Injuries and disorders of the central nervous system (CNS) present a particularly difficult challenge for modern medicine to address, given the complex nature of the tissues, obstacles in researching ...and implementing therapies, and barriers to translating efficacious treatments into human patients. Recent advancements in neural stem cell (NSC) transplantation, endogenous neurogenesis, and
reprogramming of non-neural cells into the neuronal lineage represent multiple approaches to resolving CNS injury. However, we propose that one practice that must be incorporated universally in neuroregeneration studies is the use of extracellular matrix (ECM)-mimicking biomaterials to supply the architectural support and cellular microenvironment necessary for partial or complete restoration of function. Through consideration of developmental processes including neurogenesis, cellular migration, and establishment of functional connectivity, as well as evaluation of process-specific interactions between cells and ECM components, insights can be gained to harness and modulate native and induced neurobiological processes to promote CNS tissue repair. Further, evaluation of the current landscape of regenerative medicine and tissue engineering techniques external to the neurosciences provides key perspectives into the role of the ECM in the use of stem cell-based therapies, and the potential directions future neuroregenerative approaches may take. If the most successful of these approaches achieve wide-spread adoption, innovative paired NSC-ECM strategies for neuroregeneration may become prominent in the near future, and with the rapid advances these techniques are poised to herald, a new era of treatment for CNS injury may dawn.
Objectives Antibacterial efficacy of azithromycin could be improved by achieving higher concentrations at the sites of infection. Azithromycin extended release (azithromycin-ER) formulation was ...developed to enable a higher dosage of 2 g to be administered as a single oral dose without decreasing the safety profile. The aim of this study was to compare the pharmacokinetics of azithromycin in serum, epithelial lining fluid (ELF), alveolar macrophages (AMs) and lung tissue following a single oral dose of azithromycin-ER or azithromycin immediate release (azithromycin-IR) formulation. Patients and methods A total of 64 patients, diagnosed with lung cancer, requiring open-chest surgery for lung resection, completed the study. Subjects were randomized to receive oral administration of either a single 2 g dose of azithromycin-ER (32 subjects) or a single 500 mg dose of azithromycin-IR (32 subjects). Simultaneously, subjects within each treatment group were randomized to one of eight specific nominal post-dose time points for bronchoalveolar lavage and lung tissue sampling. Results For azithromycin-IR formulation, the AUC0–24 in serum, ELF, AMs and lung tissue was 3.1, 2.3, 1674 mg·h/L and 130 mg·h/kg, respectively. For azithromycin-ER formulation, the AUC0–24 in serum, ELF, AMs and lung tissue were 10.0, 17.6, 7028 mg·h/L and 505 mg·h/kg, respectively. The AUC0–24 ratio following administration of azithromycin-ER relative to azithromycin-IR was 3.2, 7.7, 4.2 and 3.9 in serum, ELF, AMs and lung tissue, respectively. Conclusions Within the first 24 h, a single 2 g azithromycin-ER dose produced dose-related increase in systemic exposure compared with a single 500 mg azithromycin-IR dose, which resulted in higher levels of azithromycin in ELF, AMs and lung tissue. Both formulations had similar safety profiles. By achieving high azithromycin exposure early in the course of treatment, without compromising tolerability, azithromycin-ER shows the potential for improved antibacterial efficacy compared with azithromycin-IR.
RIN(®)-150 is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg) and isoniazid (INH, 75 mg) developed for the treatment of tuberculosis.
This study was conducted at a single ...center: the Pfizer Clinical Research Unit in Singapore.
To demonstrate bioequivalence of each drug component between RIN-150 and individual products in a loose combination.
This was a randomized, open-label, single-dose, two-way crossover study. Subjects received single doses of RIN-150 or two individual reference products under fasting conditions in a crossover fashion, with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC).
Of 28 subjects enrolled, 26 completed the study. The adjusted geometric mean ratios of Cmax and AUClast between the FDC and single-drug references and 90% confidence intervals were respectively 91.63% (90%CI 83.13-101.01) and 95.45% (90%CI 92.07-98.94) for RMP, and 107.58% (90%CI 96.07-120.47) and 103.45% (90%CI 99.33-107.75) for INH. Both formulations were generally well tolerated in this study.
The RIN-150 FDC tablet formulation is bioequivalent to the two single-drug references for RMP and INH at equivalent doses.
In vitro microfluidic experimentation holds great potential to reveal many insights into the microphysiological phenomena occurring in conditions such as acute respiratory distress syndrome (ARDS) ...and ventilator-induced lung injury (VILI). However, studies in microfluidic channels with dimensions physiologically relevant to the terminal bronchioles of the human lung currently face several challenges, especially due to difficulties in establishing appropriate cell culture conditions, including media flow rates, within a given culture environment. The presented protocol describes an image-based approach to evaluate the structure of NCI-H441 human lung epithelial cells cultured in an oxygen-impermeable microfluidic channel with dimensions physiologically relevant to the terminal bronchioles of the human lung. Using phalloidin-based filamentous-actin staining, the cytoskeletal structures of the cells are revealed by confocal laser scanning microscopy, allowing for the visualization of individual as well as layered cells. Subsequent quantification determines whether the cell culture conditions being employed are producing uniform monolayers suitable for further experimentation. The protocol describes cell culture and layer evaluation methods in microfluidic channels and traditional fixed-well environments. This includes channel construction, cell culture and requisite conditions, fixation, permeabilization and staining, confocal microscopic imaging, image processing, and data analysis.
To compare single- and multiple-dose maraviroc exposures in cervicovaginal fluid (CVF) and vaginal tissue (VT) with blood plasma (BP) and quantify maraviroc protein binding in CVF.
Open-label ...pharmacokinetic study.
In 12 HIV-negative women, 7 paired CVF and BP samples were collected over 12 hours after 1 maraviroc dose. Subjects then received maraviroc twice daily for 7 days. After the last dose, subjects underwent CVF and BP sampling as on day 1, with additional sampling during terminal elimination. VT biopsies were obtained at steady state.
Day 1 and day 7 median maraviroc CVF AUCtau were 1.9- and 2.7-fold higher, respectively, than BP. On day 1, 6 of 12 subjects had detectable maraviroc CVF concentrations within 1 hour; 12 of 12 were detectable within 2 hours, and all exceeded the protein-free IC90. On day 7, maraviroc CVF protein binding was 7.6% and the VT AUCtau was 1.9-fold higher than BP. Maraviroc CVF concentrations 72 hours after dose and BP concentrations 12 hours after dose were similar.
Higher maraviroc exposure in the female genital tract provides a pharmacologic basis for further evaluation of chemokine receptor 5 antagonists in HIV infection prophylaxis. This is the first study to report antiretroviral VT concentrations, CVF protein binding, and CVF terminal elimination.
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