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Aims: Intravenous high‐dose free methylprednisolone (MP) hemisuccinate is the primary treatment for an acute relapse in relapsing–remitting multiple sclerosis. However, it is inconvenient and its side effects are undesirable. Both dose and dosing frequency can be reduced by incorporating free MP in glutathione‐PEGylated liposomes, creating a slow‐release formulation with reduced toxicity and prolonged peripheral efficacy. This first‐in‐human study was designed to assess the safety, pharmacokinetics and pharmacodynamics of glutathione‐PEGylated liposomes containing MP (2B3–201). Methods: The first part was a double‐blind, three‐way cross over study in 18 healthy male subjects, receiving ascending doses of 2B3–201, active comparator (free MP) or placebo. Part 2 of the study was an open‐label infusion of 2B3–201 (different doses), exploring pretreatment with antihistamines and different infusion schedules in another 18 healthy male subjects, and a cross‐over study in six healthy female subjects. MP plasma concentrations, lymphocyte counts, adrenocorticotropic hormone, osteocalcin and fasting glucose were determined. Safety and tolerability profiles were assessed based on adverse events, safety measurements and central nervous system tests. Results: The most frequent recorded AE related to 2B3–201 was an infusion related reaction (89%). 2B3–201 was shown to have a plasma half‐life between 24 and 37 h and caused a prolonged decrease in the lymphocyte count, adrenocorticotropic hormone and osteocalcin, and a rise in fasting glucose. Conclusion: 2B3–201 is considered safe, with no clinically relevant changes in central nervous system safety parameters and no serious adverse events. In addition, 2B3–201 shows a long plasma half‐life and prolonged immunosuppressive effects. [ABSTRACT FROM AUTHOR]

O01 Serum IL-1RL1-A levels predict an eosinophilic subtype of asthma in preschool wheezing ch... M. E. Ketelaar 1, K. Van De Kant 2, F. N. Dijk 1, E. M. M. Klaassen 3, N. Grotenboer 4,... 1 University Medical Center Groningen, Beatrix Children's Hospital, Groningen Research Instit... B Correspondence b : Maria Elizabeth Ketelaar - m.e.ketelaar@student.rug.nl I Clinical and Translational Allergy i 2017, B 7(Suppl 2) b :O01 B Introduction b : Respiratory symptoms are common in preschool children. The children were divided into four groups - 10 children with scoliosis without asthma (Sc),10 children with scoliosis and asthma (AS), 10 children with moderate asthma (BA), 10 children with severe asthma (SA) and 10 healthy children (HC). B Keywords b : Preschool Wheezing, Respiratory Viruses, Asthma Exacerbation, Severity P09 Tele-monitoring decreases unscheduled outpatient visits in pediatric patients with severe... Mihai Craiu, Iustina Violeta Stan INSMC Alessandrescu-Rusescu, Bucharest, Romania B Correspondence b : Mihai Craiu - mcraiu@yahoo.com I Clinical and Translational Allergy i 2017, B 7(Suppl 2) b :P09 B Introduction b : Pediatric asthma patients originating from poor-resource areas experience a significant increase of unscheduled and emergency department visits and most of medical care for them is delivered in such a facility. [Extracted from the article]

Δ⁹-Tetrahydrocannabinol (THC) produces transient psychomimetic effects in healthy volunteers, constituting a pharmacological model for psychosis. The dopaminergic antagonist haloperidol has previously been shown to reduce these effects. This placebo-controlled, cross-over study in 49 healthy, male, mild cannabis users aimed to further explore this model by examining the effect of a single oral dose of olanzapine (with dopaminergic, serotonergic, adrenergic, muscarinergic and histaminergic properties) or two oral doses of diphenhydramine (histamine antagonist) on the effects of intrapulmonarily administered THC. Transient psychomimetic symptoms were seen after THC administration, as measured on the positive and negative syndrome scale (20.6% increase on positive subscale, p<0.001) and the visual analogue scale for psychedelic effects (increase of 10.7 mm on feeling high). Following the combination of THC and olanzapine, the positive subscale increased by only 13.7% and feeling high by only 8.7 mm. This reduction of THC effects on the positive subscale failed to reach statistical significance (p=0.066). However, one-third of the subjects did not show an increase in psychomimetic symptoms after THC alone. Within responders, olanzapine reduced the effects of THC on the positive subscale (p=0.005). Other outcome measures included pharmacokinetics, eye movements, postural stability, pupil/iris ratio, and serum concentrations of cortisol and prolactin. [ABSTRACT FROM AUTHOR]

Background. A reliable asthma diagnosis is challenging in preschool wheezing children. As inhaled corticosteroids (ICS) are more effective in asthmatics than in children with transient wheeze, an ICS responsemight be helpful in early asthma diagnosis. Methods. 175 children (aged two-four years) with recurrent wheeze received 200 μg Beclomethasone extra-fine daily for eight weeks. Changes in Exhaled Breath Condensate (EBC) biomarkers (pH, interleukin (IL)-1α, IL-2, IL-4, IL-5, IL-10, IFN-γ, sICAM, and CCL-11), Fractional exhaled Nitric Oxide (FeNO), airway resistance, and symptoms were assessed. At six years of age a child was diagnosed as transient wheezer or asthmatic. Adjusted logistic regression analysis was performed with multiple testing correction. Results. 106 transient wheezers and 64 asthmatics were analysed at six years of age. Neither changes in EBC biomarkers, nor FeNO, airway resistance, or symptoms during ICS trial at preschool age were related to asthma diagnosis at six years of age. However, asthmatics had more airway symptoms before the start of the ICS trial than transient wheezers (P < 0.01). Discussion. Although symptom score in preschool wheezing children at baseline was associated with asthma at six years of age, EBC biomarkers, airway resistance, or symptom response to ICS at preschool age could not predict asthma diagnosis at six years of age. [ABSTRACT FROM AUTHOR]

Presents information on a study which focused on timing-based servo technology developed specifically for linear tape drives. Discussion on timing-based servo patterns; Servowriting head; Pattern optimization.

Abstract Background Asthma is the most common chronic disease in childhood, characterized by chronic airway inflammation. There are problems with the diagnosis of asthma in young children since the majority of the children with recurrent asthma-like symptoms is symptom free at 6 years, and does not have asthma. With the conventional diagnostic tools it is not possible to differentiate between preschool children with transient symptoms and children with asthma. The analysis of biomarkers of airway inflammation in exhaled breath is a non-invasive and promising technique to diagnose asthma and monitor inflammation in young children. Moreover, relatively new lung function tests (airway resistance using the interrupter technique) have become available for young children. The primary objective of the ADEM study (Asthma DEtection and Monitoring study), is to develop a non-invasive instrument for an early asthma diagnosis in young children, using exhaled inflammatory markers and early lung function measurements. In addition, aetiological factors, including gene polymorphisms and gene expression profiles, in relation to the development of asthma are studied. Methods/design A prospective case-control study is started in 200 children with recurrent respiratory symptoms and 50 control subjects without respiratory symptoms. At 6 years, a definite diagnosis of asthma is made (primary outcome measure) on basis of lung function assessments and current respiratory symptoms ('golden standard'). From inclusion until the definite asthma diagnosis, repeated measurements of lung function tests and inflammatory markers in exhaled breath (condensate), blood and faeces are performed. The study is registered and ethically approved. Discussion This article describes the study protocol of the ADEM study. The new diagnostic techniques applied in this study could make an early diagnosis of asthma possible. An early and reliable asthma diagnosis at 2–3 years will have consequences for the management of the large group of young children with asthma-like symptoms. It will avoid both over-treatment of children with transient wheeze and under-treatment of children with asthma. This might have a beneficial influence on the prognosis of asthma in these young children. Besides, insight into the pathophysiology and aetiology of asthma will be obtained. Trial registration This study is registered by clinicaltrials.gov (NCT00422747).

NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human, randomized, double-blind, placebo-controlled study, which evaluated the safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects. Single-ascending doses (50-1,600 mg) were administered in a (partial) cross-over design; multiple-ascending doses (200-600 mg q.d.; 400 mg b.i.d.) were administered in a parallel design. Differences in pharmacokinetics between males/females and fed/fasted states were evaluated. Pharmacodynamic effects were evaluated using muscle velocity recovery cycles (MVRC) and analyzed using mixed-effects modeling. NMD670 was generally safe and well-tolerated in healthy subjects, with the only dose-related adverse event being myotonia occurring at the highest dose levels tested (single dose of 1,200, and 1,600 mg). Moreover, NMD670 significantly increased the following MVRC parameters after a single dose of 1,200 mg compared with placebo: early supernormality (estimated difference (ED) 2.04; 95% confidence interval (CI) 0.379, 3.70; P = 0.0242); early supernormality after 5 conditioning stimuli (ED 2.51; 95%CI 0.599, 4.41; P = 0.0177); supernormality at 20 ms (ED 2.78; 95%CI 1.377, 4.181; P = 0.0021). Importantly, the results of this study indicate pharmacological target engagement at well-tolerated dose levels in healthy subjects; firstly, because myotonia was an expected exaggerated on-target pharmacological effect, and secondly, because the effects on MVRC indicate increased muscle cell excitability. This study in healthy subjects indicates proof-of-mechanism and provides a solid base for translation to patients with neuromuscular diseases., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression., Objective: The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients., Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160μg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μg on Day 1, 40μg on Day 2, 80μg on Days 3-7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests., Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2-AR effects were observed with clenbuterol., Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS.

The development of pharmacological therapies for mitochondrial diseases is hampered by the lack of tissue-level and circulating biomarkers reflecting effects of compounds on endothelial and mitochondrial function. This phase 0 study aimed to identify biomarkers differentiating between patients with mitochondrial disease and healthy volunteers (HVs). In this cross-sectional case-control study, eight participants with mitochondrial disease and eight HVs matched on age, sex, and body mass index underwent study assessments consisting of blood collection for evaluation of plasma and serum biomarkers, mitochondrial function in peripheral blood mononuclear cells (PBMCs), and an array of imaging methods for assessment of (micro)circulation. Plasma biomarkers GDF-15, IL-6, NT-proBNP, and cTNI were significantly elevated in patients compared to HVs, as were several clinical chemistry and hematology markers. No differences between groups were found for mitochondrial membrane potential, mitochondrial reactive oxygen production, oxygen consumption rate, or extracellular acidification rate in PBMCs. Imaging revealed significantly higher nicotinamide-adenine-dinucleotide-hydrogen (NADH) content in skin as well as reduced passive leg movement-induced hyperemia in patients. This study confirmed results of earlier studies regarding plasma biomarkers in mitochondrial disease and identified several imaging techniques that could detect functional differences at the tissue level between participants with mitochondrial disease and HVs. However, assays of mitochondrial function in PBMCs did not show differences between participants with mitochondrial disease and HVs, possibly reflecting compensatory mechanisms and heterogeneity in mutational load. In future clinical trials, using a mix of imaging and blood-based biomarkers may be advisable, as well as combining these with an in vivo challenge to disturb homeostasis., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aim: We assessed whether total sleep deprivation (TSD) in combination with pain tests yields a reliable method to assess altered pain thresholds, which subsequently may be used to investigate (novel) analgesics in healthy subjects., Methods: This was a two-part randomized crossover study in 24 healthy men and 24 women. Subjects were randomized 1:1 to first complete a day of nonsleep-deprived nociceptive threshold testing, followed directly by a TSD night and morning of sleep-deprived testing, or first complete the TSD night and morning sleep-deprived testing, returning 7 days later for a day of nonsleep-deprived testing. A validated pain test battery (heat, pressure, electrical burst and stair, cold pressor pain test and conditioned pain modulation [CPM] paradigm) and sleep questionnaires were performed., Results: Subjects were significantly sleepier after TSD as measured using sleepiness questionnaires. Cold pressor pain tolerance (PTT, estimate of difference [ED] -10.8%, 95% CI -17.5 to -3.6%), CPM PTT (ED -0.69 mA, 95% CI -1.36 to -0.03 mA), pressure PTT (ED -11.2%, 95% CI -17.5% to -4.3%) and heat pain detection thresholds (ED -0.74 °C, 95% CI -1.34 to -0.14 °C) were significantly decreased after TSD compared to the baseline morning assessment in the combined analysis (men + women). Heat hyperalgesia was primarily driven by an effect of TSD in men, whereas cold and pressure hyperalgesia was primarily driven by the effects of TSD observed in women., Conclusions: TSD induced sex-dependent hyperalgesia on cold, heat and pressure pain, and CPM response. These results suggest that the TSD model may be suitable to evaluate (novel) analgesics in early-phase drug studies., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

TAK-653 is a novel AMPA receptor positive allosteric modulator in clinical development for the treatment of major depressive disorder (MDD). This study aimed to measure the functional pharmacodynamic central nervous system (CNS) effects of TAK-653. A randomised, double-blind, placebo-controlled, three-way crossover (placebo, TAK-653 0.5 mg and 6 mg) study with 24 healthy volunteers was performed. NeuroCart tests consisting of body sway (BS), saccadic peak velocity (SPV), smooth pursuit eye movements (SP), adaptive tracking (AT), Bowdle and Bond and Lader Visual Analogue Scales (B-VAS and BL-VAS) and Stroop test were performed pre-dose and 3.5 and 4 h post-dose. Data were analysed using a mixed model analysis of covariance with baseline as covariate. It was found that TAK-653 did not affect BS and subjective drug effects as measured by B-VAS and BL-VAS at either dose level. TAK-653 0.5 mg increased SPV (degrees/second) (19.49 [5.98, 32.99], P = 0.02) and affected Stroop difference in reaction time between correct congruent and correct incongruent answers and number of correct responses in incongruent trials (22.0 [4.0, 40.0], P = 0.05 and -0.3 [-0.5, -0.1], P = 0.02, respectively). TAK-653 6 mg improved AT (%) (1.68 [0.51, 2.84], P = 0.02) and increased SPV (degrees/s) (15.40 [1.91, 28.90], P = 0.06) and SP (%) (2.32 [0.37, 4.27], P = 0.05). Based on these findings it can be concluded that TAK-653 demonstrated a psychostimulant-like pharmacodynamic profile on the NeuroCart consistent with previously reported increase of cortical excitability following Transcranial Magnetic Stimulation (TMS) of the human motor cortex., (© 2022. The Author(s).)

Background: Topical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be a potential novel treatment for cutaneous warts., Objectives: To assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT., Methods: Treatment with ICVT was assessed for efficacy, safety and tolerability in a single- centre, randomized, double-blind, placebo-controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed-model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643., Results: Wart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (-3·0 mm, 95% confidence interval -4·9 to -1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (-94%, 95% confidence interval -100 to -19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts., Conclusions: This study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts., (© 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Purpose: The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS)., Methods: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements., Findings: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo. Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: DNA viruses such as HPV rely on K + influx for replication. Both digoxin and furosemide inhibit the K + influx by interacting with cell membrane ion co-transporters (Na + /K + -ATPase and Na + -K + -2Cl - co-transporter-1, respectively). We therefore hypothesized that these two compounds in a topical formulation may be valuable in the treatment of HPV-induced warts. This new approach is called Ionic Contra-Viral Therapy (ICVT)., Objective: To evaluate systemic exposure, safety and tolerability of ICVT with a combination of furosemide and digoxin after repeated topical application in subjects with common warts. Furthermore, we aimed to evaluate pharmacodynamics effects of ICVT., Methods: Twelve healthy subjects with at least four common warts on their hands were included in the study and treated with a fixed dose of 980 mg topical gel containing 0.125% (w/w) digoxin and 0.125% (w/w) furosemide for 7 consecutive days on their lower back to assess safety and systemic exposure. Two warts were treated with 10 mg each and two served as negative controls to obtain preliminary evidence of treatment effect., Results: ICVT was well tolerated topically, and there was no evidence of systemic exposure of digoxin or furosemide. There were no clinical relevant safety findings and no serious adverse events (SAEs). A rapid and statistically significant reduction in diameter, height and volume of the warts was already observed at day 14., Conclusion: ICVT was found to be safe for administration to humans and 7 days of active treatment showed a statistical significant wart reduction compared to untreated control lesions, clearly indicating pharmacological activity., (© 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Aim: Xen2174 is a synthetic 13-amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects., Methods: This was a randomized, blinded, placebo-controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks)., Results: Twenty-five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration-time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post-lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg-placebo (95% confidence interval), 22.2% (-5.0%, 57.1%); P = 0.1131]., Conclusions: At the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed., (© 2016 The British Pharmacological Society.)

Background: Aberrant toll-like receptors (TLRs) 7, 8, and 9 activation by self-nucleic acids is implicated in immune-mediated inflammatory diseases (IMIDs) such as psoriasis. In preclinical IMID models, blocking TLR-activation reduced disease severity. IMO-8400 is a first-in-class, oligonucleotide-based antagonist of TLRs 7, 8, and 9. We evaluated the short-term safety and proof-of-concept for efficacy of IMO-8400 in a first-in-patient phase 2 trial., Methods: Forty-six psoriasis patients were randomly assigned to IMO-8400 in four dose levels or placebo for 12weeks. Post-treatment follow-up was seven weeks. Primary outcome was incidence of adverse events. Secondary, exploratory outcomes included changes in psoriasis area and severity index (PASI)., Results: IMO-8400 across all dose levels did not cause any serious or severe adverse events. The most common treatment-related adverse events were dose-dependent injection-site reactions. All IMO-8400 groups showed clinical improvement, but a clear dose-response relationship and statistically significant differences with placebo were not observed (P=0.26). Eleven (38%) of 29 subjects on IMO-8400 achieved ≥50% PASI-reduction, compared to 1 (11%) of 9 subjects on placebo. Five (17%) and 2 (7%) IMO-8400-treated subjects achieved PASI-75 and PASI-90, respectively, compared to none on placebo., Conclusions: Short-term IMO-8400-treatment was well tolerated and reduced psoriasis severity. These findings warrant further investigation of endosomal TLR-antagonism as a therapeutic approach in psoriasis and other TLR-mediated IMIDs., Trial Registration: EudraCT 2013-000164-28 and Clinicaltrials.govNCT01899729., (Copyright © 2016 Elsevier Inc. All rights reserved.)

ISIS 388626 is an antisense sodium-glucose cotransporter 2 (SGLT2) inhibitor designed to treat type 2 diabetes mellitus by induction of glucosuria. ISIS 388626 was demonstrated to be safe and effective in preclinical trails in several species. We undertook the present study to evaluate the safety and efficacy of 13 weekly doses of 50, 100, and 200 mg of ISIS 388626 in humans. ISIS 388626 increased 24-hour urinary glucose excretion dose dependently with 508.9 ± 781.45 mg/day in the 100-mg and 1299.8 ± 1833.4 mg/day in the 200-mg cohort, versus 88.7 ± 259.29 mg/day in the placebo group. ISIS 388626 induced a reversible increase in serum creatinine, with the largest effect after eight doses of ISIS 388626 (200 mg; 0.38 ± 0.089 mg/dl; 44% increase over baseline). Three subjects were discontinued as a result of creatinine increases. The renal clearance test revealed no indications for impairment of glomerular filtration or renal perfusion. The creatinine increases were accompanied by a rise in the levels of urinary renal damage markers [β-2-microglobulin (B2M), total protein, kidney injury molecule (KIM1), α-glutathione S-transferase (aGST), N-acetyl-β-(d)-glucosaminidase (NAG)]. Other treatment-related adverse events included mild injection site reactions occurring in 8-19% of the subjects. In conclusion, ISIS 388626 treatment induced glucosuria at a dose level of 200 mg/week. This intended pharmacological effect was small, amounting to approximately 1% of the total amount of filtered glucose. Changes in serum and urinary markers were indicative of transient renal dysfunction, most probably of tubular origin. Whether the glucosuria is caused by specific SGLT2 inhibition or general tubular dysfunction or a combination remains uncertain., (Copyright © 2016 by The Author(s).)

The psychomimetic effects that occur after acute administration of ketamine can constitute a model of psychosis and antipsychotic drug action. However, the optimal dose/concentration has not been established and there is a large variety in outcome measures. In this study, 36 healthy volunteers (21 males and 15 females) received infusions of S(+)-ketamine or placebo to achieve pseudo-steady state concentrations of 180 and 360 ng/mL during two hours. The target of 360 ng/mL induced increasingly more intensive effects than expected, and the targets were subsequently reduced to 120 and 240 ng/mL, which were considered tolerable. There was a clear, concentration-dependent psychomimetic effect as shown on all subscales of the positive and negative syndrome scale (e.g. positive subscale +43.7%, 95%CI 34.4-53.7%, p < 0.0001 for 120 ng/mL and +70.5%, 95%CI 59.0-82.8%, p < 0.0001 for 240 ng/mL) and different visual analogue scales. The startle reflex was inhibited (prepulse inhibition) by both main target concentrations to a similar extent, suggesting a maximum effect. Ketamine was found to constitute a robust model for induction of psychomimetic symptoms and the optimal concentration range for a drug interaction study would be between 100 and 200 ng/mL., (© The Author(s) 2015.)

Background/aims: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test., Methods: In 40 children referred for an oral clonidine test, blood samples were drawn for clonidine and GH. Vital statistics and sedation scores were recorded until 210 min post-dose. We explored the relationship between clonidine concentrations and effects such as GH peak and blood pressure., Results: Of 40 participants, 5 children were GH deficient. Peak clonidine concentrations of 0.846 ± 0.288 ng/ml were reached after 1 h. Serum levels declined slowly, with concentrations of 0.701 ± 0.189 ng/ml 210 min post-dose. A large interindividual variation of serum levels was observed. During the procedure, systolic blood pressure dropped by 12.8%, diastolic blood pressure by 19.7% and heart rate by 8.4%. Moderate sedation levels were observed. Concentration-effect modeling showed that the amount of GH available for secretion as determined by previous bursts was an important factor influencing GH response., Conclusion: Clonidine concentrations during the test were higher than necessary according to model-based predictions. A lower clonidine dose may be sufficient and may produce fewer side effects., (Copyright © 2013 S. Karger AG, Basel.)

Background: Ketamine has previously been shown to induce delusion-like or referential beliefs, both acutely in healthy volunteers and naturalistically among nonintoxicated users of the drug. Delusions are theoretically underpinned by increased superstitious conditioning or the erroneous reinforcement of random events., Materials and Methods: Using a novel and objectively measured superstitious conditioning task, experiment 1 assessed healthy volunteers before and during placebo (n = 16), low-dose (n = 15), and high-dose ketamine (n = 16) under randomized and double-blind conditions. Experiment 2 used the same task to compare ketamine users (n = 18), polydrug controls (n = 19), and nondrug-using controls (n = 17)., Results: In experiment 1, ketamine produced dose-dependent psychotomimetic effects but did not cause changes in superstitious conditioning. Experiment 2 found increased levels of superstitious conditioning among ketamine users compared to polydrug and nondrug-using controls, respectively, as evidenced by both objective task responses and subjective beliefs following the task., Conclusions: Results indicate that chronic but not acute exposure to ketamine may increase the propensity to adopt superstitious conditioning. These findings are discussed in terms of acute and chronic ketamine models of delusion-like belief formation in schizophrenia.

Acute administration of the N-methyl-D-aspartate receptor antagonist ketamine induces schizophrenia-like symptoms in healthy volunteers; furthermore, a window on ketamine's chronic effects is provided by regular recreational users. The current study utilized both acute ketamine administration in healthy volunteers and chronic ketamine abusers to investigate semantic processing, one of the key cognitive deficits in schizophrenia. Semantic processing was examined using a semantic priming paradigm. In experiment 1, acute effects of low (75 ng/mL) and high (150 ng/mL) ketamine doses were compared in a placebo-controlled double-blind independent group design with 48 participants. In experiment 2, 19 regular recreational ketamine users were compared with 19 ketamine-naive polydrug controls and 26 non-drug-using controls. In both experiments, semantic priming parameters were manipulated to distinguish between ketamine's effects on (1) automatic and strategic processing and (2) the facilitation and inhibition components of semantic priming for strongly (directly) related primes and targets. Acute effects of ketamine on semantic priming for weakly (indirectly) related primes and targets were also assessed in experiment 1. Acutely, ketamine impaired the employment of strategic mechanisms but not automatic processing within both the direct and indirect semantic priming tasks. Acute ketamine administration also induced clear schizophrenia-like symptoms. Schizotypy traits in the cognitive and perceptual domains tended to correlate with increased semantic priming in long-term ketamine users. In summary, acute and chronic ketamine-induced changes partially mirrored the findings on semantic priming in schizophrenia.

Background: New strategies are required to optimize care in increasing numbers of chronic heart failure patients. The aim of this randomised trial was to evaluate a remote guidance system., Methods: Intervention group patients received a home TV-channel providing educational materials. Tele-guidance was performed by a Medical Service Centre. Control group patients were followed by cardiologists and HF-nurses. Primary endpoints were total days in hospital for all causes and days alive and out of hospital. Secondary endpoints were: quality of life and knowledge of disease and self care., Results: 214 patients were enrolled, median age was 66 years, 89% had systolic LV dysfunction, and 90% were in NYHA class II or III. The mean LVEF was 31%. Over a mean follow-up duration of 288 days, there were 199 hospital admissions in 105 patients. Comparison of the groups revealed no differences for the primary outcomes or for QoL or self care behaviour. Knowledge about heart failure however, increased significantly more in the Intervention group (p<0.001)., Conclusion: Tele-guidance may play a role in the management of heart failure patients since it takes over some of the tasks of HF-nurses. This may facilitate delivery of optimal care to more patients with the same level of experienced staff.

The relatively high coefficient of friction of silicone elastomers can limit the range of applications of these materials. A liquid silicone rubber top coat can be used to improve surface friction of silicone elastomer parts. It can be applied using conventional coating methods. The performance benefits it offers and potential product applications are described.

The effects of selenium supplementation on mastitis parameters in milk and on glutathione peroxidase (GPx) levels in blood were evaluated. Fifty-five Estonian dairy cows were allocated to selenium-supplemented (n=39) and nonsupplemented (n=16) groups. The supplemented group received 0.2 ppm organic selenium in the form of selenium yeast in their diet daily for 8 weeks. The nonsupplemented cows received their standard diet with no selenium supplementation. Mastitis parameters (i.e., bacteriologic findings and somatic cell count, N-acetyl-beta-D-glucosaminidase, and bovine serum albumin concentration) and GPx levels were monitored. The increase in the activity of GPx was significantly (P<.001) greater in selenium-supplemented cows than in nonsupplemented ones. Milk samples from each quarter were examined before and 8 weeks after initiation of the study. The proportion of quarters still pathogen-free after 8 weeks was significantly (P<.01; odds ratio [OR]=9.7) higher in selenium-supplemented cows than in nonsupplemented cows. However, when quarters milk-tested as pathogen-infected at the start of the study were reexamined after 8 weeks, there was no significant (P=.14; OR 3.6) difference in the proportion of pathogen-free quarters between selenium-supplemented cows and nonsupplemented cows. Differential positive rate (Youden's index) revealed that individual quarters were more prone to be infected by pathogens when the blood GPx activities in cows were below the cutoff value of 3.3 microkat/g hemoglobin than when GPx activity was above this value. It was concluded that selenium supplementation in cows with low GPx activity seems to support udder defense mechanisms that favor reduction of the incidence of new mastitis cases.

Background: Although knowledge concerning the impact of acne vulgaris on quality of life has increased in recent years, relatively few studies have assessed the effect of a change in clinical severity on psychosocial state., Objective: Assessment of the effect of a change in clinical acne severity on psychosocial state., Methods: This was investigated by means of questionnaires and clinical assessments by acne patients and dermatologists. Fifty females with mild to moderate facial acne were seen before and after a 9-month treatment with oral contraceptives., Results: The results showed a great variability in psychosocial impairment between individuals. After 9 months, a significant reduction in clinical severity was seen overall which did not relate to the significant improvements in self-esteem, stability of self-esteem and acceptance of appearance., Conclusion: Perceived psychosocial impairment is individually based, is greater in women who subjectively overrate their acne and does not relate to clinical improvement., (Copyright 2001 S. Karger AG, Basel)

This study aimed to assess the role of specific human papillomavirus type 16 (HPV-16) variants, in combination with p53 codon 72 polymorphism genotypes, in cervical carcinogenesis. An initial sequence analysis of HPV-16 long control, E6 and E7 regions of 53 well-defined cervical samples containing HPV-16 revealed that a T to G transition at nucleotide position 350 within the E6 open reading frame was the most common variation, the frequency of which seemed to decrease with increasing severity of the lesion. Therefore, a total of 246 cervical samples of residents of The Netherlands was specifically analysed for HPV-16 350G/T variants and/or p53 codon 72 genotypes. These comprised HPV-negative normal cervical scrapes (n=40), normal cervical scrapes containing HPV-16 (n=46), scrapes containing HPV-16 from women with abnormal cervical cytology participating in a non-intervention follow-up study without (n=38) and with (n=51) a histologically proven cervical intraepithelial neoplasia (CIN) III lesion at the end of the study, and cervical squamous cell carcinomas (n=71). Neither specific HPV-16 350G/T variants nor specific p53 genotypes were associated with a higher risk of developing CIN III or cervical cancer. However, HPV-16 350T variants were significantly over-represented in p53 Arg homozygous women with cervical cancer. This suggests that, in p53 Arg/Arg women, infection with HPV-16 350T variants confers a higher risk of cervical cancer.

The secondary structures of human hY1 and hY5 RNAs were determined using both chemical modification techniques and enzymatic structure probing. The results indicate that both for hY1 and for hY5 RNA the secondary structure largely corresponds to the structure predicted by sequence alignment and computerized energy-minimization. However, some important deviations were observed. In the case of hY1 RNA, two regions forming a predicted helix appeared to be single-stranded. Furthermore, the pyrimidine-rich region of hY1 RNA appeared to be very resistant to reagents under native conditions, although it was accessible to chemical reagents under semi-denaturing conditions. This may point to yet unidentified tertiary interactions for this region of hY1 RNA. In the case of hY5 RNA, two neighbouring internal loops in the predicted structure appeared to form one large internal loop.