AimsDysfunction of nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate signalling is implicated in the pathophysiology of cognitive impairment. Zagociguat is a central... Show moreAimsDysfunction of nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate signalling is implicated in the pathophysiology of cognitive impairment. Zagociguat is a central nervous system (CNS) penetrant sGC stimulator designed to amplify nitric oxide-cyclic guanosine monophosphate signalling in the CNS. This article describes a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. MethodsIn this randomized crossover study, 24 healthy participants aged & GE;65 years were planned to receive 15 mg zagociguat or placebo once daily for 2 15-day periods separated by a 27-day washout. Adverse events, vital signs, electrocardiograms and laboratory tests were conducted to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and cerebrospinal fluid (CSF). Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco-electroencephalography, passive leg movement and biomarkers in blood, CSF and brain. ResultsTwenty-four participants were enrolled; 12 participants completed both treatment periods, while the other 12 participants completed only 1 treatment period. Zagociguat was well-tolerated and penetrated the blood-brain barrier, with a CSF/free plasma concentration ratio of 0.45 (standard deviation 0.092) measured 5 h after the last dose of zagociguat on Day 15. Zagociguat induced modest decreases in blood pressure. No consistent effects of zagociguat on other pharmacodynamic parameters were detected. ConclusionZagociguat was well-tolerated and induced modest blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound. Show less
To compare EEG-patterns after instillation of cyclopentolate versus placebo eye drops. Prospective, randomized, placebo-controlled, and observational pilot study is presented. Ophthalmology... Show moreTo compare EEG-patterns after instillation of cyclopentolate versus placebo eye drops. Prospective, randomized, placebo-controlled, and observational pilot study is presented. Ophthalmology outpatient clinic Dutch metropolitan hospital. Healthy 6- to 15-year-old volunteers with normal or low BMI requiring a cycloplegic refraction/retinoscopy. Randomized; 1 visit 2 drops cyclopentolate-1% and 1 visit 2 drops placebo (saline-0.9%). Single-blind: conducting researcher. Double blind: subjects, parents, clinical-neurophysiology staff, neurologist, and statistician. A 10-min baseline EEG-recording, drop-application, and follow-up to at least 45 min. Primary outcome: Detection of CNS changes, i.e. EEG-pattern changes, following two drops of cyclopentolate-1%. Secondary outcome: Determination of the extent of these pattern changes. Thirty-six cyclopentolate-1% saline-0.9% EEG registrations were made in 33 subjects; 18 males and 15 females. Three subjects were tested twice (interval 7 months). Nine out of fourteen (64%) of the 11- to 15-year-old children reported impaired memory, attention, alertness, as well as mind wandering following cyclopentolate. Drowsiness and sleep were seen in EEG-recordings of 11 subjects (33%) following cyclopentolate. We observed no drowsiness nor sleep during placebo recordings. The mean time to drowsiness was 23 min. Nine subjects arrived in stage-3 sleep but none arrived in REM-sleep. In subjects without sleep (N=24), significant changes compared to placebo-EEG were present for many leads and parameters. The main findings during awake eye-open recording were as follows: 1) a significant increase of temporal Beta-1,2 and 3-power, and 2) a significant decrease in: a) the parietal and occipital Alpha-2-power, b) the frontal Delta-1-power, c) the frontal total power, and d) the occipital and parietal activation synchrony index. The former finding reflects cyclopentolate uptake in the CNS, and the latter findings provide evidence for CNS suppression. Cyclopentolate-1% eye drops can affect the CNS and may cause altered consciousness, drowsiness, and sleep with concomitant EEG results in both young children and children in puberty. There is evidence that cyclopentolate has the potency to act as a short acting CNS depressant. Nevertheless, however, cyclopentolate-1% can safely be used in children and young adolescents. Show less
Soluble guanylate cyclase (sGC) and its product, cyclic guanosine monophosphate, play a role in learning and memory formation. Zagociguat (CY6463) is a novel stimulator of sGC being developed for... Show moreSoluble guanylate cyclase (sGC) and its product, cyclic guanosine monophosphate, play a role in learning and memory formation. Zagociguat (CY6463) is a novel stimulator of sGC being developed for the treatment of neurodegenerative disease. Single zagociguat doses of 0.3, 1, 3, 10, 20, 30, and 50 mg were administered once to healthy participants in a single-ascending-dose phase; then zagociguat 2, 5, 10, and 15 mg was administered q.d. for 14 days in a multiple-ascending-dose phase; and, finally, zagociguat 10 mg was administered once in both fed and fasted state in a food-interaction phase. Safety of zagociguat was evaluated by monitoring treatment-emergent adverse events, suicide risk, vital signs, electrocardiography, and laboratory tests. Pharmacokinetics of zagociguat were assessed through blood, urine, and cerebrospinal fluid sampling. Pharmacodynamic effects of zagociguat were evaluated with central nervous system (CNS) tests and pharmaco-electroencephalography. Zagociguat was well-tolerated across all doses evaluated. Zagociguat exposures increased in a dose-proportional manner. Median time to maximum concentration ranged from 0.8 to 5 h and mean terminal half-life from 52.8 to 67.1 h. CNS penetration of the compound was confirmed by cerebrospinal fluid sampling. Zagociguat induced up to 6.1 mmHg reduction in mean systolic and up to 7.5 mmHg reduction in mean diastolic blood pressure. No consistent pharmacodynamic (PD) effects on neurocognitive function were observed. Zagociguat was well-tolerated, CNS-penetrant, and demonstrated PD activity consistent with other sGC stimulators. The results of this study support further development of zagociguat. Show less
Pagan, L.; Yfanti, C.; Rijneveld, R.; Todd, M.; Jongste, P.; Feijen, J.J.; ... ; Rissmann, R. 2022
The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were... Show moreThe safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 ± 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (Tmax ) ~ 4 hours, geometric mean terminal half-life (t½) ~ 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (Emax ) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema Emax -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders. Show less
Pagan, L.; Yfanti, C.; Rijneveld, R.; Todd, M.; Jongste, P.; Feijen, J.J.; ... ; Rissmann, R. 2022
The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were... Show moreThe safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 +/- 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (T-max) similar to 4 hours, geometric mean terminal half-life (t1/2) similar to 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (E-max) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema E-max -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders. Show less
Saghari, M.; Gal, P.; Gilbert, S.; Yateman, M.; Porter-Brown, B.; Brennan, N.; ... ; Rissmann, R. 2022
The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were... Show moreThe safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 +/- 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (T-max) similar to 4 hours, geometric mean terminal half-life (t1/2) similar to 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (E-max) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema E-max -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders. Show less
Pagan, L.; Yfanti, C.; Rijneveld, R.; Todd, M.; Jongste, P.; Feijen, J.J.; ... ; Rissmann, R. 2021
Aim Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in... Show moreAim Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324 in healthy male participants. Methods This was a randomised, double-blind, placebo-controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004-11.475 mg h(-1) of STR-324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two-group, partial crossover design with four treatment periods separated by 1 month wash-out, and in part 2, 48 participants divided into three groups received either the active drug (1.25-11.25 mg h(-1)) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated. Results No clinically relevant changes in safety parameters were observed. All treatment-emergent adverse events were mild and transient. The pharmacokinetics of STR-324 could not be determined due to most concentrations being below quantifiable limits. STR-324 metabolite concentrations were measurable, showing dose proportionality of C-max and AUC(inf) with an estimated t(1/2) of 0.2-0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose-dependent. Conclusion STR-324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h(-1). Although pharmacokinetic characterisation of STR-324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed. Trial registry: EudraCT (2014-002402-21) and toetsingonline.nl (63085). Show less
Bakker, C.; Aart, J. van der; Labots, G.; Liptrot, J.; Cross, D.M.; Klaassen, E.S.; ... ; Groeneveld, G.J. 2021
Introduction HTL0018318 is a selective muscarinic M-1 receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer's disease. Clinically, HTL0018318... Show moreIntroduction HTL0018318 is a selective muscarinic M-1 receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer's disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g. donepezil). Objective We investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil. Methods This was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics. Results AEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] -3.1 to -0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI -3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5-5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other's pharmacokinetics. Conclusion HTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil. Show less
Aims HTL0009936 is a selective M-1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory... Show moreAims HTL0009936 is a selective M-1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF).Methods Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests.Results Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine.Conclusions HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement. Show less
Background: The cholinergic system and M-1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M-1 receptor partial agonist HTL0018318 is under... Show moreBackground: The cholinergic system and M-1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M-1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects.Methods: This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions.Results: HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (+/- 4.61) in younger adult subjects and 14.3 h (+/- 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes.Conclusion: Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. Show less
Aims HTL0018318 is a selective M-1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other... Show moreAims HTL0018318 is a selective M-1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses.Methods This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects.Results Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance.Conclusion HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias. Show less
Rijsbergen, M.; Rijneveld, R.; Todd, M.; Feiss, G.L.; Kouwenhoven, S.T.P.; Quint, K.D.; ... ; Poelgeest, M.I.E. van 2020
AIMS\nMETHODS\nRESULTS\nCONCLUSION\n To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous... Show moreAIMS\nMETHODS\nRESULTS\nCONCLUSION\n To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous intraepithelial lesions (HSIL).\nTwo randomized controlled trials in patients with external AGW and vulvar HSIL were conducted. Patients received topical omiganan 2.5% or placebo gel once daily for 12 weeks with a follow-up of 12 weeks. Safety and tolerability were monitored and pharmacodynamics and clinical efficacy of omiganan were assessed by analysing lesion count, size and viral load. Self-reported pain, itch and quality of life were assessed by an electronic diary and questionnaire.\nTwenty-four AGW and 12 vulvar HSIL patients were enrolled. All patients had a high treatment adherence (99%). No serious adverse events occurred and all adverse events (n = 27) were mild, transient and self-limiting. The treatment groups were not different in terms of safety and tolerability, lesion count and size, and patient-reported outcomes pain, itch and quality of life. Human papillomavirus load significantly reduced after 12 weeks of treatment with omiganan compared to placebo (-96.6%; 95% confidence interval -99.9 to -7.4%; P = .045) in AGW patients only.\nTopical omiganan appears to be safe in patients with AGW and vulvar HSIL and reduced human papillomavirus load after 12 weeks of treatment in AGW patients. Show less
Grievink, H.W.; Gal, P.; Ozsvar Kozma, M.; Klaassen, E.S.; Kuiper, J.; Burggraaf, J.; ... ; Moerland, M. 2020
using the Prevenar-13 vaccine. Twenty-four healthy male volunteers were vaccinated with Prevenar-13, either three times, twice or once in a double-blind, placebo-controlled, randomized single... Show moreusing the Prevenar-13 vaccine. Twenty-four healthy male volunteers were vaccinated with Prevenar-13, either three times, twice or once in a double-blind, placebo-controlled, randomized single center clinical study. Anti-pneumococcal wall, oxLDL and phosphorycholine antibody levels were measured at a fixed serum dilution, as well as circulating lipid levels over the course of 68 weeks. A significant increase in anti-oxLDL IgG and IgM was seen in the group receiving two doses six months apart compared to the placebo. However, these differences were not observed in the groups receiving a single dose, two doses one month apart, or three doses. This study shows that vaccination with Prevenar-13 does not result in robust anti-oxLDL IgM levels in humans. Further research would be required to test alternative pneumococcal-based vaccines, vaccination regimens or study populations, such as cardiovascular disease patients. Show less
Rijsbergen, M.; Rijneveld, R.; Todd, M.; Feiss, G.L.; Kouwenhoven, S.T.P.; Quint, K.D.; ... ; Poelgeest, M.I.E. van 2020
Aims To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous intraepithelial lesions (HSIL).... Show moreAims To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous intraepithelial lesions (HSIL). Methods Two randomized controlled trials in patients with external AGW and vulvar HSIL were conducted. Patients received topical omiganan 2.5% or placebo gel once daily for 12 weeks with a follow-up of 12 weeks. Safety and tolerability were monitored and pharmacodynamics and clinical efficacy of omiganan were assessed by analysing lesion count, size and viral load. Self-reported pain, itch and quality of life were assessed by an electronic diary and questionnaire. Results Twenty-four AGW and 12 vulvar HSIL patients were enrolled. All patients had a high treatment adherence (99%). No serious adverse events occurred and all adverse events (n =27) were mild, transient and self-limiting. The treatment groups were not different in terms of safety and tolerability, lesion count and size, and patient-reported outcomes pain, itch and quality of life. Human papillomavirus load significantly reduced after 12 weeks of treatment with omiganan compared to placebo (-96.6%; 95% confidence interval -99.9 to -7.4%;P =.045) in AGW patients only. Conclusion Topical omiganan appears to be safe in patients with AGW and vulvar HSIL and reduced human papillomavirus load after 12 weeks of treatment in AGW patients. Show less
Gal, P.; Klaassen, E.S.; Bergmann, K.R.; Saghari, M.; Burggraaf, J.; Kemme, M.J.B.; ... ; Edvardsson, N. 2020
Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca(2+)activated K+(K(Ca)2) channel blocker, prolonged the atrial effective... Show morePharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca(2+)activated K+(K(Ca)2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 +/- 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (C-max) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 +/- 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel K(Ca)2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion. Show less
Niemeyer-van der Kolk, T.; Assil, S.; Buters, T.P.; Rijsbergen, M.; Klaassen, E.S.; Feiss, G.; ... ; Moerland, M. 2020
Omiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a... Show moreOmiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a human model for proof-of-concept, and to explore the potential of OMN add-on treatment for viral skin diseases. Sixteen healthy volunteers received topical IMQ, OMN, or a combination of both for up to 4 days on tape-stripped skin. Skin inflammation was quantified by laser speckle contrast imaging and 2D photography, and molecular and cellular responses were analyzed in biopsies. IMQ treatment induced an inflammatory response of the skin. Co-treatment with OMN enhanced this inflammatory response to IMQ, with increases in perfusion (+17.1%; 95% confidence interval (CI) 5.6%-30%; P < 0.01) and erythema (+1.5; 95% CI 0.25%-2.83; P = 0.02). Interferon regulatory factor-driven and NF kappa B-driven responses following TLR7 stimulation were enhanced by OMN (increases in IL-6, IL-10, MXA, and IFN gamma), and more immune cell infiltration was observed (in particular CD4+, CD8+, and CD14+ cells). These findings are in line with the earlier mechanistic in vitro data, and support evaluation of imiquimod/OMN combination therapy in human papillomavirus-induced skin diseases. Show less
Background To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive... Show moreBackground To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI), we investigated whether a single dose of a monoaminergic drug (methylphenidate) improves executive functioning and whether a single dose of a cholinergic drug (galantamine) improves memory in VCI patients. Methods STREAM-VCI is a single-center, double-blind, three-way crossover trial. We included 30 VCI patients (Mini-Mental State Examination (MMSE) >= 16 and Clinical Dementia Rating score 0.5-1.0) with cerebrovascular pathology on MRI. All patients received single doses of methylphenidate (10 mg), galantamine (16 mg), and placebo in random order on three separate study visits. We used the NeuroCart (R), a computerized test battery, to assess drug-sensitive cognitive effects. Predefined main outcomes, measured directly after a single dose of a study drug, were (i) change in performance on the adaptive tracker for executive functioning and (ii) performance on the Visual Verbal Learning Test-15 (VVLT-15) for memory, compared to placebo. We performed mixed model analysis of variance. Results The study population had a mean age of 67 +/- 8 years and MMSE 26 +/- 3, and 9 (30%) were female. Methylphenidate improved performance on the adaptive tracker more than placebo (mean difference 1.40%; 95% confidence interval [CI] 0.56-2.25; p = 0.002). In addition, methylphenidate led to better memory performance on the VVLT-15 compared to placebo (mean difference in recalled words 0.59; 95% CI 0.03-1.15; p = 0.04). Galantamine did not improve performance on the adaptive tracker and led to worse performance on delayed recall of the VVLT-15 (mean difference - 0.84; 95% CI - 1.65, - 0.03; p = 0.04). Methylphenidate was well tolerated while galantamine produced gastrointestinal side effects in a considerable number of patients. Conclusions In this proof-of-principle study, methylphenidate is well tolerated and improves executive functioning and immediate recall in patients with VCI. Galantamine did not improve memory or executive dysfunction. Results might be influenced by the considerable amount of side effects seen. Show less
