Publications by authors named "Dimitrios Ziagkos"

7 Publications

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Comprehensive evaluation of microneedle-based intradermal adalimumab delivery vs. subcutaneous administration: results of a randomized controlled clinical trial.

Br J Clin Pharmacol 2021 Jan 5. Epub 2021 Jan 5.

Department of Pediatric Rheumatology Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, the Netherlands.

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 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 = 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.
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http://dx.doi.org/10.1111/bcp.14729DOI Listing
January 2021

A randomized controlled trial with a delayed-type hypersensitivity model using keyhole limpet haemocyanin to evaluate adaptive immune responses in man.

Br J Clin Pharmacol 2021 Apr 28;87(4):1953-1962. Epub 2020 Oct 28.

Centre for Human Drug Research, Leiden, the Netherlands.

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 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 μg 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 μg 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.
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http://dx.doi.org/10.1111/bcp.14588DOI Listing
April 2021

Additive effect of erythropoietin use on exercise-induced endothelial activation and hypercoagulability in athletes.

Eur J Appl Physiol 2020 Aug 14;120(8):1893-1904. Epub 2020 Jun 14.

Centre for Human Drug Research, Zernikedreef 8, 2333 CL, Leiden, The Netherlands.

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 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-β; 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.
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http://dx.doi.org/10.1007/s00421-020-04419-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340646PMC
August 2020

Quantification of tremor using consumer product accelerometry is feasible in patients with essential tremor and Parkinson's disease: a comparative study.

J Clin Mov Disord 2020 7;7. Epub 2020 Apr 7.

1Centre for Human Drug Research, Zernikedreef 8, Leiden, 2333 CL The Netherlands.

Background: To quantify pharmacological effects on tremor in patients with essential tremor (ET) or Parkinson's Disease (PD), laboratory-grade accelerometers have previously been used. Over the last years, consumer products such as smartphones and smartwatches have been increasingly applied to measure tremor in an easy way. However, it is unknown how the technical performance of these consumer product accelerometers (CPAs) compares to laboratory-grade accelerometers (LGA). This study was performed to compare the technical performance of CPAs with LGA to measure tremor in patients with Parkinson's Disease (PD) and essential tremor (ET).

Methods: In ten patients with PD and ten with ET, tremor peak frequency and corresponding amplitude were measured with 7 different CPAs (Apple iPhone 7, Apple iPod Touch 5, Apple watch 2, Huawei Nexus 6P, Huawei watch, mbientlabMetaWear (MW) watch, mbientlab MW clip) and compared to a LGA (Biometrics ACL300) in resting and extended arm position.

Results: Both in PD and ET patients, the peak frequency of CPAs did not significantly differ from the LGA in terms of limits of agreement. For the amplitude at peak frequency, only the iPhone and MW watch performed comparable to the LGA in ET patients, while in PD patients all methods performed comparable except for the iPod Touch and Huawei Nexus. Amplitude was higher when measured with distally-located CPAs (Clip, iPhone, iPod) compared with proximally-located CPAs (all watches). The variability between subjects was higher than within subjects for frequency (25.1% vs. 13.4%) and amplitude measurement (331% vs. 53.6%). Resting arm position resulted in lower intra-individual variability for frequency and amplitude (13.4 and 53.5%) compared to extended arm position (17.8 and 58.1%).

Conclusions: Peak frequencies of tremor could be measured with all tested CPAs, with similar performance as LGA. The amplitude measurements appeared to be driven by anatomical location of the device and can therefore not be compared. Our results show that the tested consumer products can be used for tremography, allowing at-home measurements, in particular in studies with a cross-over or intra-individual comparison design using the resting arm position.

Trial Registration: This trial was registered in the Dutch Competent Authority (CCMO) database with number NL60672.058.17 on May 30th 2017.
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http://dx.doi.org/10.1186/s40734-020-00086-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137336PMC
April 2020

Evaluation of simulated driving in comparison to laboratory-based tests to assess the pharmacodynamics of alprazolam and alcohol.

J Psychopharmacol 2019 07 26;33(7):791-800. Epub 2019 Mar 26.

1 Centre for Human Drug Research, Leiden, The Netherlands.

Rationale: Assessment of the effects of medicines on the risks of car driving must be derived from laboratory tests, simulated driving or real on-road driving tests. Relevance of tests is determined by their sensitivity and predictive ability for the probability of accidents or damage. This cannot be determined directly, but methods should be able to at least detect the effects of a positive control in dosage known to be clearly associated with increased risk.

Objectives: A driving simulator was evaluated in comparison with a battery of validated tests of CNS performance, the NeuroCart®. Alcohol in a concentration exactly at the legal limit (0.5 g L) and well above (1.0 g L) as well as alprazolam (1 mg) was used as positive control.

Methods: This was a randomised, cross-over study using a double dummy blinded design in 24 healthy study subjects (12 M, 12 F) aged 20-43 years. Alcohol was infused intravenously using a validated clamping protocol to obtain concentrations of 0.5 g L and on another occasion 1.0 g L. Alprazolam was given orally. Driving tests and lab tests were done at regular time intervals during a study day.

Results: Alprazolam and alcohol significantly affected the main parameters of driving in the simulator and affected scores of safe driving and alprazolam increased the odds ratio of a virtual crash. Several laboratory measurements of psychomotor performance were affected by the reference substances as expected and correlated significantly with the driving performance.

Conclusions: The driving simulator can detect effects of reference substances at levels that are known to negatively affect driving.
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http://dx.doi.org/10.1177/0269881119836198DOI Listing
July 2019

Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

Clin Pharmacol Ther 2018 12 19;104(6):1136-1145. Epub 2018 Jun 19.

Centre for Human Drug Research, Leiden, the Netherlands.

Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis (ALS) may be a relevant factor leading to motor neuron damage. This randomized, double-blind, three-way crossover, placebo-controlled study evaluated peripheral motor nerve excitability testing as a biomarker of hyperexcitability and assessed the effects of riluzole and retigabine in 18 patients with ALS. We performed excitability testing at baseline, and twice after participants had received a single dose of either 100 mg riluzole, 300 mg retigabine, or placebo. Between- and within-day repeatability was at least acceptable for 14 out of 18 recorded excitability variables. No effects of riluzole on excitability testing were observed, but retigabine significantly decreased strength-duration time-constant (9.2%) and refractoriness at 2 ms (10.2) compared to placebo. Excitability testing was shown to be a reliable biomarker in patients with ALS, and the acute reversal of previously abnormal variables by retigabine justifies long-term studies evaluating the impact on disease progression and survival.
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http://dx.doi.org/10.1002/cpt.1096DOI Listing
December 2018

T and B Cell Markers in Dried Blood Spots of Neonates with Congenital Cytomegalovirus Infection: B Cell Numbers at Birth Are Associated with Long-Term Outcomes.

J Immunol 2017 01 30;198(1):102-109. Epub 2016 Nov 30.

Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.

Congenital CMV infection (cCMV) is the most common congenital infection that can cause long-term impairment (LTI). The pathogenesis of LTI is not completely understood. Fetal immunity may play a role in controlling the infection and preventing LTI, although immune activation may also contribute to fetal immunopathology. In this study, we analyzed various molecular markers of T and B cell numbers in neonatal dried blood spots of 99 children with cCMV and 54 children without cCMV: δRec-ψJα signal joints on TCR excision circles, intron recombination signal sequence k-deleting element signal joints on Igκ-deleting recombination excision circles, genomic intron recombination signal sequence k-deleting element coding joint, genomic Vδ1-Jδ1, and Vδ2-Jδ1 rearrangements. Of this cohort, clinical symptoms at birth and LTI at 6 y of age were recorded. Neonates with cCMV had fewer TCR excision circles in their blood than non-infected controls. Furthermore, cCMV infection was associated with increased numbers of γδ T cells and B cells, and these numbers were positively correlated with CMV viral load in the dried blood spots. Infected children with a better long-term outcome had higher numbers of B cells at birth than those who developed LTI; no difference in B cell replication was observed. The potential protective role of B cells in controlling cCMV-related disease and the clinical value of this marker as a predictor of long-term outcome merit further evaluation.
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http://dx.doi.org/10.4049/jimmunol.1601182DOI Listing
January 2017