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Little is known about how intranasally administered oxytocin reaches the brain and modulates social behavior and cognition. Pupil dilation is a sensitive index of attentional allocation and effort, and inter-individual variability in pupil diameter during performance of social-cognitive tasks may provide a better assessment of pharmacological effects on the brain than behavioral measures. Here, we leverage the close relationship between pupil and neural activity to inform our understanding of nose-to-brain oxytocin routes and possible dose–response relationships. To this end, we assessed pupil diameter data from a previously reported functional magnetic resonance imaging (fMRI) study under four treatment conditions—including two different doses of intranasal oxytocin using a novel Breath Powered nasal device, intravenous (IV) oxytocin, and placebo—and investigated the association with amygdala activation in response to emotional stimuli. The study used a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. A significant main effect of treatment condition on pupil diameter was observed. Posthoc tests revealed reduced pupil diameter after 8IU intranasal oxytocin compared to placebo, but no significant difference between 8IU intranasal oxytocin and either 24IU intranasal oxytocin or IV oxytocin treatment conditions. Analysis also showed a significant relationship between pupil diameter and right amygdala activation after 8IU intranasal oxytocin. Although there was no significant difference between 8IU intranasal oxytocin and IV oxytocin on right amygdala activity and pupil diameter, the significant difference between 8IU intranasal oxytocin and placebo is consistent with the hypothesis that oxytocin can travel to the brain via a nose-to-brain route.

Background: CD37, an antigen highly expressed in B-cell malignancies, served as the target in the LYMRIT-37-01 Part B (PARADIGME) and Part C studies employing a single intravenous injection of the radioimmunoconjugate 177Lu–lilotomab satetraxetan (Betalutin®). Methods: Patients with follicular lymphoma (FL), grades I–IIIa, who had received at least two previous lines of therapy and were refractory to at least one previous regimen with rituximab or an anti-CD20 agent, were included. They were randomized to receive either a 40 mg lilotomab pretreatment and an activity dosage of 15 MBq/kg Betalutin (“40/15” regimen) or 100 mg/m2 of lilotomab and 20 MBq/kg of Betalutin (“100/20” regimen). In total, 109 patients were enrolled and received Betalutin, 72 of whom received the 40/15 regimen and 28 received the 100/20 regimen. An additional heavily pretreated “special population” of nine patients received 40/12.5 (i.e., a reduced Betalutin dosage) due to low platelets and/or a previous autologous stem cell transplant. Part C was a small expansion cohort of four patients, all receiving the 40/15 regimen, and was designed to obtain supplementary pharmacokinetic data. Results: The efficacy analysis set comprised a total of 100 patients from the PARADIGME study. The overall response rates were 38.9% and 32.1%, and the complete response rates were 20.8% and 14.3% in the 40/15 and 100/20 groups, respectively. Correspondingly, the median response durations were 8.5 months and 3.4 months in the two groups. Hence, increasing the Betalutin activity dose by using the stronger protective CD37 pre-dosing (“100/20”) did not improve the therapeutic benefit. The most common grade ≥ 3 adverse events were hematologic, including neutropenia (11.5%) and thrombocytopenia (8.0%), with nadirs occurring around weeks 5–7 and recovery by week 11. Conclusions: A single-dose administration of Betalutin had a mild toxicity profile with a clinically relevant response rate. It represents a viable treatment alternative in FL patients who are not suitable for more toxic and long-lasting treatments. Trial Registration: This trial was registered at clinicaltrials.gov under #NCT 01796171.

Astatine-211 ( 211 At) has physical properties that make it one of the top candidates for use as a radiation source for alpha particle-based radionuclide therapy, also referred to as targeted alpha therapy (TAT). Here, we summarize the main results of the completed clinical trials, further describe ongoing trials, and discuss future prospects.

The neuropeptide oxytocin plays an evolutionarily conserved role in mammalian social behavior. Despite striking effects on animal social behavior after intracerebroventricular drug delivery, this delivery mode is impractical in humans. Intranasal oxytocin delivery provides a noninvasive alternative to increase central oxytocin activity, and has shown promise as a treatment for psychiatric illnesses. Intranasal oxytocin delivery is purported to increase central oxytocin concentrations via channels surrounding trigeminal and olfactory nerve fibers, which may facilitate increased activity at central oxytocin receptors. This report outlines the evidence for intranasal oxytocin delivery increasing central concentrations or activity, identifies current knowledge gaps and highlights future research opportunities. Recent efforts to enhance intranasal oxytocin delivery via improved intranasal delivery technology and dose-ranging studies are discussed.

Background: CD37, an antigen highly expressed in B-cell malignancies, served as the target in the LYMRIT-37-01 Part B (PARADIGME) and Part C studies employing a single intravenous injection of the radioimmunoconjugate [sup.177]Lu–lilotomab satetraxetan (Betalutin[sup.®]). Methods: Patients with follicular lymphoma (FL), grades I–IIIa, who had received at least two previous lines of therapy and were refractory to at least one previous regimen with rituximab or an anti-CD20 agent, were included. They were randomized to receive either a 40 mg lilotomab pretreatment and an activity dosage of 15 MBq/kg Betalutin (“40/15” regimen) or 100 mg/m[sup.2] of lilotomab and 20 MBq/kg of Betalutin (“100/20” regimen). In total, 109 patients were enrolled and received Betalutin, 72 of whom received the 40/15 regimen and 28 received the 100/20 regimen. An additional heavily pretreated “special population” of nine patients received 40/12.5 (i.e., a reduced Betalutin dosage) due to low platelets and/or a previous autologous stem cell transplant. Part C was a small expansion cohort of four patients, all receiving the 40/15 regimen, and was designed to obtain supplementary pharmacokinetic data. Results: The efficacy analysis set comprised a total of 100 patients from the PARADIGME study. The overall response rates were 38.9% and 32.1%, and the complete response rates were 20.8% and 14.3% in the 40/15 and 100/20 groups, respectively. Correspondingly, the median response durations were 8.5 months and 3.4 months in the two groups. Hence, increasing the Betalutin activity dose by using the stronger protective CD37 pre-dosing (“100/20”) did not improve the therapeutic benefit. The most common grade ≥ 3 adverse events were hematologic, including neutropenia (11.5%) and thrombocytopenia (8.0%), with nadirs occurring around weeks 5–7 and recovery by week 11. Conclusions: A single-dose administration of Betalutin had a mild toxicity profile with a clinically relevant response rate. It represents a viable treatment alternative in FL patients who are not suitable for more toxic and long-lasting treatments. Trial Registration: This trial was registered at clinicaltrials.gov under #NCT 01796171.

Background Cardiovascular complications are common in kidney transplant patients and calcification propensity of blood, measured as T 50 , is associated with cardiovascular outcomes. Paricalcitol supplementation affects calcium/phosphate homeostasis and may affect calcification propensity. To assess this hypothesis we measured T 50 in kidney transplant recipients participating in a randomized study comparing paricalcitol versus no treatment during the first year after kidney transplantation. Methods Stored serum samples from 76 kidney transplant recipients (paricalcitol n  = 37, no treatment n  = 39) were analyzed. Analyses were performed at inclusion (8 weeks after transplantation) and repeated one year after transplantation. Results There were no statistically significant differences in T 50 between the paricalcitol and placebo groups, neither at baseline ( p  = 0.56) nor at 1 year ( p  = 0.61). Also, there were no significant changes in T 50 over time in either group or when pooling all data ( p  <  0.20). In multivariate regression analysis, out of 16 potentially relevant covariates, comprising clinical and biochemical parameters, only plasma PTH and T 50 at baseline were significantly correlated to T 50 after one year. ( p  <  0.03 and p  < 0.01, respectively). Conclusions Calcium propensity measured as T 50 score remained unchanged with paricalcitol treatment in kidney transplant recipients, and was not changed over time during the study period of one year. Trial registration ClinicalTrials.gov, NCT01694160 , registered 23 September 2012.

The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) play important and interrelated roles in modulating mammalian social behaviour. While the OT system has received considerable research attention for its potential to treat psychiatric symptoms, comparatively little is known about the role of the AVP system in human social behaviour. To better understand the intraindividual stability of basal AVP, the present study assessed the reproducibility of basal plasma AVP concentrations. Basal plasma AVP was assessed at four sampling points separated by 8 days, on average, in 16 healthy adult males. Only one out of six comparisons revealed strong evidence for reproducibility of basal AVP concentrations (visit 2 vs. visit 4: r=0.8, p0.1). The concordance correlation coefficient [0.15, 95% CI (-0.55, 0.73)] also revealed poor overall reproducibility. Poor reliability of basal AVP concentrations suggests future work covarying AVP with trait markers should proceed with careful consideration of intraindividual fluctuations.

: CD37, an antigen highly expressed in B-cell malignancies, served as the target in the LYMRIT-37-01 Part B (PARADIGME) and Part C studies employing a single intravenous injection of the radioimmunoconjugate Lu-lilotomab satetraxetan (Betalutin ). : Patients with follicular lymphoma (FL), grades I-IIIa, who had received at least two previous lines of therapy and were refractory to at least one previous regimen with rituximab or an anti-CD20 agent, were included. They were randomized to receive either a 40 mg lilotomab pretreatment and an activity dosage of 15 MBq/kg Betalutin (\"40/15\" regimen) or 100 mg/m of lilotomab and 20 MBq/kg of Betalutin (\"100/20\" regimen). In total, 109 patients were enrolled and received Betalutin, 72 of whom received the 40/15 regimen and 28 received the 100/20 regimen. An additional heavily pretreated \"special population\" of nine patients received 40/12.5 (i.e., a reduced Betalutin dosage) due to low platelets and/or a previous autologous stem cell transplant. Part C was a small expansion cohort of four patients, all receiving the 40/15 regimen, and was designed to obtain supplementary pharmacokinetic data. The efficacy analysis set comprised a total of 100 patients from the PARADIGME study. The overall response rates were 38.9% and 32.1%, and the complete response rates were 20.8% and 14.3% in the 40/15 and 100/20 groups, respectively. Correspondingly, the median response durations were 8.5 months and 3.4 months in the two groups. Hence, increasing the Betalutin activity dose by using the stronger protective CD37 pre-dosing (\"100/20\") did not improve the therapeutic benefit. The most common grade ≥ 3 adverse events were hematologic, including neutropenia (11.5%) and thrombocytopenia (8.0%), with nadirs occurring around weeks 5-7 and recovery by week 11. A single-dose administration of Betalutin had a mild toxicity profile with a clinically relevant response rate. It represents a viable treatment alternative in FL patients who are not suitable for more toxic and long-lasting treatments. Trial Registration: This trial was registered at clinicaltrials.gov under #NCT01796171.

Background In active run-in trials, where patients may be excluded after a run-in period based on their response to the treatment, it is implicitly assumed that patients have individual treatment effects. If individual patient data are available, active run-in trials can be modelled using patient-specific random effects. With more than one trial on the same medication available, one can obtain a more precise overall treatment effect estimate. Methods We present a model for joint analysis of a two-sequence, four-period cross-over trial (AABB/BBAA) and a three-sequence, two-period active run-in trial (AB/AA/A), where the aim is to investigate the effect of a new treatment for patients with pain due to osteoarthritis. Results Our approach enables us to separately estimate the direct treatment effect for all patients, for the patients excluded after the active run-in trial prior to randomisation, and for the patients who completed the active run-in trial. A similar model approach can be used to analyse other types of run-in trials, but this depends on the data and type of other trials available. Limitations We assume equality of the various carry-over effects over time. Conclusions The proposed approach is flexible and can be modified to handle other designs. Our results should be encouraging for those responsible for planning cost-efficient clinical development programmes.

The objective was to study whether a yoghurt containing isolated soya protein with standardised levels of isoflavones, cotyledon soya fibres and soya phospholipids is more effective in lowering total and LDL-cholesterol than a placebo. One hundred and forty-three subjects were randomised to the soya group (n 69) or to the placebo (n 74). The mean baseline levels were 7·6 and 5·1mmol/l for total and LDL-cholesterol, respectively. Fasting serum lipoproteins were assessed five times during the 8-week intervention period, and 4 weeks thereafter. The results were analysed by a mixed model for unbalanced repeated measurements. During the intervention, there were highly significant differences in lipid-lowering effect in favour of the active soya intervention group compared with the control group. The significant differences were for total cholesterol (estimated mean difference 0·40mmol/l; P<0·001), LDL-cholesterol (0·39mmol/l; P<0·001), non-HDL-cholesterol (0·40mmol/l; P<0·001) and for the total:HDL-cholesterol ratio (0·23; P=0·005). There was no difference in the effects on HDL-cholesterol, triacylglycerols or homocysteine. The lipid-lowering effect occurred within 1–2 weeks of intervention, and was not due to weight loss. The safety profile for active soya was similar to the placebo group, except for gastrointestinal symptoms, which caused a significantly higher dropout rate (fourteen v. three subjects) among the subjects taking active soya.