Pharmaceutical Research最新文献

Background: Osteoarthritis is the prevailing form of inflammatory condition in joints of adults and the aging population, leading to long-term disability and chronic pain. Current therapeutic options have variable therapeutic efficacy and/or several side effects.

Methods: A randomized, placebo-controlled, double-blind clinical trial was conducted in 62 participants using a nutraceutical [standardized Boswellia serrata Roxb. gum resin (300 mg) and Apium graveolens L. seed extract (250 mg)], to determine its safety and efficacy for supporting cartilage health and reduction in knee osteoarthritis symptoms. All participants were assessed for physical function and pain with the help of WOMAC, VAS, Physicians' Global Assessment for the six-minute walk test/pain. Knee X-ray, KOOS questionnaire score, and FACIT-F score were assessed. Additionally, inflammatory, cartilage degeneration and regeneration biomarkers in serum and urine were evaluated at baseline and after 90 days of treatment.

Results: Oral administration of the nutraceutical resulted in prolonged symptomatic relief with reduced pain, stiffness, and swelling. Inflammatory (serum IL-7, IL-1, IL-6, hs-CRP, TNF-α, ESR) and cartilage degeneration biomarkers (serum CTX-II, COMP, MMP-3 and urinary CTX-II) were decreased in the nutraceutical group compared to baseline and placebo. Furthermore, serum N-propeptide of collagen IIA (PIIANP) and procollagen-type-C propeptide (PIICP) levels were increased in the nutraceutical group, suggesting collagen synthesis contributing to cartilage regeneration. At given doses for 90 days, there were no adverse effects based on the clinical examination, biochemical, hematological, and ECG analysis.

Conclusions: Taken together, the combination of Boswellia and celery could be a safe and promising herbal nutraceutical option for managing osteoarthritis and cartilage health effectively.

The U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a public workshop on May 2-3, 2024, titled "Considerations and Potential Regulatory Applications for a Model Master File (Lachaine et al Can J Psychiatry. 60:S40-S47, 2015)". The workshop aimed to discuss the application of the Model Master File (MMF) concept in regulatory submissions that contain model integrated evidence (MIE), improving model sharing, model standardization, regulatory consistency, and regulatory efficiency. On Day 1, there was a session dedicated to MMF applications for long-acting injectables (LAIs). This perspective summarizes presentations, panel discussion, and small group discussion for the potential applications of MMFs in LAI product development, including case studies and potential situations in which MMFs can support regulatory submissions. The scientific presentations discussed the application of MMFs in mechanistic physiologically based pharmacokinetic (PBPK), multiphysics simulation, and population pharmacokinetics (popPK) models, as well as the potential utility of a model-integrated bioequivalence (MI-BE) framework. Additionally, challenges and considerations of implementing MMFs for LAIs were discussed in the panel and small groups. The anticipated benefits of MMFs are recognized among model developers, industries, and regulators.

Purpose: Tylvalosin Tartrate (TAT), a new-generation macrolide antibiotic, undergoes significant degradation in the stomach and in vivo rapid elimination upon oral administration, resulting in poor bioavailability. This study developed TAT enteric amorphous pellets by liquid layering (TAT/EAP-LL) with pH-sensitive and burst release characteristics, to enhance drug stability in the stomach and concentration enrichment in the duodenum.

Methods: The drug loading layer, isolation layer and enteric layer were formed on the surface of the blank core pellets. Investigation into the characteristics of TAT/EAP-LL revealed that stable amorphous solid dispersions in the drug loading layer were formed by liquid layering. Then, DSC analysis confirmed that triethyl citrate significantly improved the film-forming properties of Methacrylic-ethyl acrylate copolymer. Additionally, TAT/EAP-LL was confirmed to exist in the amorphous state by DSC、PXRD and PLM.

Results: In vitro, TAT/EAP-LL demonstrated a similar 4.07% release within 2 h at pH 1.0 as TAT enteric pellets (TAT/EP-LL) and a much faster burst release at pH 6.8, with complete release within 15 min. In vivo, the oral bioavailability of TAT/EAP-LL was improved to 1.71 times compared to commercial formulations and 1.47 times compared to TAT/EP-LL.

Conclusion: This study offers a novel platform for the enhanced oral delivery of TAT and proposes effective formulation strategies for pulsatile drug delivery.

Purpose: To investigate how obesity affects the pharmacokinetics of biologics in a rat model.

Method: Male Long-Evans rats were fed a high-fat diet from the age of 3 weeks and development of obesity was monitored by measuring body size and composition (fat and lean mass). The animals received nivolumab (1 and 8 mg/kg) or recombinant human erythropoietin (rHuEPO, 1000 IU/kg) by intravenous or subcutaneous injection. Serum samples were collected and analyzed using an enzyme-linked immunosorbent assay (ELISA). Endogenous rat IgG was also measured in the nivolumab study. A standard noncompartmental analysis was performed to calculate pharmacokinetic parameters.

Results: When dosed at mg/kg of total body weight approach, no significant differences in pharmacokinetics of nivolumab and rHuEPO between lean and obese cohorts were observed despite significant differences in the body composition. Subcutaneous bioavailability of nivolumab was inversely dependent on the dose level.

Conclusions: Pharmacokinetic parameters of two biologics tested in this work were not affected by obesity, and mg/kg dosing approach was necessary to achieve equivalent exposure in serum. The results were different from our previous findings of significant effect of obesity on pharmacokinetics of human IgG in rats. Additional studies with other biologics are urgently needed in preclinical and clinical settings.

Purpose: Therapeutic monoclonal antibodies (mAbs) are prone to degradation via aggregation and fragmentation. In this study, forced degradation of trastuzumab (TmAb) was explored in saline and in-vitro models having H₂O₂ and exposed to UV light (case study 1)_, both bleomycin (BML) formulation and ferrous ions (Fe²⁺) (case study 2)_, and sodium hypochlorite (NaOCl) (case study 3).

Methods: Size exclusion chromatography, dynamic light scattering, spectroscopic analysis, and fluorescence microscope image processing was carried out for characterizing TmAb degradation.

Results: Saline samples containing TmAb and 0.1% H₂O₂ incubated at 40ºC for 1 h in the presence of UV light showed increased monomer loss by more than 40% compared to TmAb sample without H₂O₂ exposed to UV light. Saline containing TmAb having both 0.1-unit BML and 0.25 mM Fe²⁺ showed increased monomer loss by more than 50% compared to TmAb in saline having only Fe²⁺ or BML. A higher TmAb degradation was also observed in saline containing 0.01% NaOCl compared to saline without NaOCl. Samples containing aggregates of mAb showed altered protein structure. Degradation of TmAb in saline increased with time, temperature, and concentrations of H₂O₂, Fe²⁺_, and NaOCl. At different analysis time points, TmAb monomer loss was higher in saline compared to human serum filtrate, an in-vitro model. Aggregate particles (> 2 µm size) of TmAb were also observed in serum containing both Fe²⁺ and BML.

Conclusion: It can be concluded that rapid TmAb degradation significantly enhanced due to various stress factors, and the aggregates could result in enhanced immunogenic risk to the patients.

Improving the bioavailability  of poorly water-soluble drugs presents a significant challenge in pharmaceutical development. Amorphous solid dispersions (ASDs) have garnered substantial attention for their capability to augment the solubility and dissolution rate of poorly water-soluble drugs, thereby markedly enhancing their bioavailability. ASDs, characterized by a metastable equilibrium where the active pharmaceutical ingredient (API) is molecularly dispersed, offer enhanced absorption compared to crystalline forms. This review explores recent research advancements in ASD, emphasizing dissolution mechanisms, phase separation phenomena, and the importance of drug loading and congruency limits on ASD performance. Principal occurrences such as liquid-liquid phase separation (LLPS) and supersaturation are discussed, highlighting their impact on drug solubility, absorption and subsequent bioavailability. Additionally, it addresses the role of polymers in controlling supersaturation, stabilizing drug-rich nanodroplets, and inhibiting recrystallization. Recent advancements and emerging technologies offer new avenues for ASD characterization and production and demonstrate the potential of ASDs to enhance bioavailability and reduce variability, making possible for more effective and patient-friendly pharmaceutical formulations. Future research directions are proposed, focusing on advanced computational models for predicting ASD stability, use of novel polymeric carriers, and methods for successful preparations.

Background: Nonalcoholic fatty liver disease (NAFLD) comprises multiple heterogeneous pathophysiological conditions commonly evaluated by suboptimal liver biopsies. This study aimed to elucidate the role of 13 diverse histological liver scores in assessing NAFLD disease activity using an in silico pharmacometric model-based approach. We further sought to investigate various noninvasive patient characteristics for their ability to reflect all 13 histological scores and the NAFLD activity score (NAS).

Methods: A histological liver score model was built upon 13 biopsy-based pathological features (binary and categorical scores) from the extensive NASH-CRN (Nonalcoholic Steatohepatitis-Clinical Research Network) observational NAFLD Database study (n = 914 adults) using the concept of item response theory. The impact of 69 noninvasive biomarkers potentially reflecting NAFLD activity was quantitatively described across the entire spectrum of all 13 histological scores.

Results: The model suggested that four different disease facets underlie the cardinal NAFLD features (steatosis, inflammation, hepatocellular ballooning (= NAS); fibrosis; highest correlations: corr_{ballooning-fibrosis} = 0.69/corr_{inflammation-ballooning} = 0.62/corr_{steatosis-inflammation} = 0.60). The 13 histological liver scores were best described by contrasting noninvasive biomarkers: Age and platelets best reflected the fibrosis score, while alanine and aspartate aminotransferase best described the NAS, with diverging contributions of the three individual NAS components to the results of the overall NAS.

Conclusions: An in silico histological liver score model allowed to simultaneously quantitatively analyze 13 features beyond NAS and fibrosis, characterizing different disease facets underlying NAFLD and revealing the contrasting ability of 69 noninvasive biomarkers to reflect the diverse histological (sub-)scores.

Metabolic alterations are commonly associated with various cancers and are recognized as contributing factors to cancer progression, invasion, and metastasis. Drug repurposing, a strategy in drug discovery, utilizes existing knowledge to recommend established drugs for new indications based on clinical data or biological evidence. This approach is considered a less risky alternative to traditional drug development. Metformin, a biguanide, is a product of Galega officinalis (French lilac) primarily prescribed for managing type 2 diabetes, is recognized for its ability to reduce hepatic glucose production and enhance insulin sensitivity, particularly in peripheral tissues such as muscle. It also improves glucose uptake and utilization while decreasing intestinal glucose absorption. Statins, first isolated from the fungus Penicillium citrinum is another class of medication mainly used to lower cholesterol levels in individuals at risk for cardiovascular diseases, work by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is essential for cholesterol biosynthesis in the liver. Metformin is frequently used in conjunction with statins to investigate their potential synergistic effects. Combination of metformin and simvastatin has gathered much attention in cancer research because of its potential advantages for cancer prevention and treatment. In this review, we analyze the effects of metformin and simvastatin, both individually and in combination, on key cancer hallmarks, and how this combination affects the expression of biomolecules and associated signaling pathways. We also summarize preclinical research, including clinical trials, on the efficacy, safety, and potential applications of repurposing metformin and simvastatin for cancer therapy.

Purpose: Recombinant human B-type natriuretic peptide (rhBNP) has been extensively proven to be an effective mean of heart failure (HF) therapy, but its clinical application is limited by its very short half-life. This study aims to combine in vitro transcribed mRNA (IVT mRNA) and fusion protein technology to develop a rhBNP-Fc mRNA drug with long half-life, high efficiency and few side effects to treat HF.

Methods: The rhBNP-Fc fusion mRNA with IgG4-Fc sequence was produced by IVT technology. rhBNP-Fc mRNA was transfected into HEK293T cells to examine the expression in vitro. rhBNP-Fc mRNA encapsulated in LNP was injected into normal mice to detect the translation efficiency, half-life and negative effects in vivo. Finally, it was injected into doxorubicin-induced HF mice to screen the cardiac protective effect.

Results: The rhBNP-Fc fusion mRNA extended the half-life of rhBNP, showing sustained expression in cell line for at least one day. rhBNP-Fc mRNA translation showed dose-dependent levels, and was still detectable 5 d after injection in vivo. In the HF mouse model, a single administration of rhBNP-Fc mRNA-LNP improved cardiac function, including improving heart ejection and reducing HF biomarkers expression. Additionally, rhBNP-Fc mRNA-LNP treatment mitigated myocardial damage, normalized cardiomyocyte structure, and reduced the levels of pro-inflammatory cytokines.

Conclusion: The rhBNP-Fc mRNA has the potential to serve as an alternative to traditional protein therapies, thereby reducing clinical dosages, injection frequencies, and treatment costs. Our findings offer new insights into the development and application of mRNA drugs, emphasizing their therapeutic potential in long-acting drugs.

Purpose: Epigenetic modifications, such as aberrant DNA methylation, histone alterations, non-coding RNA remodeling, and modulation of transcription factors, are pivotal in the pathogenesis of diverse malignancies. Reactive oxygen species (ROS) have the capacity to impact these epigenetic mechanisms, including DNA methylation, throughout the different stages of cancer development. Therefore, the aim of this review is to address the impact of.

Methods: Published papers were searched in Pubmed and Google Scholar databases using the keywords "epigenetic", or "DNA methylation", or "phytochemicals", or "chemoprevention" to prepare this review.

Results: There is mounting evidence indicating that diminishing ROS accumulation within cells can regulate the function of DNA methyltransferases (DNMTs). Moreover, activation of the cellular defense system can impede and potentially reverse the progression of tumors in cancerous cells. As a result, ROS scavengers, antioxidants, and demethylating agents have emerged as potential therapeutic approaches for specific types of cancer. Additionally, dietary phytochemicals present in fruits, vegetables, and herbs, which have been utilized for centuries, exhibit the capability to modulate transcription factors, decrease inflammation, deliver antioxidant benefits, induce cell-cycle arrest, and stimulate apoptosis.

Conclusion: These phytochemicals can also renew and reprogram the expression of genes that suppress cancer. Thus, prolonged exposure to phytochemicals at low doses represents an innovative therapeutic tactic for the prevention of cancer.