Background:Up to 40% of patients suffering from anxiety disorders do not benefit from currently available pharmacological treatments. Overactivity of the orexin-1 receptor (OX1R) has been... Show moreBackground:Up to 40% of patients suffering from anxiety disorders do not benefit from currently available pharmacological treatments. Overactivity of the orexin-1 receptor (OX1R) has been implicated in anxiety- and panic-related states.Aim & methods:We investigated the pharmacokinetics and characterized the pharmacodynamic (PD) profile of the OX1R antagonist JNJ-61393215 using a battery of central nervous system assessments investigating relevant functional domains such as alertness, attention, (visuo)motor coordination, balance, subjective effects and resting-state electroencephalography in a single ascending dose placebo-controlled study in doses from 1 to 90 mg inclusive, assessing PD up to 10 h after dosing, safety and pharmacokinetic in 48 healthy male subjects.Results:Average time to maximal plasma concentration (Tmax) ranged between 1.0 and 2.25 h; average half-life ranged from 13.6 to 24.6 h and average maximum plasma concentration ranged from 1.4 to 136.8 ng/mL in the 1 and 90 mg groups, respectively. JNJ-61393215 did not demonstrate any statistically significant or clinically meaningful effects on any PD endpoint at any dose investigated at Tmax nor over the total period up to 10 h post-dose and was well tolerated. The reported somnolence rate was 16.7% (which was attributable to the cohorts receiving 6 mg and higher doses) compared to 12.5% in placebo.Conclusion:This observation is in line with our knowledge about the OX1R in preclinical studies, where only inconsistent and non-dose-dependent changes in electroencephalography or other behavioural measures were observed under non-challenged conditions, potentially exemplifying the need for a challenged subject. Show less
Low muscle quality and a sedentary lifestyle are indicators for a slow recovery after a total knee arthroplasty (TKA). Mitochondrial function is an important part of muscle quality and a key driver... Show moreLow muscle quality and a sedentary lifestyle are indicators for a slow recovery after a total knee arthroplasty (TKA). Mitochondrial function is an important part of muscle quality and a key driver of sarcopenia. However, it is not known whether it relates to recovery. In this pilot study, we monitored activity after TKA using a wrist mounted activity tracker and assessed the relation of mitochondrial function on the rate of recovery after TKA. Additionally, we compared the increase in activity as a way to measure recovery to traditional outcome measures. Patients were studied 2 weeks before TKA and up to 6 months after. Activity was monitored continuously. Baseline mitochondrial function (citrate synthase and complex [CP] 1-5 abundance of the electron transport chain) was determined on muscle tissue taken during TKA. Traditional outcome measures (Knee Injury and Osteoarthritis Outcome Score [KOOS], timed up-and-go [TUG] completion time, grip, and quadriceps strength) were performed 2 weeks before, 6 weeks after, and 6 months after TKA. Using a multivariate regression model with various clinical baseline parameters, the following were significantly related to recovery: CP5 abundance, grip strength, and activity (regression weights 0.13, 0.02, and 2.89, respectively). During recovery, activity correlated to the KOOS-activities of daily living (ADL) score (r = 0.55, p = 0.009) and TUG completion time (r = -0.61, p = 0.001). Mitochondrial function seems to be related to recovery, but so are activity and grip strength, all indicators of sarcopenia. Using activity trackers before and after TKA might give the surgeon valuable information on the expected recovery and the opportunity to intervene if recovery is low. Show less
Wind, S.S.; Jansen, M.A.A.; Rijsbergen, M.; Esdonk, M.J. van; Ziagkos, D.; Cheng, W.C.; ... ; Rissmann, R. 2022
Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human... Show moreMycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm2 on 400 cm2, with a mean Cavg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean Cavg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs. Show less
Wind, S.S.; Jansen, M.A.A.; Rijsbergen, M.; Esdonk, M.J. van; Ziagkos, D.; Cheng, W.C.; ... ; Rissmann, R. 2022
Simple Summary Primary cutaneous T-cell lymphomas (CTCLs) are a group of lymphomas that present in the skin without extracutaneous localizations at diagnosis. Recent studies in clinical and... Show moreSimple Summary Primary cutaneous T-cell lymphomas (CTCLs) are a group of lymphomas that present in the skin without extracutaneous localizations at diagnosis. Recent studies in clinical and translational research augmented our understanding of the pathogenesis and pathophysiology of different subtypes of CTCL, enabling the identification of novel therapeutic drug targets. In this study, the primary focus is on bimiralisib gel 2%, a dual pan-class PI3K/mTOR inhibitor, and its potential to inhibit the PI3K/AKT/mTOR signaling pathway as a novel therapeutic target in CTCL. Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 mu g/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm(2) on 400 cm(2), with a mean C-avg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean C-avg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 mu g/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs. Show less
Aims The purpose of this study was to investigate pharmacodynamic effects of drugs targeting cortical excitability using transcranial magnetic stimulation (TMS) combined with electromyography (EMG)... Show moreAims The purpose of this study was to investigate pharmacodynamic effects of drugs targeting cortical excitability using transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) in healthy subjects, to further develop TMS outcomes as biomarkers for proof-of-mechanism in early-phase clinical drug development. Antiepileptic drugs presumably modulate cortical excitability. Therefore, we studied effects of levetiracetam, valproic acid and lorazepam on cortical excitability in a double-blind, placebo-controlled, 4-way cross-over study. Methods In 16 healthy male subjects, single- and paired-pulse TMS-EMG-EEG measurements were performed predose and 1.5, 7 and 24 hours postdose. Treatment effects on motor-evoked potential, short and long intracortical inhibition and TMS-evoked potential amplitudes, were analysed using a mixed model ANCOVA and cluster-based permutation analysis. Results We show that motor-evoked potential amplitudes decreased after administration of levetiracetam (estimated difference [ED] -378.4 mu V; 95%CI: -644.3, -112.5 mu V; P < .01), valproic acid (ED -268.8 mu V; 95%CI: -532.9, -4.6 mu V; P = .047) and lorazepam (ED -330.7 mu V; 95%CI: -595.6, -65.8 mu V; P = .02) when compared with placebo. Long intracortical inhibition was enhanced by levetiracetam (ED -60.3%; 95%CI: -87.1%, -33.5%; P < .001) and lorazepam (ED -68.2%; 95%CI: -94.7%, -41.7%; P < .001) at a 50-ms interstimulus interval. Levetiracetam increased TMS-evoked potential component N45 (P = .004) in a central cluster and decreased N100 (P < .001) in a contralateral cluster. Conclusion This study shows that levetiracetam, valproic acid and lorazepam decrease cortical excitability, which can be detected using TMS-EMG-EEG in healthy subjects. These findings provide support for the use of TMS excitability measures as biomarkers to demonstrate pharmacodynamic effects of drugs that influence cortical excitability. Show less
Background: Pediatric patients admitted for acute lung disease are treated and monitored in the hospital, after which full recovery is achieved at home. Many studies report in-hospital recovery,... Show moreBackground: Pediatric patients admitted for acute lung disease are treated and monitored in the hospital, after which full recovery is achieved at home. Many studies report in-hospital recovery, but little is known regarding the time to full recovery after hospital discharge. Technological innovations have led to increased interest in home-monitoring and digital biomarkers. The aim of this study was to describe at-home recovery of 3 common pediatric respiratory diseases using a questionnaire and wearable device. Methods: In this study, patients admitted due to pneumonia (n = 30), preschool wheezing (n = 30), and asthma exacerbation (AE; n = 11) were included. Patients were monitored with a smartwatch and a questionnaire during admission, with a 14-day recovery period and a 10-day "healthy" period. Median compliance was calculated, and a mixed-effects model was fitted for physical activity and heart rate (HR) to describe the recovery period, and the physical activity recovery trajectory was correlated to respiratory symptom scores. Results: Median compliance was 47% (interquartile range [IQR] 33-81%) during the entire study period, 68% (IQR 54-91%) during the recovery period, and 28% (IQR 0-74%) during the healthy period. Patients with pneumonia reached normal physical activity 12 days postdischarge, while subjects with wheezing and AE reached this level after 5 and 6 days, respectively. Estimated mean physical activity was closely correlated with the estimated mean symptom score. HR measured by the smartwatch showed a similar recovery trajectory for subjects with wheezing and asthma, but not for subjects with pneumonia. Conclusions: The digital biomarkers, physical activity, and HR obtained via smartwatch show promise for quantifying postdischarge recovery in a noninvasive manner, which can be useful in pediatric clinical trials and clinical care. Show less
Jacobse, J.; Voorde, W. ten; Tandon, A.; Romeijn, S.G.; Grievink, H.W.; Maaden, K. van der; ... ; Cate, R. ten 2021
Aims To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single... Show moreAims To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle.Methods In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography, clinical photography, thermal imaging, and laser speckle contrast imaging to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device.Results While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 100-point visual analogue scale). Initial absorption rate and relative bioavailability were higher after i.d. adalimumab (time to maximum plasma concentration = 95 h [47-120]; F-rel = 129% [6.46%]) compared to s.c. adalimumab (time to maximum plasma concentration = 120 h [96-221]). Anti-adalimumab antibodies were detected in 50% and 83% of the subjects after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (P < .0001). Cytokine secretion after whole blood lipopolysaccharide challenge was comparable between administration routes.Conclusions Intradermal injection of adalimumab using hollowing microneedles was perceived as more painful and less accepted than s.c. administration, but yields a higher relative bioavailability with similar safety and pharmacodynamic effects. Show less
Jacobse, J.; Voorde, W. ten; Tandon, A.; Romeijn, S.G.; Grievink, H.W.; Maaden, K. van der; ... ; Cate, R. ten 2021
Aims To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single... Show moreAims To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle.Methods In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography, clinical photography, thermal imaging, and laser speckle contrast imaging to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device.Results While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 100-point visual analogue scale). Initial absorption rate and relative bioavailability were higher after i.d. adalimumab (time to maximum plasma concentration = 95 h [47-120]; F-rel = 129% [6.46%]) compared to s.c. adalimumab (time to maximum plasma concentration = 120 h [96-221]). Anti-adalimumab antibodies were detected in 50% and 83% of the subjects after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (P < .0001). Cytokine secretion after whole blood lipopolysaccharide challenge was comparable between administration routes.Conclusions Intradermal injection of adalimumab using hollowing microneedles was perceived as more painful and less accepted than s.c. administration, but yields a higher relative bioavailability with similar safety and pharmacodynamic effects. Show less
Saghari, M.; Gal, P.; Ziagkos, D.; Burggraaf, J.; Powell, J.F.; Brennan, N.; ... ; Moerland, M. 2020
Aims Keyhole limpet haemocyanin (KLH) immunization is a clinical model for the evaluation of human antibody responses. The current study evaluated the anti-KLH antibody response after KLH... Show moreAims Keyhole limpet haemocyanin (KLH) immunization is a clinical model for the evaluation of human antibody responses. The current study evaluated the anti-KLH antibody response after KLH immunization and the delayed-type hypersensitivity response following intradermal KLH administration, using objective imaging techniques.Methods Healthy male subjects aged 24.5 +/- 5.4 years were randomized to intramuscular immunization with 100 mu g KLH (n = 12) or placebo (n = 3). Anti-KLH antibody (Ig) M and IgG titres were determined before and every 7 days after KLH immunization for a total of 28 days. Twenty-one days after the immunization, all subjects received 1 mu g KLH intradermally. Prior to and 2 days after intradermal KLH administration, skin blood perfusion, erythema and oedema were quantified using noninvasive imaging tools. Repeated measures ANCOVAs were used to analyse data.Results Anti-KLH IgM and IgG titres increased after KLH immunization compared to placebo (estimated difference [ED]: 37%, 95% confidence interval [CI]: 19-51% and ED: 68%, 95% CI: 56-76% respectively). Upon intradermal KLH administration an increase in skin blood perfusion (ED: 10.9 arbitrary units (AU), 95% CI: 1.4-20.4 AU) and erythema (ED: 0.3 AU, 95% CI: 0.1-0.5 AU) was observed in KLH-immunized subjects compared to placebo.Conclusion KLH immunization followed by intradermal KLH administration resulted in increased anti-KLH IgM and IgG titres and a delayed-type hypersensitivity response quantified by an increase in skin blood perfusion and erythema. Using noninvasive imaging tools the KLH model has the potential to serve as an objective tool to study the pharmacodynamics of T-cell-directed immunomodulatory drugs. Show less
Saghari, M.; Gal, P.; Ziagkos, D.; Burggraaf, J.; Powell, J.F.; Brennan, N.; ... ; Moerland, M. 2020
Aims Keyhole limpet haemocyanin (KLH) immunization is a clinical model for the evaluation of human antibody responses. The current study evaluated the anti-KLH antibody response after KLH... Show moreAims Keyhole limpet haemocyanin (KLH) immunization is a clinical model for the evaluation of human antibody responses. The current study evaluated the anti-KLH antibody response after KLH immunization and the delayed-type hypersensitivity response following intradermal KLH administration, using objective imaging techniques.Methods Healthy male subjects aged 24.5 +/- 5.4 years were randomized to intramuscular immunization with 100 mu g KLH (n = 12) or placebo (n = 3). Anti-KLH antibody (Ig) M and IgG titres were determined before and every 7 days after KLH immunization for a total of 28 days. Twenty-one days after the immunization, all subjects received 1 mu g KLH intradermally. Prior to and 2 days after intradermal KLH administration, skin blood perfusion, erythema and oedema were quantified using noninvasive imaging tools. Repeated measures ANCOVAs were used to analyse data.Results Anti-KLH IgM and IgG titres increased after KLH immunization compared to placebo (estimated difference [ED]: 37%, 95% confidence interval [CI]: 19-51% and ED: 68%, 95% CI: 56-76% respectively). Upon intradermal KLH administration an increase in skin blood perfusion (ED: 10.9 arbitrary units (AU), 95% CI: 1.4-20.4 AU) and erythema (ED: 0.3 AU, 95% CI: 0.1-0.5 AU) was observed in KLH-immunized subjects compared to placebo.Conclusion KLH immunization followed by intradermal KLH administration resulted in increased anti-KLH IgM and IgG titres and a delayed-type hypersensitivity response quantified by an increase in skin blood perfusion and erythema. Using noninvasive imaging tools the KLH model has the potential to serve as an objective tool to study the pharmacodynamics of T-cell-directed immunomodulatory drugs. Show less
Background and aims: Following an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the... Show moreBackground and aims: Following an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the acute inflammatory response induced by a human endotoxemia model, and its effect on pain perception using evoked pain tests in two different dose levels. We also attempted to determine whether combining a human endotoxemia challenge with measurement of pain thresholds in healthy subjects could serve as a model to study drug effects on inflammatory pain.Methods and results: This was a placebo-controlled, randomized, cross-over study in 24 healthy males. Twelve subjects were administered a bolus of 1 ng/kg LPS intravenously, and twelve 2 ng/kg LPS. Before days of placebo/LPS administration, subjects completed a full study day without study drug administration, but with identical pain threshold testing. Blood sampling and evoked pain tests (electrical burst and -stair, heat, pressure, and cold pressor test) were performed pre-dose and at frequent intervals up to 10hr post-dose. Data were analysed with a repeated-measures ANCOVA. For both dose levels, LPS induced an evident acute inflammatory response, but did not significantly affect any of the pain modalities. In a post-hoc analysis, lowering of pain thresholds was observed in the first 3 h after dosing, corresponding with the peak of the acute inflammatory response around 1-3 h post-dose.Conclusion: Mild acute systemic inflammation, as induced by 1 ng/kg and 2 ng/kg LPS intravenous administration, did not significantly change pain thresholds in this study. The endotoxemia model in combination with evoked pain tests is not suitable to study acute inflammatory hyperalgesia in healthy males. Show less
Purpose Recombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping... Show morePurpose Recombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping legislation, but this risk has not been investigated thoroughly. This analysis was designed to evaluate whether rHuEPO impacts hemostatic profile and endothelial and platelet activation markers in trained subjects, and whether the combination with exercise affects exercise induced alterations. Methods This double-blind, randomized, placebo-controlled trial enrolled healthy, trained male cyclists aged 18-50 years. Participants were randomly allocated (1:1) to receive subcutaneous injections of rHuEPO (epoetin-beta; mean dose 6000 IU per week) or placebo (0.9% NaCl) for 8 weeks. Subjects performed five maximal exercise tests and a road race, coagulation and endothelial/platelet markers were measured at rest and directly after each exercise effort. Results rHuEPO increased P-selectin (+ 7.8% (1.5-14.5),p = 0.02) and E-selectin (+ 8.6% (2.0-15.7),p = 0.01) levels at rest. Maximal exercise tests significantly influenced all measured coagulation and endothelial/platelet markers, and in the rHuEPO group maximal exercise tests led to 15.3% ((7.0-24.3%),p = 0.0004) higher E-selectin and 32.1% ((4.6-66.8%),p = 0.0207) higher Platelet factor 4 (PF4) levels compared to the placebo group. Conclusion In conclusion, rHuEPO treatment resulted in elevated E- and P-selectin levels in trained cyclists, indicating enhanced endothelial activation and/or platelet reactivity. Exercise itself induces hypercoagulability, and the combination of rHuEPO and exercise increased E-selectin and PF4 levels more than either intervention alone. Based on this, exercise potentially increases thrombotic risk, a risk that might be enhanced in combination with rHuEPO use. Show less
Cremers, E.M.P.; Witte, T. de; Wreede, L. de; Eikema, D.J.; Koster, L.; Biezen, A. van; ... ; Kroger, N. 2019
