Biorelevant In Vitro Skin Permeation Testing and In Vivo Pharmacokinetic Characterization of Lidocaine from a Nonaqueous Drug-in-Matrix Topical System.

Recently, lidocaine topical systems utilizing nonaqueous matrices have been developed and provide efficient lidocaine delivery through the skin, such that lower concentrations of drug provide equivalent or greater drug delivery than drug-in-matrix hydrogel lidocaine patches. This study characterizes drug delivery from a nonaqueous lidocaine topical system with increasing drug load both in vitro and in vivo. Topical systems formulated with either 1.

A Rapid Tool to Optimize Process Variables for Continuous Manufacturing of Metronidazole Ointment Using Melt Extrusion Technique.

The use of hot-melt extrusion (HME) technique in the preparation of semi-solid products offers several advantages over conventional processes. However, the optimization of the technique for preparation of semi-solid pharmaceuticals is challenging due to involvement of ingredients with different physical properties. Hence, a simple tool to optimize the mixing of ingredients that results in a target ratio and drug content uniformity is utmost important.

Bufalin-Loaded PEGylated Liposomes: Antitumor Efficacy, Acute Toxicity, and Tissue Distribution.

Bufalin, derived from Venenum Bufonis, exerts antitumor effects but has low bioavailability and adverse effects when administered as a single agent. The purpose of this study was to evaluate the physical and chemical properties, antitumor efficacy, general pharmacology, acute toxicity, and tissue distribution profile of bufalin-loaded PEGylated liposomes (BF/PEG-LP), which were prepared in a previous study. To evaluate the safety of the preparation, a red blood cell hemolysis test was performed, which indicated that the hemolysis rate of BF/PEG-LP was significantly lower than that of bufalin alone.

Improved Antitumor Efficacy and Pharmacokinetics of Bufalin via PEGylated Liposomes.

Bufalin was reported to show strong pharmacological effects including cardiotonic, antiviral, immune-regulation, and especially antitumor effects. The objective of this study was to determine the characterization, antitumor efficacy, and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity, which were prepared by FDA-approved pharmaceutical excipients. Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high-pressure homogenization method.

Homocysteine up-regulates endothelin type A receptor in vascular smooth muscle cells through Sirt1/ERK1/2 signaling pathway.

Sirtuin 1 (Sirt1) is a longevity gene that has protective effects in cardiovascular diseases (CVDs). The endothelin type A (ET) receptor is involved in pathogenesis of CVDs. The extracellular signal related kinases 1 and 2 (ERK1/2) signaling pathway is involved in regulation of the ET receptor induced by some CVD risk factors in vascular smooth muscle cells (VSMCs).

Salvia plebeia Extract Inhibits Xanthine Oxidase Activity In Vitro and Reduces Serum Uric Acid in an Animal Model of Hyperuricemia.

Hyperuricemia is a clinical condition characterized by an elevated level of serum uric acid and is a key risk factor for the development of gout and metabolic disorders. The existing urate-lowering therapies are often impractical for certain patient populations, providing a rationale to explore new agents with improved safety and efficacy. Here, we discovered that extract inhibited the enzyme activity of xanthine oxidase, which is a key enzyme generating uric acid in the liver.

The sirt1/NF-kB signaling pathway is involved in regulation of endothelin type B receptors mediated by homocysteine in vascular smooth muscle cells.

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases (CVDs). Endothelin type B (ET) receptors were involved in the pathogenesis of CVDs. However, Sirtuin 1(Sirt1) has potential protect roles for CVDs.

Hydrogen sulfide inhibits development of atherosclerosis through up-regulating protein S-nitrosylation.

Hydrogen sulfide (HS) is an important gaseous signaling molecule that serves many important regulatory roles in physiological and pathophysiological conditions. HS exerts an anti-atherosclerotic effect through mediating the biological functions of nitric oxide (NO). However, its mechanism of action is unclear.

Mechanisms of simvastatin-induced vasodilatation of rat superior mesenteric arteries.

Independent of its lipid-lowering properties, simvastatin (Sim) induces vasorelaxation; however, the underlying mechanisms have remained elusive. The aim of the present study was to investigate the vasorelaxant effects of Sim on rat superior mesenteric arteries and the mechanisms involved. The isometric tension of rat superior mesenteric arterial rings was recorded on a myograph.

Endothelium-dependent and-independent relaxation induced by resveratrol in rat superior mesenteric arteries.

Resveratrol (Res) is a specific agonist of sirtuin 1, and has many cardioprotective effects. Although Res is able to relax various vascular beds, its pharmacological properties in rat superior mesenteric arteries and the underlying mechanism are not well clarified. The aim of present study was to investigate the vasorelaxant effects of Res on rat superior mesenteric arteries and the mechanisms involved.

Homocysteine regulates endothelin type B receptors in vascular smooth muscle cells.

Vascular smooth muscle endothelin type B (ET) receptor is involved in the pathogenesis of cardiovascular diseases (CVDs). Hyperhomocysteinemia is an independent risk factor for CVDs. The present study was designed to examine the hypothesis that homocysteine (Hcy) up-regulates vascular smooth muscle ET receptors.

In Vitro and In Vivo Sustained Zero-Order Delivery of Rapamycin (Sirolimus) From a Biodegradable Intraocular Device.

Purpose: We created implantable intraocular devices capable of constant and continuous rapamycin release on the scale of months to years.

Methods: Polycaprolactone (PCL) thin films were used to encapsulate rapamycin to create implantable and biodegradable intraocular devices. Different film devices were studied by modifying the size, thickness, and porosity of the PCL films.

Robust and Rugged Stability-Indicating HPLC Method for the Determination of Plerixafor and Its Related Impurities in Drug Substances.

A novel, reversed-phase high-performance liquid chromatographic method was developed and validated for the determination of related substances in Plerixafor (PLX) drug substance. PLX is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients. The method is efficient for estimation of all degradation and process-related impurities.

Synthesis, characterization and in vitro anticancer activity of C-5 curcumin analogues with potential to inhibit TNF-α-induced NF-κB activation.

In a search of new compounds active against cancer, synthesis of a series of C-5 curcumin analogues was carried out. The new compounds demonstrated good cytotoxicity against chronic myeloid leukemia (KBM5) and colon cancer (HCT116) cell lines. Further, these compounds were found to have better potential to inhibit TNF-α-induced NF-κB activation in comparison to curcumin, which show their potential to act as anti-inflammatory agents.

[Pro-angiogenic effects of four Chinese medicines and three herbal prescription in chicken chorioallantoic membrane model].

Objective: To observe the pro-angiogenic effect of four Chinese medicines and three herbal prescriptions, screen the effective components from them.

Methods: Chicken chorioallantoic membrane (CAM) model was employed to observe the pro-angiogenic activities of Angelicae Sinensis Radix, Salviae Miltiorrhizae Radix, Notoginseng Radix, Astragali Radix, Xuefuzhuyu decoction, Dangguibuxue decoction and Taohongsiwu decoction, all of them were claimed to promote angiogenesis. The effective components were screened from the extracts.

A PAT approach to improve process understanding of high shear wet granulation through in-line particle measurement using FBRM C35.

This article summarizes the investigation of in-line particle characterization during high shear wet granulation (HSWG) using focused beam reflectance measurement (FBRM) for enhanced process understanding, which is part of an effort to develop this drug product within the framework of quality by design (QbD) and process analytical technology (PAT). Traditionally, the effectiveness of in-line monitoring of HSWG processes is hindered by wet and sticky material fouling the probe resulting in inconsistent and erroneous data collection. For this study, a FBRM C35 probe was used which incorporates a scraping mechanism to maintain a clean probe window ensuring consistent measurements throughout each batch.

Quality by design case study: an integrated multivariate approach to drug product and process development.

To facilitate an in-depth process understanding, and offer opportunities for developing control strategies to ensure product quality, a combination of experimental design, optimization and multivariate techniques was integrated into the process development of a drug product. A process DOE was used to evaluate effects of the design factors on manufacturability and final product CQAs, and establish design space to ensure desired CQAs. Two types of analyses were performed to extract maximal information, DOE effect & response surface analysis and multivariate analysis (PCA and PLS).

Cardiac glycosides as novel cancer therapeutic agents.

The class of steroid-like compounds designated cardiac glycosides includes well-known drugs such as digoxin, digitoxin, and ouabain. Their continued efficacy in treatment of congestive heart failure and as anti-arrhythmic agents is well appreciated. Less well known, however, is the emerging role of this category of compounds in the prevention and/or treatment of proliferative diseases such as cancer.

Bioavailability of curcumin: problems and promises.

Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination.

Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule.

In pretransplantation therapy busulfan is typically given every 6 hours. We infused busulfan once daily at 130 mg/m2 for 4 days, performing pharmacokinetic analyses on plasma concentration-time data (n = 60 patients) on days 1, 3, and/or 4. Mean (percent coefficient of variation) maximum concentration, volume of distribution, half-life, and clearance were 3.

Evaluation of risk and benefit in the implementation of near-infrared spectroscopy for monitoring of lubricant mixing.

On-line near-infrared spectroscopy (NIRS) was used to monitor lubricant blending to ensure the quality of the final dosage form. A quantitative multivariate NIR model was developed using different lubricant concentration levels. Real-time model predictions correlated well with the expected lubricant concentration during blending, which allowed determination of blend quality.

A Process Analytical Technology approach to near-infrared process control of pharmaceutical powder blending. Part I: D-optimal design for characterization of powder mixing and preliminary spectral data evaluation.

Experimental design, multivariate data acquisition, and analysis in addition to real time monitoring and control through process analyzers, represent an integrated approach for implementation of Process Analytical Technology (PAT) in the pharmaceutical industry. This study, which is the first in a series of three parts, uses an experimental design approach to identify critical factors affecting powder blending. Powder mixtures composed of salicylic acid and lactose were mixed in an 8 qt.

A Process Analytical Technology approach to near-infrared process control of pharmaceutical powder blending: Part II: Qualitative near-infrared models for prediction of blend homogeneity.

The successful implementation of near-infrared spectroscopy (NIRS) in process control of powder blending requires constructing an inclusive spectral database that reflects the anticipated voluntary or involuntary changes in processing conditions, thereby minimizing bias in prediction of blending behavior. In this study, experimental design was utilized as an efficient way of generating blend experiments conducted under varying processing conditions such as humidity, blender speed and component concentration. NIR spectral data, collected from different blending experiments, was used to build qualitative models for prediction of blend homogeneity.

A Process Analytical Technology approach to near-infrared process control of pharmaceutical powder blending. Part III: Quantitative near-infrared calibration for prediction of blend homogeneity and characterization of powder mixing kinetics.

The Process Analytical Technology (PAT) initiative, undertaken by the Food and Drug Administration (FDA), paves the way for improvement of drug manufacturing through real-time measurements that allow better process understanding. This study is the third and final Part in a series of studies that represent an integrated approach for real-time blend uniformity assessment using near-infrared (NIR) technology. In this study, the development of a quantitative NIR model for prediction of blending end point is presented.

Regulation of hyaluronan synthases in mouse uterine cervix.

We examined the expression pattern of hyaluronan synthase (HAS) mRNAs in the uterine cervix of pregnant mice. The expression levels of HAS-1 and -2 mRNAs peaked at delivery, whereas that of HAS-3 mRNA peaked on the 15th day of pregnancy. The regulation of HAS mRNA expression was examined in pregnant mouse uterine cervical fibroblasts.