FRONTIER1: a partially randomized phase 2 study assessing the safety, pharmacokinetics, and pharmacodynamics of Mim8, a factor VIIIa mimetic.

BACKGROUND: Mim8 (denecimig) is a factor VIII (FVIII) mimetic bispecific antibody in development for the treatment of hemophilia. Data from the phase 1 part of FRONTIER1 (EudraCT: 2019-000465-20, NCT04204408, and NN7769-4513) suggested that Mim8 was well tolerated in healthy participants and exhibited pharmacokinetic (PK) properties consistent with dose proportionality. OBJECTIVES: The partially randomized, phase 2, multiple ascending dose (MAD) part of FRONTIER1 aimed to evaluate the safety, PK, pharmacodynamics (PD), and exploratory efficacy of Mim8 in participants with hemophilia A with or without FVIII inhibitors. METHODS: The MAD part of FRONTIER1 consisted of 42 participants, assigned to 5 cohorts, with participants in cohorts 3 and 4 randomized 1:1 to dosing weekly or every 4 weeks, respectively. Four of the 42 participants (9.5%) had FVIII inhibitors prior to study enrolment. The primary endpoint was treatment-emergent adverse events (TEAEs). PK and PD were evaluated by Mim8 plasma concentration and thrombin generation, respectively. Exploratory efficacy was assessed via the number of treated bleeds. Safety and PD parameters were also evaluated from an exploratory cohort treated with emicizumab. RESULTS: Mim8 was well tolerated, with 1 serious TEAE (anxiety-related chest pain) deemed unrelated to Mim8. There was no dose dependency on the number, causality, type, or severity of TEAEs. PK/PD properties supported weekly to monthly dosing approaches, and few participants experienced treated bleeds beyond the lowest dose cohort (1 in cohorts 2 and 3, and 3 in cohort 5). CONCLUSION: These data support the continued clinical development of Mim8, and FRONTIER1 has proceeded onto an extension phase.

Stabilising phycocyanin by anionic micelles.

Phycocyanins are pigment-protein complexes with potential application as natural food colourants. The perceived colour of phycocyanins varies with pH, and a method to stabilise the colour over a broad range of pH values is requested by the food industry. In this work, the stabilising effect of sodium dodecyl sulphate (SDS) micelles on pH-induced colour variations of phycocyanin was examined. SDS was shown to stabilise the blue conformation of phycocyanin, preventing formation of the green conformation, which is prevalent at low pH. The studies indicated that the stabilising effect occurred through interaction or entrapment of the non-protonated, circular helical (blue) structure of phycocyanin and the anionic SDS micelles. The interaction prevented conversion into protonated, partially unfolded (green) phycocyanin species. This information opens for new possibilities to stabilise the blue conformation of phycocyanin and to apply the stabilised form in food products as a natural blue food colourant.

Biochemical and anthropometric correlates of bio-electrical impedance parameters in severely malnourished children: A cross-sectional study.

INTRODUCTION: Despite expanding use of bio-impedance (BI), little is known about its pathophysiologic significance and biological correlates OBJECTIVE: Determine correlations of BI parameters with anthropometry and biomarkers of electrolyte homeostasis, inflammation and liver function in children with severe acute malnutrition (SAM). METHODS: We studied Ethiopian children with SAM (mid-arm circumference <11·0 cm or weight-for-height <70% of the NCHS growth reference median and/or nutritional oedema) at hospitalization. Impedance (Z, Ohm), resistance (R, Ohm), reactance (Xc, Ohm) and phase angle (PA, degree) were measured at 50 kHz. R and Xc were height-indexed. Anthropometric Z-scores were calculated. Serum phosphate, Ca, Na, K, Mg, alkaline phosphatase, bilirubin, α1-acid glycoprotein, albumin and haemoglobin were measured. Healthy children were used for BI comparison. Correlates of BI were established using forward selection after comparing models using likelihood ratio test. RESULTS: The sample comprised 55 children with SAM (age 36 ± 24 months; 60% males; 72.7% oedematous) and 80 healthy control children (age 28 ± 15 months; 47.5% males). Oedematous children had the lowest BI parameters compared with reference and non-oedematous children. Similarly, they had lower serum albumin, K and alkaline phosphatase levels than non-oedematous children. Oedema was independent negative correlate of R, Xc and PA. Serum albumin level and weight-for-height Z-score were positive correlates of R, whereas serum calcium and Cl levels were positive correlates of Xc. MUAC correlated positively with PA. CONCLUSION: Nutritional oedema explained the divergence of BI parameters from normality. Soft tissue mass, serum albumin, Ca and Cl accounted for variability of BI parameters in children with SAM.

Data for the size of cholesterol-fat micelles as a function of bile salt concentration and the physico-chemical properties of six liquid experimental pine-derived phytosterol formulations in a cholesterol-containing artificial intestine fluid.

The data in this paper are additional information to the research article entiltled "Inhibition of cholesterol transport in an intestine cell model by pine-derived phytosterols" (Yi et al.,2016) [1]. The data derived from the measurement on six liquid formulations of commercial pine-derived phytosterol (CPP) by dynamic light scattering. The data cover micelle size and the zeta-potential for formulations with cholesterol including monoglyceride, oleic acid, and bile salt. The data demonstrate the critical effect of the bile salt concentration on the size of cholesterol-digested fat micelles.

Inhibition of cholesterol transport in an intestine cell model by pine-derived phytosterols.

We have quantified the inhibition of intestinal cholesterol transport by pine-derived phytosterols using an HT29-MTX intestine cell model that forms a mucus layer similar to that in the intestine. An artificial intestinal fluid consisting of digested fat, bile salt, cholesterol, and phytosterols was formulated in order to mimic the conditions in the intestine. The apparent permeability coefficient (Papp) of the positive control, i.e., 0.1mM of cholesterol solubilized in the artificial intestine fluid, was found to be 0.33 (±0.17)×10-6cm/s. When 0.1mM ß-sitosterol was solubilized alongside, Papp was effectively zero, corresponding to a total inhibition of cholesterol transport. A similar strong inhibition was found when commercial pine-derived phytosterols, PinVita™ FSP DuPont, were co-solubilized with cholesterol in the dietary model micelles, leading to Papp=0.06 (±0.06)×10-6cm/s, i.e., 5.5 times lower than the cholesterol positive control. Additionally, the effect of potential oral administration formulations generated by the pine-derived phytosterols was also characterized. The formulations were produced as a liquid formulation of the cholesterol-containing artificial intestine fluid. Six liquid formulations were tested of which four displayed a Papp in the range of 0-0.09×10-6cm/s. The remaining two formulations did not show any inhibition effect on cholesterol transport and even enhanced cholesterol transport. It was furthermore observed that the phytosterols were found in the collected intestine cells but not transported to the basolateral region in the intestinal cell model system.

Cow's milk in treatment of moderate and severe undernutrition in low-income countries.

Cow's milk products have a central role in treatment of under nutrition, and the introduction of products with a high milk content (F-100 and ready to use therapeutic foods) has resulted in marked improvements in weight gain and reduction in mortality. Milk also has a specific effect on linear growth. Milk protein has a high quality score (PDCAAS) and contains many peptides and other bioactive factors, which might have special effects on recovery from under nutrition. Milk is an important source of minerals supporting growth (type II nutrients), such as potassium, magnesium, phosphorus and zinc, and the high lactose content also seems to support growth due to a prebiotic effect and improved absorption of minerals. The risk that the use of cow's milk products suppresses breastfeeding should be prevented by supporting mothers in breastfeeding. There is consensus that children with severe under nutrition should be treated with products with high milk content, but because of the high cost of milk there is a need to perform more studies to determine the minimal amount of milk protein needed to make a clinically relevant difference in treating the 36 million children with moderate wasting. Such studies should not only focus on weight gain but also on linear growth, body composition, physical activity and cognitive development.

[The effect of tesofensine on body weight and body composition in obese subjects--secondary publication]. / Effekt af tesofensine på kropsvaegt og kropssammensaetning hos svaert overvaegtige--sekundaerpublikation.

Results from a phase II trial with Tesofensine for treatment of obesity are presented. In total 203 obese persons were randomised to treatment with Tesofensine 0.25, 0.5, or 1.0 mg, or placebo daily for 24 weeks. Treatment with Tesofensine resulted in a mean weight reduction of 4.5, 9.2 and 10.6% higher than that of placebo for 0.25, 0.5 and 1.0 mg, respectively. Tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved anti-obesity drugs. Findings of safety and efficacy of 0.5 mg Tesofensine need confirmation in phase III trials.

Cyclodextrin modified hydrogels of PVP/PEG for sustained drug release.

Hydrogels are water swollen networks of polymers and especially hydrogels consisting of poly vinylpyrrolidone/poly ethyleneglycol-dimethacrylate (PVP/PEG-DMA) blends show promising wound care properties. Enhanced functionality of the hydrogels can be achieved by incorporating drugs and other substances that may assist wound healing into the gel matrix. Controlling the release of active compounds from the hydrogels may be possible by carefully modifying the polymer matrix. For this purpose, cyclodextrins (CD) were grafted to the polymer matrix in 4-5 w/w% in an attempt to retard the release of water-soluble drugs. Ibuprofenate (IBU) was chosen as model drug and loaded in IBU/CD ratios of 0.6, 1.2, and 2.5. Vinyl derivatives of alpha-, beta- and gamma-CD were produced, added to the prepolymer blend and cured by UV-light. During this curing process the CD derivatives were covalently incorporated into the hydrogel matrix. The modified hydrogels were loaded with ibuprofenate by swelling. The release of the model drug from CD modified hydrogels show that especially covalently bonded beta-cyclodextrin can change both the release rate and the release profile of ibuprofen.