Development of cordycepin formulations for preclinical and clinical studies

There is extensive literature on in vivo studies with cordycepin but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is a promising drug candidate in multiple therapeutic areas and there is a growing interest in studies aimed at assessing the pharmacological activity of this compound in relevant animal disease models. It is likely that many reported in vivo studies used formulations in which cordycepin was incompletely soluble. This can potentially confound the interpretation of pharmacokinetics and efficacy results. Furthermore, the presence of particles in intravenously administered suspension can cause adverse effects and should be avoided. Here we present the results from our development of simple and readily applicable formulations of cordycepin based on quantitative solubility assessment. Homogeneous solutions of cordycepin were prepared in phosphate-buffered saline (PBS) at different pH levels, suitable as formulations for both intravenously and oral administration. For the purpose of high-dose oral administration we also developed propylene glycol (PPG)-based vehicles in which cordycepin is completely soluble. The stability of the newly developed formulations was also assessed, as well the feasibility of their sterilisation by filtration. Additionally, an HPLC-UV method for the determination of cordycepin in the formulations, which may also be useful for other purposes, was developed and validated. Our study could provide useful information for improvement of future preclinical and clinical studies involving cordycepin

Defining the Earliest Transcriptional Steps of Chondrogenic Progenitor Specification during the Formation of the Digits in the Embryonic Limb

The characterization of genes involved in the formation of cartilage is of key importance to improve cell-based cartilage regenerative therapies. Here, we have developed a suitable experimental model to identify precocious chondrogenic events in vivo by inducing an ectopic digit in the developing embryo. In this model, only 12 hr after the implantation of a Tgfβ bead, in the absence of increased cell proliferation, cartilage forms in undifferentiated interdigital mesoderm and in the course of development, becomes a structurally and morphologically normal digit. Systematic quantitative PCR expression analysis, together with other experimental approaches allowed us to establish 3 successive periods preceding the formation of cartilage. The “pre-condensation stage”, occurring within the first 3 hr of treatment, is characterized by the activation of connective tissue identity transcriptional factors (such as Sox9 and Scleraxis) and secreted factors (such as Activin A and the matricellular proteins CCN-1 and CCN-2) and the downregulation of the galectin CG-8. Next, the “condensation stage” is characterized by intense activation of Smad 1/5/8 BMP-signaling and increased expression of extracellular matrix components. During this period, the CCN matricellular proteins promote the expression of extracellular matrix and cell adhesion components. The third period, designated the “pre-cartilage period”, precedes the formation of molecularly identifiable cartilage by 2–3 hr and is characterized by the intensification of Sox 9 gene expression, along with the stimulation of other pro-chondrogenic transcription factors, such as HifIa. In summary, this work establishes a temporal hierarchy in the regulation of pro-chondrogenic genes preceding cartilage differentiation and provides new insights into the relative roles of secreted factors and cytoskeletal regulators that direct the first steps of this process in vivo

A review of the current treatment methods for posthaemorrhagic hydrocephalus of infants

Posthaemorrhagic hydrocephalus (PHH) is a major problem for premature infants, generally requiring lifelong care. It results from small blood clots inducing scarring within CSF channels impeding CSF circulation. Transforming growth factor – beta is released into CSF and cytokines stimulate deposition of extracellular matrix proteins which potentially obstruct CSF pathways. Prolonged raised pressures and free radical damage incur poor neurodevelopmental outcomes. The most common treatment involves permanent ventricular shunting with all its risks and consequences

Measurement of nuclear modification factors of ϒ(1S), ϒ(2S), and ϒ(3S) mesons in PbPb collisions at √sNN = 5.02 TeV

The cross sections for ϒ(1S), ϒ(2S), and ϒ(3S) production in lead–lead (PbPb) and proton–proton (pp) collisions at √sNN = 5.02 TeV have been measured using the CMS detector at the LHC. The nuclear modification factors, RAA, derived from the PbPb-to-pp ratio of yields for each state, are studied as functions of meson rapidity and transverse momentum, as well as PbPb collision centrality. The yields of all three states are found to be significantly suppressed, and compatible with a sequential ordering of the suppression, RAA(ϒ(1S)) > RAA(ϒ(2S)) > RAA(ϒ(3S)). The suppression of ϒ(1S) is larger than that seen at √sNN = 2.76 TeV, although the two are compatible within uncertainties. The upper limit on the RAA of ϒ(3S) integrated over pT, rapidity and centrality is 0.096 at 95% confidence level, which is the strongest suppression observed for a quarkonium state in heavy ion collisions to date

Nanoformulations of Coumarins and the Hybrid Molecules of Coumarins with Potential Anticancer Effects

Coumarins are the secondary metabolites of some plants, fungi, and bacteria. Coumarins and the hybrid molecules of coumarins are the compounds which have been widely studied for their potential anticancer effects. They belong to benzopyrone chemical class, more precisely benzo-a-pyrones, where benzene ring is fused to pyrone ring. In nature, coumarins are found in higher plants like Rutaceae and Umbelliferae and some essential oils like cinnamon bark oil, cassia leaf oil and lavender oil are also rich in coumarins. The six main classes of coumarins are furanocoumarins, dihydrofuranocoumarins, pyrano coumarins, pyrone substituted coumarins, phenylcoumarins and bicoumarins. As well as their wide range of biological activities, coumarins and the hybrid molecules of coumarins are proven to have an important role in anticancer drug development due to the fact that many of its derivatives have shown an anticancer activity on various cell lines. Osthol, imperatorin, esculetin, scopoletin, umbelliprenin, angelicine, bergamottin, limettin, metoxhalen, aurapten and isopimpinellin are some of these coumarins. This review summarizes the anticancer effects of coumarins and their hybrid molecules including the novel pharmaceutical formulations adding further information on the topic for the last ten years and basically focusing on the structureactivity relationship of these compounds in cancer

Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements.

10.3390/biom9110735Biomolecules91173

Management of Craniovertebral Junction Tuberculosis Presenting with Atlantoaxial Dislocation

Tuberculosis (TB) rarely involves the craniovertebral junction (CVJ). Atlantoaxial dislocation (AAD) is one of the most commonly encountered lesions in craniocervical TB. The incidence of TB and its craniovertebral manifestation is increasing even in developed countries because of intercontinental migration and increased prevalence rates of immunosuppression conditions. While the treatment of craniovertebral TB is well standardized and relies on conservative measures, the treatment of TB with AAD is disputable. In this paper we present a review of the literature and elucidate our approach to craniovertebral TB with AAD through a case illustration