The challenge of downstream processing of spray dried amorphous solid dispersions into minitablets designed for the paediatric population - A sustainable product development approach.

Poorly water-soluble drugs present a significant challenge in the development of oral solid dosage forms (OSDs). In formulation development the appropriate use of excipients to adjust solubility, and the choice of manufacturing method and pharmaceutical processes to obtain a dosage form to meet the needs of the patient group, is crucial. Preparing an amorphous solid dispersion (ASD) is a well-established method for solubility enhancement, and spray drying (SD) a common manufacturing method. However, the poor flowability of spray dried materials poses a significant challenge for downstream processing. Promoting sustainability in OSD development involves embracing a versatile formulation design, which enables a broader spectrum of patients to use the product, as opposed to altering existing dosage forms retrospectively. The objective of the current study was to develop a formulation of spray dried indomethacin ASD suited to the production, by direct compression, of instant release paediatric minitablets. Excipients evaluated were PVP or HPMCAS in solid dispersions at the preformulation phase, and MCC and lactose as a filler in direct compression. From the studied formulations, a 3:1 ratio blend of Vivapur 200/Pharmatose 200 M (MCC/lactose) with 0.5% (w/w) magnesium stearate was found to be the most promising in tableting, and minitablets containing a 6.22% content of spray-dried ASD of indomethacin/PVP K 29-32 could be obtained with desired tablet hardness and pharmaceutical quality, complying with tests of weight variation and fast disintegration in an aqueous environment. As a case example, this study provides a good foundation for further studies in harnessing a sustainable approach to the development of pharmaceutical formulations that can appropriately serve different patient sub-populations.

Normative isometric plantarflexion strength values for professional level, male rugby union athletes.

OBJECTIVES: The primary aim was to establish normative values of isometric plantarflexor muscle strength in professional male rugby union players and compare forwards with backs. The secondary aims were to examine how individual playing position or age influences isometric plantarflexor strength. DESIGN: Cross-sectional. SETTING: Testing at professional rugby clubs. PARTICIPANTS: 355 players (201 forwards and 154 backs) from 9 clubs in the English Premiership club competition. MAIN OUTCOME MEASURES: Maximal unilateral isometric plantarflexion strength was measured, using a Fysiometer C-Station, in a seated position with a flexed knee and in maximal available dorsiflexion. Values are reported normalised to body mass and specific to playing position. RESULTS: Mean combined limb isometric plantarflexion strength for the group was 193.1 kg (SD 32) or 1.86 xBW. (SD 0.31). Forwards were significantly weaker than backs (forwards = 1.75xBW (SD 0.26), backs = 2.00xBW (SD 0.28) (p=<0.0001)). Age category revealed no influence on plantarflexor strength. CONCLUSION: This study presents normative isometric plantarflexion strength values for professional male rugby union players. Forwards are typically relatively weaker than backs.

Novel biomechanical injury risk score demonstrates correlation with lower limb posterior chain injury in 50 elite-level rugby union athletes.

OBJECTIVES: Lower limb posterior chain injury (PCI) is common among athletic populations, with multifactorial risk factors including age, previous injury, strength measurements, range of motion and training load. Biomechanics are commonly considered in the prevention and rehabilitation of PCI by performance staff. However, there is no documented testing method to assess for associations between biomechanics and PCI. The aim of this study was to investigate whether there is an association between an easily applicable, novel biomechanical assessment tool and PCI. METHODS: Fifty male elite-level rugby union athletes (age 22.83±5.08) participating in the highest tier of England were tested at the start of the 2019 preseason period and PCIs (N=48) were recorded over the 2019/2020 playing season. Participants' biomechanics were analysed using two-dimensional video analysis against an injury risk score (IRS) system in the performance of the combined movement-prone hip extension and knee flexion. Participants' biomechanics in carrying out this movement were scored against the 10-point IRS, where the more compensatory movement recorded sees an increase in an individual's IRS. Participants' IRS was then compared against the number of PCIs sustained and Spearman's correlation coefficient was used for statistical analysis. RESULTS: There is a significant association between IRS and PCI (R=0.542, p<0.001). Linear regression demonstrated that an increase in 1 in IRS was associated with a 35% increase in PCI incidence (R²=0.346). CONCLUSION: A significance between the IRS and PCI provides preliminary support for its use as an injury risk assessment tool.

BACE1 inhibitors: a head group scan on a series of amides.

A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of their basicity as well as their properties as substrates of P-glycoprotein revealed that a 2-amino-1,3-oxazine head group would be a suitable starting point for further development of brain penetrating compounds for potential Alzheimer's disease treatment.

Evaluation of a cognitive remediation therapy group for adolescents with anorexia nervosa: pilot study.

OBJECTIVE: Cognitive remediation therapy (CRT) has been used with adults with anorexia nervosa (AN) in individual and group formats; however, evaluation of CRT with adolescents in this population is very limited. METHOD: Seven CRT groups were carried out with a total of 30 adolescents with AN. Adolescents' cognitive flexibility and motivation was assessed before and after the group, and they completed qualitative questionnaires after the group to determine their perceptions. RESULTS: There was a small effect size in self-reported cognitive flexibility post group. Adolescents found the group interesting and useful; however, some wanted more support with application to real life. DISCUSSION: Cognitive remediation therapy has the potential to be used with adolescents with AN. More research is needed to determine if CRT is beneficial for young people with AN.

Evidence against a direct role for oxidative stress in cadmium-induced axial malformation in the chick embryo.

Cadmium (Cd) is a powerful inducer of oxidative stress. It also causes ventral body wall defects in chick embryos treated at Hamburger-Hamilton stages 16-17. By measuring malondialdehyde levels (TBARS method) and cotreating with antioxidants (tempol, ascorbate, and N-acetylcysteine), we sought to determine if oxidative stress were directly related to teratogenesis. We also investigated the expression of mRNAs for antioxidant enzymes superoxide dismutase (SOD) -1 and -2, catalase (CAT), and glutathione peroxidase (GPx). RT-PCR showed reductions in SOD-1, SOD-2, and CAT 1 hour after treatment with Cd. MDA levels increased 4 hours after Cd, and remained elevated 24 hours after treatment. Of the antioxidants, only N-acetylcysteine reduced MDA levels to control values. Nonetheless, no antioxidant could reduce embryo lethality or malformation rates. Furthermore, MDA levels 24 hours after treatment were identical in malformed and normal embryos exposed to Cd. Hence, we conclude that oxidative stress may not have a direct role in Cd teratogenesis.

Synthesis of novel ketoconazole derivatives as inhibitors of the human Pregnane X Receptor (PXR; NR1I2; also termed SXR, PAR).

PXR, pregnane X receptor, in its activated state, is a validated target for controlling certain drug-drug interactions in humans. In this context, there is a paucity of inhibitors directed toward activated PXR. Using prior observations with ketoconazole as a PXR inhibitor, the target compound 3 was synthesized from (s)-glycidol with overall 56% yield. (+)-Glycidol was reacted with 4-bromophenol and potassium carbonate in DMF to yield the ring opened compound 6. This was then heated to reflux in benzene along with 2', 4'-difluoroacetophenone and catalytic amount of para-toluene sulfonic acid to yield 8. The resultant acetal 8 was then functionalized using Palladium chemistry to yield the target compound 3. The activity of the compound was compared with ketoconazole and UCL2158H. However, in contrast with ketoconazole (IC(50) approximately 0.020 microM; approximately 100% inhibition), 3 has negligible effects on inhibition of microsomal CYP450 (maximum approximately 20% inhibition) at concentrations >40 microM. In vitro, micromolar concentration of ketoconazole is toxic to passaged human cell lines, while 3 does not exhibit cytotoxicity up to concentrations approximately 100 microM (viability >85%). This is the first demonstration of a chemical analog of a PXR inhibitor that retains activity against activated PXR. Furthermore, in contrast with ketoconazole, 3 is less toxic in human cell lines and has negligible CYP450 activity.

Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity.

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.

Partial structures of ketoconazole as modulators of the large conductance calcium-activated potassium channel (BK(Ca)).

A series of partial structures of ketoconazole has been synthesized and tested for activity on the large conductance calcium-activated potassium channel (BK) in bovine smooth muscle cells. This has provided openers and blockers of the channel. The results suggest that the phenyl and phenoxy moieties are important for interaction with BK, whereas the imidazole group is unimportant. The properties of the phenoxy moiety seem to determine whether the compounds act to open or block the channel.