Pharmaceutical Research最新文献

Purpose: This study aims to evaluate the effects of prebiotics and probiotics on colorectal cancer (CRC) progression in an AOM/DSS-induced mouse model.

Methods: In AOM/DSS-induced mouse model, treatment groups received either S. herbacea as a prebiotic (PRE) or in combination with Lactobacillus plantarum as a probiotic (PRO). PCNA, Ki-67, β-catenin, c-Myc, and Nrf2 were evaluated using immunohistochemistry (IHC). The impact on polyp formation and progression was assessed by categorizing polyps according to their size.

Results: Both PRE and PRO treatments resulted in a significant reduction in large polyp formation when compared to AOM/DSS induced control group. IHC analyses demonstrated reduced biomarker expression for cell proliferation in PRE and PRO groups, specifically showing decreased staining for PCNA, Ki-67, β-catenin, and c-Myc, indicating downregulation of Wnt signaling and suppressed cell proliferation. Reduced Nrf2 expression highlights the impact of treatments interfering with cancer cell defenses. Notably, there were no significant differences in the outcomes between PRE and PRO groups, suggesting that prebiotics show anticancer effects.

Conclusion: The study suggests that S. herbacea, a prebiotic, effectively suppresses CRC progression, with limited additional benefits from combining with probiotics. These findings underscore the therapeutic potential of prebiotics in CRC.

Purpose: This study aimed to develop a new index, Distribution Uniformity Index (DUI), to assess the "intra-tablet" homogeneity.

Methods: High-resolution hyperspectral Raman imaging was adopted to scan a tablet to get the components' distribution. The heuristic algorithm was applied to generate a Raman heatmap with RGB colors quantitatively correlated with the concentrations of each component. DUI is defined as the ratio of the area under the uniformity curve of the sample image to that of the randomized image. The accuracy and applicability of DUI were verified by constructing model images with controlled uniformity and random regions. The effects of "intra-tablet" homogeneity on the disintegration and dissolution of spironolactone tablets were investigated.

Results: DUI value was directly obtained from heuristic visual analysis of macro-pixel from hyperspectral Raman images. A good linear relationship and good repeatability were confirmed between DUI and the uniformity of model images. The size of CaSO₄·2H₂O affected the "intra-tablet" homogeneity of spironolactone tablets, which was detected by the DUI value. The better "intra-tablet" homogeneity led to a higher disintegration and dissolution of spironolactone tablets.

Conclusions: DUI represents a novel index to evaluate the "intra-tablet" homogeneity and is beneficial for formulation research and development.

Purpose: Since the first human experience in space, the interest in space research and medicine to explore universe is growing day by day. The extreme space conditions mainly radiation and microgravity effects on human physiology, antimicrobial susceptibility, and efficacy, safety, and stability of drugs. Therefore, the aim of this review is to address the impact of extreme space conditions, mainly microgravity and radiation, on human physiology and highlights the need for future approaches by evaluating the effectiveness of strategies to prevent or mitigate health problems.

Methods: Published papers and NASA technical documents were searched in Pubmed and Google Scholar databases using the keywords ''antimicrobial susceptibility or drug resistance or drug stability or innovations or pharmacokinetic or pharmacodynamics'' and ''radiation or microgravity or space environments or space medicine or space pharmacy'' to prepare this review.

Results: In this review, the challenges regarding physiological effects and drug-related problems are examined through the evaluation of extreme conditions in space. Medications used in spaceflight are summarized, and the role of pharmacists specializing in space medicine is briefly explained. Last but not least, to overcome the aforementioned issues, novel approaches have been addressed, such as personalised treatments, development of space-resistant formulations and various microbial applications.

Conclusions: Further research in the space medicine is required to facilitate the safe and healthy travel of humans to the Moon, Mars and other extraterrestrial destinations. One bear in mind that space research will contribute not only to the exploration of the universe, but also to the advancement of health and technological discoveries on Earth.

Embedded within the field of drug metabolism and pharmacokinetics (DMPK), biotransformation is a discipline that studies the origins, disposition, and structural identity of metabolites to provide a comprehensive safety assessment, including the assessment of exposure coverage in toxicological species. Spanning discovery and development, metabolite identification (metID) scientists employ various strategies and tools to address stage-specific questions aimed at guiding the maturation of early chemical matter into drug candidates. During this process, the identity of major (and minor) circulating human metabolites is ascertained to comply with the regulatory requirements such as the Metabolites in Safety Testing (MIST) guidance. Through the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), the "Translatability of MetID In Vitro Systems Working Group" was created within the Translational and ADME Sciences Leadership Group. The remit of this group was to objectively determine how accurate commonly employed in vitro systems have been with respect to prediction of circulating human metabolites, both qualitatively and quantitatively. A survey composed of 34 questions was conducted across 26 pharmaceutical companies to obtain a foundational understanding of current metID practices, preclinically and clinically, as well as to provide perspective on how successful these practices have been at predicting circulating human metabolites. The results of this survey are presented as an initial snapshot of current industry-based metID practices, including our perspective on how a harmonized framework for the conduct of in vitro metID studies could be established. Future perspectives from current practices to emerging advances with greater translational capability are also provided.

Objective: The oral absorption of a peptide is driven by a high local concentration of a permeation enhancer (PE) in the gastrointestinal tract. We hypothesized that a controlled release of both PE and peptide from a solid formulation, capable of maintaining an effective co-localized concentration of PE and peptide could enhance oral peptide absorption. In this study, we aimed to develop a 3D-printed two-compartment capsular device with controlled pulsatile release of peptide and sodium caprate (C10).

Methods: 3D-printed two-compartment capsular device was fabricated using a fused deposition modeling method. This device was then filled with LY peptide and C10. The release profile was modulated by changing the thickness and polymer type of the capsular device. USP apparatus II dissolution test was used to evaluate the impacts of device thickness and polymer selection on release profile in vitro. An optimal device was then enteric coated with HPMCAS.

Results: A strong linear relationship between the thickness of capsular devices and the delay in the release onset time was observed. An increase in the device thickness or the use of PLA decreased the release rate. The capsular device with compartment 1, compartment 2 and fence thickness of 0.4; 0.95 and 0.5 mm, respectively, and the use of PVA achieved desired pulsatile release profiles of both peptide and C10. Furthermore, enteric-coated capsular devices with HPMCAS had similar pulsatile release profiles compared to non-enteric coated devices.

Conclusion: These findings suggest potential application of 3D-printing techniques in the formulation development for complex modified drug release products.

Objective: To explore the potential of transnasal drug delivery systems (DDS) as an effective means of bypassing the bloodbrain barrier (BBB) for enhanced central nervous system (CNS) targeting, aiming to improve therapeutic outcomes for CNS disorders while reducing systemic side effects.

Methods: A review of current and emerging DDS technologies, including polymer nanoparticles, liposomes, and micelles, was conducted to assess their suitability for precision-targeted delivery to the brain through the transnasal route.

Results: The investigated DDS demonstrate promising capabilities for CNS targeting via the nasal pathway, effectively preserving both the nasal mucosa and CNS integrity. These systems enhance drug precision within neural tissues, potentially improving therapeutic outcomes without harming adjacent tissues.

Conclusions: Transnasal DDS offer a promising alternative to traditional delivery methods, with significant potential to advance the treatment of cerebrovascular diseases, neurodegenerative disorders, brain tumors, and psychiatric conditions. This approach represents an evolving frontier in neurotherapeutics, with the potential to transform CNS drug delivery practices.

Background: Fingolimod hydrochloride (FH) has emerged as a vital medication for managing Multiple Sclerosis (MS). Despite its high oral bioavailability of 93%, it is plagued by slow oral absorption (T_max = 8-12 h) and extensive hepatic metabolism. Intranasal administration has emerged as an alternative to address these limitations, ensuring efficient central nervous system delivery and minimizing peripheral exposure and first-pass metabolism.

Objective: This study aims to develop and evaluate FH nasal films for enhanced drug delivery.

Methods: A Design of Experiments approach was employed to formulate FH nasal films, utilizing HPMC E50 as a film-forming polymer, PEG 400 as a plasticizer, and Me-β-CD as a permeation enhancer. Two formulations with superior in vitro and ex vivo performance were selected for in vivo evaluation. A comparative pharmacokinetic study was conducted in C57BL/6 J mice in the brain and serum after administration of nasal films and oral FH solution, respectively. Sparse sampling and non-compartmental analysis were used.

Results: FH nasal films efficiently delivered the drug to both serum (C_max(F3) = 0.35 ± 0.021, C_max(F4) = 0.38 ± 0.029 μg/mL) and brain (C_max(F3) = 0.39 ± 0.05, C_max(F4) = 0.44 ± 0.048 μg/mL), achieving higher levels than oral delivery. Brain relative bioavailability (% F_{rel (0-6 h)}) was 519% and 534%, while serum % F_{rel (0-6 h)} was 295% and 343%.

Conclusions: The rapid nose-to-brain delivery within 30 min, in contrast to 10-h Tmax of the oral solution, indicates the potential of a combined IN and oral treatment regimen. This approach could expedite the attainment of steady-state concentrations, offering a promising method for managing multiple sclerosis (MS).

Objective: Glutamate transporters play a crucial role in neurotransmitter homeostasis, but studying their structure and function is challenging due to their membrane-bound nature. This study aims to investigate whether water-soluble QTY-variants of glutamate transporters EAA1, EAA2 and EAA3 retain the conformational characteristics and dynamics of native membrane-bound transporters.

Methods: Molecular dynamics simulations and comparative genomics were used to analyze the structural dynamics of both native transporters and their QTY-variants. Native transporters were simulated in lipid bilayers, while QTY-variants were simulated in aqueous solution. Lipid distortions, relative solvent accessibilities, and conformational changes were examined. Evolutionary conservation profiles were correlated with structural dynamics. Statistical analyses included multivariate analysis to account for confounding variables.

Results: QTY-variants exhibited similar residue-wise conformational dynamics to their native counterparts, with correlation coefficients of 0.73 and 0.56 for EAA1 and EAA3, respectively (p < 0.001). Hydrophobic interactions of native helices correlated with water interactions of QTY- helices (rs = 0.4753, p < 0.001 for EAA1). QTY-variants underwent conformational changes resembling the outward-to-inward transition of native transporters.

Conclusions: Water-soluble QTY-variants retain key structural properties of native glutamate transporters and mimic aspects of native lipid interactions, including conformational flexibility. This research provides valuable insights into the conformational changes and molecular mechanisms of glutamate transport, potentially offering a new approach for studying membrane protein dynamics and drug interactions.

Purpose: We have shown previously that benzyl isothiocyanate (BITC) derived from cruciferous vegetables inhibits self-renewal of breast cancer stem-like cells (bCSC). The current study provides insights into the mechanism of bCSC inhibition by BITC.

Methods: Quantitative real time-polymerase chain reaction and western blot analysis were performed to detect microRNAs (miRNAs) and Forkhead box Q1 (FoxQ1) protein expression, respectively. The bCSC were characterized by aldehyde dehydrogenase 1 activity and flow cytometric analysis of CD49f ^high/CD133^high fraction.

Results: BITC treatment resulted in induction of miR-124-3p expression in MDA-MB-231 and MCF-7 cells. miR-124-3p did not affect BITC-mediated inhibition of cell migration or cell proliferation but it significantly regulated bCSC in response to BITC. We also found that miR-124-3p directly targets the 3'untranslated regions (UTR) of FoxQ1 and negatively regulates its expression. The BITC-mediated inhibition of bCSC was partially attenuated by miR-124-3p inhibitor.

Conclusions: These findings indicate that miR-124-3p plays an important role in BITC-mediated inhibition of bCSC.

Purpose: Volatiles are common in personal care products and dermatological drugs. Determining the impact of evaporation of volatiles on skin permeation is crucial to evaluate and understand their delivery, bioavailability, efficacy and safety. We aim to develop an in-silico model to simulate the impact of evaporation on the dermal absorption of volatiles.

Method: The evaporation of volatile permeants was modelled using vapour pressure as the main factor. This model considers evaporation as a passive diffusion process driven by the concentration gradient between the air-vehicle interface and the ambient environment. The evaporation model was then integrated with a previously published physiologically based pharmacokinetic (PBPK) model of skin permeation and compared with published in vitro permeation test data from the Cosmetics Europe ADME Task Force.

Results: The evaporation-PBPK model shows improved predictions when evaporation is considered. In particular, good agreement has been obtained for the distributions in the evaporative loss, and the overall percutaneous absorption. The model is further compared with published in-silico models from the Cosmetics Europe ADME Task Force where favourable results are achieved.

Conclusion: The evaporation of volatile permeants under finite dose in vitro permeation test conditions has been successfully predicted using a mechanistic model with the intrinsic volatility parameter vapour pressure. Integrating evaporation in PBPK modelling significantly improved the prediction of dermal delivery.