Activity

Thus, backbone circularization is an excellent method for enhancing the colloidal and the conformational stability of protein with minimal sequence changes. It is therefore expected to be effective in extending the storage stability of protein therapeutics, enhancing their biological stability.Diltiazem (DIL) is a calcium channel blocker antihypertensive drug commonly used in the treatment of cardiovascular disorders. Due to the high solubility and prompt dissolution of the commercial form hydrochloride (DIL-HCl) that is closely related to short elimination drug half-life, this API is known for exhibiting an unfitted pharmacokinetic profile. In an attempt to understand how engineered multicomponent ionic crystals of DIL with dicarboxylic acids can minimize these undesirable biopharmaceutical attributes, herein, we have focused on the development of less soluble and slower dissolving salt/cocrystal forms. By the traditional solvent evaporation method, two hydrated salts of DIL with succinic and oxalic acids (DIL-SUC-H2O and DIL-OXA-H2O), and one salt-cocrystal with fumaric acid (DIL-FUM-H2FUM) were successfully prepared. An in-depth crystallographic description of these new solid forms was conducted through single and powder X-ray diffraction (SCXRD, PXRD), Hirshfeld surface (HS) analysis, energy framework (EF) calculations, Fourier Transform Infrared (FT-IR) spectroscopy, and thermal analysis (TG, DSC, and HSM). Structurally, the inclusion of dicarboxylic acids in the crystal structures provided the formation of 2D-sheet assemblies, where ionic pairs (DIL+/anion-) are associated with each other via H-bonding. Consequently, a substantial lowering in both solubility (16.5-fold) and intrinsic dissolution rate (13.7-fold) of the API has been achieved compared to that of the hydrochloride salt. These findings demonstrate the enormous potential of these solid forms in preparing of novel modified-release pharmaceutical formulations of DIL.This paper reports a custom-built binder jet 3D printer for pilot-scale manufacturing of pharmaceutical tablets. The printer is equipped with high-throughput piezoelectric inkjet print heads and allows direct control of several key process parameters, including the build layer thickness, amount of jetted liquid binder, and powder spreading rate. The effects of these parameters on the properties of the as-printed tablets were studied using a powder mixture of lactose monohydrate and Kollidon® VA64 (KL) and an aqueous binder containing 5% of KL. The appropriate processing windows for two different powder spreading rates were identified, and the final properties of the printed samples were explained using a dimensionless “degree of overlap” parameter which is defined as the ratio between the penetrating depth of the binder into the powder and the build layer thickness. Lastly, 10% of indomethacin was added to the powder feedstock as a model drug. Drug-loaded tablets were produced at a rate of 32 tablets/min, having an average breaking force of 9.4 kgf, a friability of 2.5%, and an average disintegration time of 8 s. Histone Demethylase inhibitor These properties are comparable to commercially available tablets and represent one of the best values reported in the literature of 3D printed tablets thus far.Characteristics of residence time distribution (RTD) in a continuous high shear mixer granulation were investigated to promote the development of a continuous manufacturing process in the pharmaceutical industry. A continuous granulator with an impeller and a scraper was utilized. The tracer behavior in the continuous wet granulation was verified in impulse-response experiments with acetaminophen. The RTD of acetaminophen changed depending on the scraper speed (15-50 rpm), and the mean residence time could be adjusted by the scraper speed in the wet granulation. The impact of changes in the liquid-to-solid ratio (0.10-0.20) and the addition of binder were also examined, and the variance of RTD was influenced by both. The degree of axial mixing was quantitatively evaluated with a dimensionless index, the Peclet number (Pe). Higher scraper speed was found to suppress fluctuations of the axial mixing that occurred with changes in the liquid feed. Moreover, the transition of granule size distribution with the change in liquid feed reached a steady state more quickly under the higher scraper speed. These results show that scraper rotation can help to adjust the RTD and the axial mixing, leading to a more robust continuous granulation.Lipid overload-induced hepatic steatosis is a major public health problem worldwide. However, the potential molecular mechanism is not completely understood. Herein, we found that high-fat diet (HFD) or oleic acid (OA) treatment induced oxidative stress which prevented the entry of hepatocyte nuclear factor 4 alpha (HNF4α) into the nucleus by activating protein kinase C delta (PKCδ) in vivo and in vitro in large yellow croaker (Larimichthys crocea). This reduced the level of microsomal triglyceride transfer protein (MTP) transcription, resulting in the impaired secretion of very-low-density lipoprotein (VLDL) and the abnormal accumulation of triglyceride (TG) in hepatocytes. Meanwhile, the detrimental effects induced by lipid overload could be partly alleviated by pretreating hepatocytes with Go6983 (PKCδ inhibitor) or N-acetylcysteine (NAC, reactive oxygen species (ROS) scavenger). In conclusion, for the first time, we revealed that lipid overload impaired hepatic VLDL secretion via oxidative stress-mediated PKCδ-HNF4α-MTP pathway in fish. This study may provide critical insights into potential intervention strategies against lipid overload-induced hepatic steatosis of fish and human beings.

Ciprofol is a new intravenous anesthetic agent similar to propofol that has the pharmacodynamic characteristics of a rapid rate of onset and recovery in pre-clinical experiments. The aims of the present clinical trials were to compare the efficacy and safety of ciprofol emulsion for sedation or general anesthesia during colonoscopy and to define optimal doses for a subsequent phase III clinical trial.

A phase IIa multi-center, open-label, non-randomized, positive control, dose-escalating study was performed to determine a recommended phase IIb dose (RP2D) of ciprofol to induce sedation or anesthesia in patients undergoing colonoscopy. Phase IIb was also a multi-center clinical trial, but the patients were randomized into 3 groups at a ratio of 111. It was a double-blinded, propofol controlled study that administered ciprofol 0.4mg/kg (n=31) and 0.5mg/kg (n=32) or propofol at 2.0mg/kg (n=31), with the aim of establishing the optimal dose of ciprofol. The primary endpoint was the colonoscopy success rate. Sthdrawal were 6.1, 5.1, and 4.3min, and the times to discharge were 11.8, 11.2 and 10.6min, respectively. The satisfaction ratings of anesthetists in the ciprofol 0.5mg/kg group (9.5±0.8) were higher than in the ciprofol 0.4mg/kg (9.2±1.0) and propofol 2.0mg/kg (9.2±0.9) groups. The incidence of sedation and anesthesia-related AEs was highest in the propofol 2.0mg/kg group (25.8%), followed by the ciprofol 0.5mg/kg group (21.9%), and was least in the ciprofol 0.4mg/kg group (16.1%) (P=0.750).

Ciprofol was safe and well tolerated at doses ranging from 0.1mg/kg to 0.5mg/kg. Ciprofol 0.4-0.5mg/kg induced equivalent sedation/anesthesia and had a similar safety profile to propofol 2.0mg/kg during colonoscopy without producing serious AEs.

Ciprofol was safe and well tolerated at doses ranging from 0.1 mg/kg to 0.5 mg/kg. Ciprofol 0.4-0.5 mg/kg induced equivalent sedation/anesthesia and had a similar safety profile to propofol 2.0 mg/kg during colonoscopy without producing serious AEs.During the drug development process, many pharmacologically active compounds are discarded because of poor water solubility, but nanoparticle-based formulations are increasingly proposed as a solution for this problem. We therefore studied the distribution of nanoparticulate carriers and the delivery of their poorly water-soluble cargo to a structure of the central nervous system, the retina, under naive and pathological conditions. The lipophilic fluorescent dye coumarin 6 (Cou6) was encapsulated into poly(lactic-co-glycolic acid) PLGA nanoparticles (NPs). After intravenous administration in rats, we analyzed the distribution of cargo Cou6 and of the NP carrier covalently labeled with Cy5.5 in healthy animals and animals with optic nerve crush (ONC). In vivo real-time retina imaging revealed that Cou6 was rapidly released from PLGA NPs and penetrated the inner blood-retina barrier (BRB) within 15 min and PLGA NPs were gradually eliminated from the retinal blood circulation. Ex vivo microscopy of retinal flat mounts indicated that the Cou6 accumulated predominantly in the extracellular space and to a lesser extent in neurons. While the distribution of Cou6 in healthy animals and post ONC was comparable at early time point post-operation, the elimination of the NPs from the vessels was faster on day 7 post ONC. These results demonstrate the importance of considering different kinetics of nano-carrier and poorly water-soluble cargo, emphasizing the critical role of their parenchymal distribution, i.e. cellular/extracellular, and function of different physiological and pathological conditions.

Low grip work and high feelings of self-perceived fatigue could be an early characteristic of decline in reserve capacity, which comes to full expression as physical frailty in a later stage. When grip work and self-perceived fatigue can be identified as characteristics differentiating between robustness and pre-frailty it might allow to identify pre-frailty earlier. Therefore, this study aimed to investigate whether the combination of grip work and self-perceived fatigue is related to pre-frailty in well-functioning older adults aged 80 and over.

Four-hundred and five community-dwelling older adults aged 80 and over (214 robust and 191 pre-frail) were assessed for muscle endurance (grip Work corrected for body weight (GW_bw)), self-perceived fatigue (MFI-20) and frailty state (Fried Frailty Index, FFI). A Capacity to Perceived Vitality ratio (CPV) was calculated by dividing GW_bw by the MFI-20 scores. ANCOVA analysis (corrected for age and gender) was used to compare robust and pre-frail older adults, ang persons aged 80 years and over without clinical signs of exhaustion on the FFI still experience significantly higher fatigue levels (lower Grip Work, higher self-perceived fatigue and lower CPV levels) compared to robust ones. CPV ratio could therefore be a good tool to identify subclinical fatigue in the context of physical (pre-)frailty.In cancer cells, tumor suppressor proteins loss-of-function are usually the result of genetic mutations. Protein Phosphatase 2A is a tumor suppressor that inactivates several signaling pathways through removal of phosphate residues important for other proteins stability and/or activation. Different from other tumor suppressors, PP2A is, in many cancer types, inactivated by endogenous inhibitors. In physiological conditions, these inhibitors are important to balance PP2A activity. However, in cancer cells, overexpression of these inhibitors can keep PP2A inactive, resulting in sustained activation of mitogenic signaling pathways and transcription factors, metabolic reprogramming, with the resulting cancer progression and the resistance to anti-cancer therapies. One of these endogenous inhibitors is the protein SET (SE Translocation). SET is a multifunctional protein, which high expression has been associated with several types of cancer, as well as other diseases such as Alzheimer’s disease. Disruption of the interaction between SET and PP2A to rescue the activity of PP2A may represent a new therapeutic strategy and opportunity for cancer treatment.