Summary Background Childhood obesity is a major public health concern with limited treatment options. Objective The aim of this study was to assess safety, tolerability, pharmacokinetics, and pharmacodynamics during short‐term treatment with liraglutide in children (7‐11 y) with obesity. Methods In this randomized, double‐blind, placebo‐controlled trial, 24 children received at least one dose of once‐daily subcutaneous liraglutide (n = 16) or placebo (n = 8) starting at 0.3 mg with weekly dose escalations up to 3.0 mg or maximum tolerated dose, and 20 children completed the trial (14 in the liraglutide group and six in the placebo group). The primary endpoint was the number of adverse events. Results Baseline characteristics (mean ± standard deviation) included the following: age 9.9 ± 1.1 years, weight 71.5 ± 15.4 kg, and 62.5% male. Thirty‐seven adverse events were reported in nine liraglutide‐treated participants (56.3%) versus 12 events in five placebo‐treated participants (62.5%). Most adverse events were mild in severity, three were of moderate severity, and none were severe. Gastrointestinal disorders were the most frequently reported events occurring in 37.5% of liraglutide‐treated participants compared with placebo (12.5%). Six asymptomatic hypoglycaemic episodes occurred in five participants of whom four were liraglutide treated. Liraglutide exposure was consistent with dose proportionality. Body weight was the only covariate to significantly impact exposure. A significant reduction in body mass index (BMI) Z score from baseline to end of treatment (estimated treatment difference: −0.28; P = 0.0062) was observed. Conclusion Short‐term treatment with liraglutide in children with obesity revealed a safety and tolerability profile similar to trials in adults and adolescents with obesity, with no new safety issues.

In our department, gold sodium thiosulfate has become the 2nd most common allergen in routinely patch tested dermatitis patients, with a rate around 10%. Test reactions to this compound often appear late, sometimes so late that active sensitization may be suspected. This study was performed to study the time course of the allergic reaction to gold sodium thiosulfate and to elucidate whether late test reactions mean active sensitization. 10 patients with contact allergy to gold sodium thiosulfate (0.5% pet.) were retested epicutaneously (e.c.) and intracutaneously (i.c.) with dilution series. The clinical course was followed for 2 months with initially short intervals, later more extended. During the entire study, 26 positive e.c. reactions were diagnosed. Within the 1st week, 17 (65%) were recorded. 12 reactions (46% of 26) were noted at the ordinary reading, 3 days after test application. After 10 days, another 9 reactions (35%) appeared. The patients with the latter reactions also had positive test reactions within the 1st week. After 2 months, 9 reactions remained. Out of 30 i.c. tests applied, 25 became positive within 1 week. 19 (76%) of these reactions changed in morphology from thin infiltrates to deep nodules. Another 4 nodules appeared in patients with previous negative i.c. tests. All 23 nodules remained after 2 months. E.c. and i.c. test reactions to gold sodium thiosulfate are long-lasting. Positive patch test reactions emerging after 10 days do not automatically imply active sensitization. To diagnose contact allergy to gold sodium thiosulfate, the ordinary reading at day 3 is insufficient; even reading at 1 week is insufficient and must be supplemented by a reading at 3 weeks. All the i.c. test reactions, however, appeared within 1 week and, in several, a dermal nodule was formed.

Knowledge concerning the molecular mechanisms governing the influence of non-coding RNAs on protein production has emerged rapidly during the past decade. Today, two main research areas can be identified, one oriented toward the use of artificially introduced siRNAs for manipulation of gene expression, and the other one focused on the function of endogenous miRNAs. In both cases, the active molecule consists of a ∼20-nucleotide-long RNA duplex. In the siRNA case, improved systemic stability is of central interest for its further development toward clinical applications. With respect to miRNA processing and function, understanding its influence on mRNA targeting and the silencing ability of individual miRNAs, e.g., under pathological conditions, remains a scientific challenge. In the present study, a model system is presented where the influence of the two clinically used anticancer drugs, cisplatin and oxaliplatin, on siRNA's silencing capacity has been evaluated. More specifically, siRNAs targeting the 3' UTR region of Wnt-5a mRNA (NM_003352) were constructed, and the biologically active antisense RNA strand was pre-platinated. Platinum adducts were detected and characterized by a combination of gel electrophoresis and MALDI-MS techniques, and the silencing capacity was evaluated in cellular luciferase-expressing systems using HB2 cells. Data show that platination of the antisense strand of the siRNAs results in adducts with protection against hydrolytic cleavage in the proximity of the platination sites, i.e., with altered degradation patterns compared to native RNAs. The MALDI-MS method was successfully used to further identify and characterize platinated RNA, with the naturally occurring platinum isotopic patterns serving as sensitive fingerprints for metalated sites. Expression assays all confirm biological activity of antisense-platinated siRNAs, here with platination sites located outside of the seed region. A significant reduction of silencing capacity was observed as a general trend, however. Of the two complexes studied, oxaliplatin exhibits the larger influence, thus indicating subtle differences between the abilities of cis- and oxaliplatin to interfere with si- and miRNA processing.

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Wnt-5a is a secreted glycoprotein which has been shown to be involved in the regulation of cell adhesion and motility, processes which are of importance in metastasis formation by cancer cells. We here present an initial study aiming at evaluating whether small interfering RNA (siRNA) in combination with cisplatin can be used to modulate protein expression levels under in vitro conditions. For this purpose, an AU-rich region corresponding to the initial 260 bases of the Wnt-5a 3' untranslated region was chosen as the target. The effect of four different siRNAs was evaluated by analysis of protein suppression levels in rabbit reticulocyte lysate (RRL) and an immortalized noncancerous mammary epithelial (HB2) cell line by monitoring the activity of transiently expressed luciferase. The specificity and kinetics for hybridization of the siRNA with the messenger RNA target were followed by digestion techniques and analysis by polyacrylamide gel electrophoresis. Specific and temperature-dependent hybridization was observed, with a half-life of approximately 0.5 h at 4 degrees C. Significant downregulation of luciferase activity was obtained in the micromolar and nanomolar range, for RRL and HB2, respectively. In addition, the downregulation of protein production caused by addition of cisplatin could be further potentiated by addition of siRNA in a selective manner. The latter observation suggests that combined use of cisplatin and siRNA could be a method to decrease therapeutically used cisplatin concentrations. Thus, toxic side effects could be minimized while key proteins are targeted in a highly specific manner.