 distinct observers correlated well to excellently for PSV, EDV and VF during visit 1 (0.813 [0.584-0.922], 0.884 [0.597-0.945] and 0.786 [0.575-0.899], respectively) and visit 2 (0.779 [0.498-0.912], 0.861 [0.672-0.945], 0.810 [0.553-0.926], respectively). Vessel diameter measurements were poorly reproducible. CONCLUSION: Doppler ultrasound is a reproducible method for flow measurements in the superior mesenteric artery in a standardized group of healthy volunteers. Therefore, it is a promising technique to assess pharmacodynamic effects of splanchnic vasoactive compounds in early clinical drug development.

Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study.

BACKGROUND: The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. OBJECTIVES: Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. METHODS: This was a phase 1, randomized, double-blind, study with 2 parts. Part A administered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n = 26) were conducted. RESULTS: Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day 8: -1.17, P = .001; day 29: -1.18, P = .001; day 57: -0.85, P = .024) and titration SPT with birch difference in area under the curve of mean wheal diameters for subjects treated with REGN5713/14/15 versus placebo (all P < .001) were sustained for ≥2 months; similar results were observed with alder SPT. REGN5713/14/15 was well tolerated. Basophil responsiveness to birch-related allergens was significantly decreased in subjects treated with REGN5713/14/15 versus those given placebo on days 8, 57, and 113 (all P < .01). CONCLUSIONS: Single-dose REGN5713/14/15 was well tolerated and provided a rapid (1 week) and durable (2 months) reduction in allergic symptoms after birch allergen nasal allergen challenge, potentially offering a new paradigm for the treatment of birch allergy symptoms.

SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET/fMRI assessment of target engagement.

Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit. Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80 mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [11C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives. Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy. Conclusion: Single oral doses of SDI-118 up to 80 mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05486195.

Minimally invasive quantification of cerebral P2X7R occupancy using dynamic [18F]JNJ-64413739 PET and MRA-driven image derived input function.

[18F]JNJ-64413739 has been evaluated as PET-ligand for in vivo quantification of purinergic receptor subtype 7 receptor (P2X7R) using Logan graphical analysis with a metabolite-corrected arterial plasma input function. In the context of a P2X7R PET dose occupancy study, we evaluated a minimally invasive approach by limiting arterial sampling to baseline conditions. Meanwhile, post dose distribution volumes (VT) under blocking conditions were estimated by combining baseline blood to plasma ratios and metabolite fractions with an MR angiography driven image derived input function (IDIF). Regional postdose VT,IDIF values were compared with corresponding VT,AIF estimates using a arterial input function (AIF), in terms of absolute values, test-retest reliability and receptor occupancy. Compared to an invasive AIF approach, postdose VT,IDIF values and corresponding receptor occupancies showed only limited bias (Bland-Altman analysis: 0.06 ± 0.27 and 3.1% ± 6.4%) while demonstrating a high correlation (Spearman ρ = 0.78 and ρ = 0.98 respectively). In terms of test-retest reliability, regional intraclass correlation coefficients were 0.98 ± 0.02 for VT,IDIF compared to 0.97 ± 0.01 for VT,AIF. These results confirmed that a postdose IDIF, guided by MR angiography and using baseline blood and metabolite data, can be considered for accurate [18F]JNJ-64413739 PET quantification in a repeated PET study design, thus avoiding multiple invasive arterial sampling and increasing dosing flexibility.

Human biodistribution and dosimetry of [11C]-UCB-J, a PET radiotracer for imaging synaptic density.

RATIONALE: [11C]-UCB-J is an emerging tool for the noninvasive measurement of synaptic vesicle density in vivo. Here, we report human biodistribution and dosimetry estimates derived from sequential whole-body PET using two versions of the OLINDA dosimetry program. METHODS: Sequential whole-body PET scans were performed in 3 healthy subjects for 2 h after injection of 254 ± 77 MBq [11C]-UCB-J. Volumes of interest were drawn over relevant source organs to generate time-activity curves and calculate time-integrated activity coefficients, with effective dose coefficients calculated using OLINDA 2.1 and compared to values derived from OLINDA 1.1 and those recently reported in the literature. RESULTS: [11C]-UCB-J administration was safe and showed mixed renal and hepatobiliary clearance, with largest organ absorbed dose coefficients for the urinary bladder wall and small intestine (21.7 and 23.5 µGy/MBq, respectively). The average (±SD) effective dose coefficient was 5.4 ± 0.7 and 5.1 ± 0.8 µSv/MBq for OLINDA versions 1.1 and 2.1 respectively. Doses were lower than previously reported in the literature using either software version. CONCLUSIONS: A single IV administration of 370 MBq [11C]-UCB-J corresponds to an effective dose of less than 2.0 mSv, enabling multiple PET examinations to be carried out in the same subject. TRIAL REGISTRATION: EudraCT number: 2016-001190-32. Registered 16 March 2016, no URL available for phase 1 trials.

Relationship of the Calcitonin Gene-Related Peptide Monoclonal Antibody Galcanezumab Pharmacokinetics and Capsaicin-Induced Dermal Blood Flow in Healthy Subjects.

Galcanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, was recently approved for migraine prophylaxis. The pharmacokinetic/pharmacodynamic (PK/PD) relationship between galcanezumab concentration and inhibition of capsaicin-induced dermal blood flow (CIDBF) was evaluated using first-in-human data following 6 single subcutaneous doses (1 to 600 mg) or multiple (4) 150-mg doses every 2 weeks in 7 cohorts (7 actively treated subjects and 2 placebo-treated healthy subjects). Galcanezumab pharmacokinetics were best described by a 1-compartment model with delayed first-order absorption/linear elimination. Apparent estimates (between-subject variability) of clearance, volume of distribution, absorption rate constant, and lag time were 0.0106 L/h (27%CV), 11.2 L (21%CV), 0.0192 h-1 (89%CV), and 0.202 hours, respectively. Estimated elimination half-life was about 30 days. An effect compartment link model described the concentration-effect relationship; estimated maximum inhibitory effect was 70.5%, and 50% maximum inhibitory effect concentration (IC50 ) was 1060 ng/mL. Galcanezumab showed dose- and concentration-dependent potent and durable inhibition of CIDBF. Simulated effect compartment concentrations were maintained above IC50 after 12 weeks of dosing. Near-maximal CIDBF inhibition occurred with 150 mg biweekly for 12 weeks lasting ≥24 weeks or with ≥30 mg every 2 weeks or 195 mg every 13 weeks. Quantitative modeling of galcanezumab PK/PD supported dose selection for the phase 2 proof-of-concept study.

Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine.

BACKGROUND: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein. METHODS: In this multicenter, placebo-controlled, phase 1-2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule. RESULTS: After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 212 to 354), regardless of vaccine dose or age group, and reached 96% by day 57 with a further increase in titers (GMT, 288 to 488) in cohort 1a. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 15, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3. CONCLUSIONS: The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.).

TRP Channel Cooperation for Nociception: Therapeutic Opportunities.

Chronic pain treatment remains a sore challenge, and in our aging society, the number of patients reporting inadequate pain relief continues to grow. Current treatment options all have their drawbacks, including limited efficacy and the propensity of abuse and addiction; the latter is exemplified by the ongoing opioid crisis. Extensive research in the last few decades has focused on mechanisms underlying chronic pain states, thereby producing attractive opportunities for novel, effective and safe pharmaceutical interventions. Members of the transient receptor potential (TRP) ion channel family represent innovative targets to tackle pain sensation at the root. Three TRP channels, TRPV1, TRPM3, and TRPA1, are of particular interest, as they were identified as sensors of chemical- and heat-induced pain in nociceptor neurons. This review summarizes the knowledge regarding TRP channel-based pain therapies, including the bumpy road of the clinical development of TRPV1 antagonists, the current status of TRPA1 antagonists, and the future potential of targeting TRPM3.