Oral Manganese Chloride Tetrahydrate: A Novel Magnetic Resonance Liver Imaging Agent for Patients With Renal Impairment: Efficacy, Safety, and Clinical Implication.

ABSTRACT: Manganese-based contrast agents (MBCAs) show promise to complement gadolinium-based contrast agents (GBCAs) in magnetic resonance imaging (MRI) of the liver. Management of patients with focal liver lesions and severely impaired renal function uses unenhanced liver MRI or GBCA-enhanced MRI. However, unenhanced MRI risks reducing patient's survival.Gadolinium-based contrast agents, which help to detect and visualize liver lesions, are associated with increased risk of nephrogenic systemic fibrosis in renally impaired patients, a severe adverse event (AE) with potentially fatal outcome. Therefore, use of GBCA in patients with impaired renal function requires careful consideration. Other concerns are related to tissue deposition in the brain and other organs due to lack of gadolinium clearance, which could lead to concerns also for other patient populations, for example, those exposed to multiple procedures with GBCA. Of particular concern are the linear chelates that remain available for liver MRI, where there is no replacement technology. This has highlighted the urgency for safer alternatives.An alternative may be the drug candidate Ascelia-MBCA (ACE-MBCA, Orviglance), oral manganese chloride tetrahydrate. This candidate effectively visualizes and detects focal liver lesions, as demonstrated in 8 clinical studies on 201 adults (healthy or with known or suspected focal liver lesions). ACE-MBCA has a low and transient systemic exposure, which is likely the reason for its beneficial safety profile. The AEs were primarily mild and transient, and related to the gastrointestinal tract. This new, orally administered product may offer a simple imaging approach, allowing appropriate patient management in renally impaired patients when use of GBCA requires careful consideration.In this review, we highlight the clinical development of ACE-MBCA-a novel, liver-specific contrast agent. We begin with a brief overview of manganese properties, addressing the need for MBCAs and describing their optimal properties. We then review key findings on the novel agent and how this allows high-quality MRIs that are comparable to GBCA and superior to unenhanced MRI. Lastly, we provide our view of future perspectives that could advance the field of liver imaging, addressing the medical needs of patients with focal liver lesions and severe renal impairment.Our review suggests that ACE-MBCA is a promising, effective, and well-tolerated new tool in the radiologist's toolbox.

Liraglutide effects in a paediatric (7-11 y) population with obesity: A randomized, double-blind, placebo-controlled, short-term trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics.

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.

Marketing authorisation of orphan medicines in Europe from 2000 to 2013.

An analysis was performed on a data set of 157 orphan designated medicines with an outcome for marketing authorisation application (MAA) between 2000 and 2013. The intention was to understand the factors associated with marketing authorisation success, the challenges developers face regarding orphan medicine development, and how scientific advice (SA) is used during development. The results demonstrated that orphan medicines have a lower success rate compared with non-orphan medicines and that determinants for marketing authorisation success were company size and compliance with SA. Compliance with SA could help orphan medicine developers overcome clinical development challenges.

Platinum interference with siRNA non-seed regions fine-tunes silencing capacity.

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.

Cisplatin and siRNA interference with structure and function of Wnt-5a mRNA: design and in vitro evaluation of targeting AU-rich elements in the 3' UTR.

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.

Platination of the siRNA sense-strand modulates both efficacy and selectivity in vitro.

The use of short interfering RNAs (siRNA) for selective suppression of protein production has rapidly become a commonly used technique for transient modulation of protein levels. In the present paper, we investigate whether introduction of platinated bases in the sense strand can be used to modulate the efficacy of siRNAs. Four different siRNAs were studied, all targeting the initial AU-rich 3' UTR of Wnt-5a mRNA. The siRNAs were characterized with respect to melting properties and translational inhibitory effect in vitro using luciferase as a reporter gene. The translation inhibition studies reveal that all platinated siRNA remain efficient. For an siRNA with partial complementarity to the luciferase gene, platination was shown to reduce the off-target effects. All siRNAs were found to be active in cellular in vitro translation systems, reaching suppression levels well above 80% for the majority of siRNAs investigated.