Moussab/ORKG-training-evaluation-set huggingface dataset:
Research field: Medicinal Chemistry and Pharmaceutics
Title: Ferumoxytol for treatment of iron deficiency anemia in patients with chronic kidney disease
Abstract: Background: Iron deficiency anemia (IDA) is a common problem in patients with chronic kidney disease (CKD). Use of intravenous (i.v.) iron effectively treats the resultant anemia, but available iron products have side effects or dosing regimens that limit safety and convenience. Objective: Ferumoxytol (Feraheme™) is a new i.v. iron product recently approved for use in treatment of IDA in CKD patients. This article reviews the structure, pharmacokinetics, and clinical trial results on ferumoxytol. The author also offers his opinions on the role of this product in clinical practice. Methods: This review encompasses important information contained in clinical and preclinical studies of ferumoxytol and is supplemented with information from the US Food and Drug Administration. Results/conclusion: Ferumoxytol offers substantial safety and superior efficacy compared with oral iron therapy. As ferumoxytol can be administered as 510 mg in < 1 min, it is substantially more convenient than other iron products in nondialysis patients. Although further experience with this product is needed in patients at higher risk of drug reactions, ferumoxytol is likely to be highly useful in the hospital and outpatient settings for treatment of IDA.
Extracted statement — Product: Ferumoxytol
Research field: Medicinal Chemistry and Pharmaceutics
Title: Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study
Abstract: Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI). Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2* signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI. Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman ρ = 0.7824; P = 0.0016). Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors. Clin Cancer Res; 23(14); 3638–48. ©2017 AACR.
Extracted statement — Product: Ferumoxytol
Research field: Medicinal Chemistry and Pharmaceutics
Title: Galantamine-loaded solid–lipid nanoparticles for enhanced brain delivery: preparation, characterization, in vitro and in vivo evaluations
Abstract: Abstract Galantamine hydrobromide, a promising acetylcholinesterase inhibitor is reported to be associated with cholinergic side effects. Its poor brain penetration results in lower bioavailability to the target site. With an aim to overcome these limitations, solid–lipid nanoparticulate formulation of galantamine hydrobromide was developed employing biodegradable and biocompatible components. The selected galantamine hydrobromide-loaded solid–lipid nanoparticles offered nanocolloidal with size lower than 100 nm and maximum drug entrapment 83.42 ± 0.63%. In vitro drug release from these spherical drug-loaded nanoparticles was observed to be greater than 90% for a period of 24 h in controlled manner. In vivo evaluations demonstrated significant memory restoration capability in cognitive deficit rats in comparison with naive drug. The developed carriers offered approximately twice bioavailability to that of plain drug. Hence, the galantamine hydrobromide-loaded solid–lipid nanoparticles can be a promising vehicle for safe and effective delivery especially in disease like Alzheimer’s.
Extracted statement — Uses drug: Galantamine
Research field: Medicinal Chemistry and Pharmaceutics
Title: The proton permeability of self-assembled polymersomes and their neuroprotection by enhancing a neuroprotective peptide across the blood–brain barrier after modification with lactoferrin
Abstract: Biotherapeutics such as peptides possess strong potential for the treatment of intractable neurological disorders. However, because of their low stability and the impermeability of the blood-brain barrier (BBB), biotherapeutics are difficult to transport into brain parenchyma via intravenous injection. Herein, we present a novel poly(ethylene glycol)-poly(d,l-lactic-co-glycolic acid) polymersome-based nanomedicine with self-assembled bilayers, which was functionalized with lactoferrin (Lf-POS) to facilitate the transport of a neuroprotective peptide into the brain. The apparent diffusion coefficient (D*) of H(+) through the polymersome membrane was 5.659 × 10(-26) cm(2) s(-1), while that of liposomes was 1.017 × 10(-24) cm(2) s(-1). The stability of the polymersome membrane was much higher than that of liposomes. The uptake of polymersomes by mouse brain capillary endothelial cells proved that the optimal density of lactoferrin was 101 molecules per polymersome. Fluorescence imaging indicated that Lf101-POS was effectively transferred into the brain. In pharmacokinetics, compared with transferrin-modified polymersomes and cationic bovine serum albumin-modified polymersomes, Lf-POS obtained the greatest BBB permeability surface area and percentage of injected dose per gram (%ID per g). Furthermore, Lf-POS holding S14G-humanin protected against learning and memory impairment induced by amyloid-β25-35 in rats. Western blotting revealed that the nanomedicine provided neuroprotection against over-expression of apoptotic proteins exhibiting neurofibrillary tangle pathology in neurons. The results indicated that polymersomes can be exploited as a promising non-invasive nanomedicine capable of mediating peptide therapeutic delivery and controlling the release of drugs to the central nervous system.
Extracted statement — Uses drug: Humanin
Research field: Medicinal Chemistry and Pharmaceutics
Title: Paclitaxel-loaded poly(D,L-lactide-co-glycolide) nanoparticles for radiotherapy in hypoxic human tumor cells in vitro
Abstract: Radioresistant hypoxic cells may contribute to the failure of radiation therapy in controlling certain tumors. Some studies have suggested the radiosensitizing effect of paclitaxel. The poly(D,L-lactide-co-glycolide)(PLGA) nanoparticles containing paclitaxel were prepared by o/w emulsification-solvent evaporation method. The physicochemical characteristics of the nanoparticles (i.e. encapsulation efficiency, particle size distribution, morphology, in vitro release) were studied. The morphology of the two human tumor cell lines: a carcinoma cervicis (HeLa) and a hepatoma (HepG2), treated with paclitaxel-loaded nanoparticles was photomicrographed. Flow cytometry was used to quantify the number of the tumor cells held in the G2/M phase of the cell cycle. The cellular uptake of nanoparticles was evaluated by transmission electronic microscopy. Cell viability was determined by the ability of single cell to form colonies in vitro. The prepared nanoparticles were spherical in shape with size between 200nm and 800nm. The encapsulation efficiency was 85.5％. The release behaviour of paclitaxel from the nanoparticles exhibited a biphasic pattern characterised by a fast initial release during the first 24 h, followed by a slower and continuous release. Co-culture of the two tumor cell lines with paclitaxel-loaded nanoparticles demonstrated that the cell morphology was changed and the released paclitaxel retained its bioactivity to block cells in the G2/M phase. The cellular uptake of nanoparticles was observed. The free paclitaxel and paclitaxel-loaded nanoparticles effectively sensitized hypoxic HeLa and HepG2 cells to radiation. Under this experimental condition, the radiosensitization of paclitaxel-loaded nanoparticles was more significant than that of free paclitaxel.Keywords: Paclitaxel；Drug delivery；Nanoparticle；Radiotherapy；Hypoxia；Human tumor cells；cellular uptake
Extracted statement — keywords: Hypoxia
Research field: Medicinal Chemistry and Pharmaceutics
Title: Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterization
Abstract: Engineered cocrystals offer an alternative solid drug form with tailored physicochemical properties. Interestingly, although cocrystals provide many new possibilities, they also present new challenges, particularly in regard to their design and large-scale manufacture. Current literature has primarily focused on the preparation and characterization of novel cocrystals typically containing only the drug and coformer, leaving the subsequent formulation less explored. In this paper we propose, for the first time, the use of hot melt extrusion for the mechanochemical synthesis of pharmaceutical cocrystals in the presence of a meltable binder. In this approach, we examine excipients that are amenable to hot melt extrusion, forming a suspension of cocrystal particulates embedded in a pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model cocrystal reagent pair, formulations extruded with a small molecular matrix carrier (xylitol) were examined to be intimate mixtures wherein the newly formed cocrystal particulates were physically suspended in a matrix. With respect to formulations extruded using polymeric carriers (Soluplus and Eudragit EPO, respectively), however, there was no evidence within PXRD patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was established in this study that an appropriate carrier for a cocrystal reagent pair during HME processing should satisfy certain criteria including limited interaction with parent reagents and cocrystal product, processing temperature sufficiently lower than the onset of cocrystal Tm, low melt viscosity, and rapid solidification upon cooling.
Extracted statement — Uses drug: Ibuprofen
Research field: Medicinal Chemistry and Pharmaceutics
Title: The Effect of Cyclodextrins on the In Vitro and In Vivo Properties of Insulin-Loaded Poly (D,L-Lactic-Co-Glycolic Acid) Microspheres: EFFECT OF CYCLODEXTRINS ON MICROSPHERES
Abstract: In this work we describe the development and characterization of a new formulation of insulin (INS). Insulin was complexed with cyclodextrins (CD) in order to improve its solubility and stability being available as a dry powder, after encapsulation into poly (D,L-lactic-co-glycolic acid) (PLGA) microspheres. The complex INS : CD was encapsulated into microspheres in order to obtain particles with an average diameter between 2 and 6 microm. This system was able to induce significant reduction of the plasma glucose level in two rodent models, normal mice and diabetic rats, after intratracheal administration.
Extracted statement — Uses drug: Insulin
Research field: Medicinal Chemistry and Pharmaceutics
Title: Encapsulation of insulin–cyclodextrin complex in PLGA microspheres: a new approach for prolonged pulmonary insulin delivery
Abstract: The insulin administration by pulmonary route has been investigated in the last years with good perspectives as alternative for parenteral administration. However, it has been reported that insulin absorption after pulmonary administration is limited by various factors. Moreover, in the related studies one daily injection of long-acting insulin was necessary for a correct glycemic control. To abolish the insulin injection, the present study aimed to develop a new formulation for prolonged pulmonary insulin delivery based on the encapsulation of an insulin:dimethyl-β-cyclodextrin (INS:DM-β-CD) complex into PLGA microspheres. The molar ratio of insulin/cyclodextrin in the complex was equal to 1:5. The particles were obtained by the w/o/w solvent evaporation method. The inner aqueous phase of the w/o/w multiple emulsion contained the INS:DM-β-CD complex. The characteristics of the INS:DM-β-CD complex obtained were assessed by 1H-NMR spectroscopy and Circular Dichroism study. The average diameter of the microspheres prepared, evaluated by laser diffractometry, was 2.53 ± 1.8 µm and the percentage of insulin loading was 14.76 ± 1.1. The hypoglycemic response after intratracheal administration (3.0 I.U. kg−1) of INS:DM-β-CD complex-loaded microspheres to diabetic rats indicated an efficient and prolonged release of the hormone compared with others insulin formulations essayed.
Extracted statement — Uses drug: Insulin
Research field: Medicinal Chemistry and Pharmaceutics
Title: Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterization
Abstract: Engineered cocrystals offer an alternative solid drug form with tailored physicochemical properties. Interestingly, although cocrystals provide many new possibilities, they also present new challenges, particularly in regard to their design and large-scale manufacture. Current literature has primarily focused on the preparation and characterization of novel cocrystals typically containing only the drug and coformer, leaving the subsequent formulation less explored. In this paper we propose, for the first time, the use of hot melt extrusion for the mechanochemical synthesis of pharmaceutical cocrystals in the presence of a meltable binder. In this approach, we examine excipients that are amenable to hot melt extrusion, forming a suspension of cocrystal particulates embedded in a pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model cocrystal reagent pair, formulations extruded with a small molecular matrix carrier (xylitol) were examined to be intimate mixtures wherein the newly formed cocrystal particulates were physically suspended in a matrix. With respect to formulations extruded using polymeric carriers (Soluplus and Eudragit EPO, respectively), however, there was no evidence within PXRD patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was established in this study that an appropriate carrier for a cocrystal reagent pair during HME processing should satisfy certain criteria including limited interaction with parent reagents and cocrystal product, processing temperature sufficiently lower than the onset of cocrystal Tm, low melt viscosity, and rapid solidification upon cooling.
Extracted statement — Uses drug: isonicotinamide
Research field: Medicinal Chemistry and Pharmaceutics
Title: Low active loading of cargo into engineered extracellular vesicles results in inefficient miRNA mimic delivery
Abstract: ABSTRACT Extracellular vesicles (EVs) hold great potential as novel systems for nucleic acid delivery due to their natural composition. Our goal was to load EVs with microRNA that are synthesized by the cells that produce the EVs. HEK293T cells were engineered to produce EVs expressing a lysosomal associated membrane, Lamp2a fusion protein. The gene encoding pre-miR-199a was inserted into an artificial intron of the Lamp2a fusion protein. The TAT peptide/HIV-1 transactivation response (TAR) RNA interacting peptide was exploited to enhance the EV loading of the pre-miR-199a containing a modified TAR RNA loop. Computational modeling demonstrated a stable interaction between the modified pre-miR-199a loop and TAT peptide. EMSA gel shift, recombinant Dicer processing and luciferase binding assays confirmed the binding, processing and functionality of the modified pre-miR-199a. The TAT-TAR interaction enhanced the loading of the miR-199a into EVs by 65-fold. Endogenously loaded EVs were ineffective at delivering active miR-199a-3p therapeutic to recipient SK-Hep1 cells. While the low degree of miRNA loading into EVs through this approach resulted in inefficient distribution of RNA cargo into recipient cells, the TAT TAR strategy to load miRNA into EVs may be valuable in other drug delivery approaches involving miRNA mimics or other hairpin containing RNAs.
Extracted statement — Membrane protein: Lamp2a
Research field: Medicinal Chemistry and Pharmaceutics
Title: Preparation, Biodistribution and Neurotoxicity of Liposomal Cisplatin following Convection Enhanced Delivery in Normal and F98 Glioma Bearing Rats
Abstract: The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (NSCLC). The second, produced in our laboratory, was based on the ability of cisplatin to form coordination complexes with lipid cholesteryl hemisuccinate (CHEMS). The in vitro tumoricidal activity of the former previously has been described in detail by other investigators. The CHEMS liposomal formulation had a Pt loading efficiency of 25% and showed more potent in vitro cytotoxicity against F98 glioma cells than free cisplatin at 24 h. In vivo CHEMS liposomes showed high retention at 24 h after intracerebral (i.c.) convection enhanced delivery (CED) to F98 glioma bearing rats. Neurotoxicologic studies were carried out in non-tumor bearing Fischer rats following i.c. CED of Lipoplatin™ or CHEMS liposomes or their “hollow” counterparts. Unexpectedly, Lipoplatin™ was highly neurotoxic when given i.c. by CED and resulted in death immediately following or within a few days after administration. Similarly “hollow” Lipoplatin™ liposomes showed similar neurotoxicity indicating that this was due to the liposomes themselves rather than the cisplatin. This was particularly surprising since Lipoplatin™ has been well tolerated when administered intravenously. In contrast, CHEMS liposomes and their “hollow” counterparts were clinically well tolerated. However, a variety of dose dependent neuropathologic changes from none to severe were seen at either 10 or 14 d following their administration. These findings suggest that further refinements in the design and formulation of cisplatin containing liposomes will be required before they can be administered i.c. by CED for the treatment of brain tumors and that a formulation that may be safe when given systemically may be highly neurotoxic when administered directly into the brain.
Extracted statement — Type of nanocarrier: Liposomes
Research field: Medicinal Chemistry and Pharmaceutics
Title: Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain Transport
Abstract: Effectiveness of CNS-acting drugs depends on the localization, targeting, and capacity to be transported through the blood–brain barrier (BBB) which can be achieved by designing brain-targeting delivery vectors. Hence, the objective of this study was to screen the formulation and process variables affecting the performance of sertraline (Ser-HCl)-loaded pegylated and glycosylated liposomes. The prepared vectors were characterized for Ser-HCl entrapment, size, surface charge, release behavior, and in vitro transport through the BBB. Furthermore, the compatibility among liposomal components was assessed using SEM, FTIR, and DSC analysis. Through a thorough screening study, enhancement of Ser-HCl entrapment, nanosized liposomes with low skewness, maximized stability, and controlled drug leakage were attained. The solid-state characterization revealed remarkable interaction between Ser-HCl and the charging agent to determine drug entrapment and leakage. Moreover, results of liposomal transport through mouse brain endothelialpolyoma cells demonstrated greater capacity of the proposed glycosylated liposomes to target the cerebellar due to its higher density of GLUT1 and higher glucose utilization. This transport capacity was confirmed by the inhibiting action of both cytochalasin B and phenobarbital. Using C6 glioma cells model, flow cytometry, time-lapse live cell imaging, and in vivo NIR fluorescence imaging demonstrated that optimized glycosylated liposomes can be transported through the BBB by classical endocytosis, as well as by specific transcytosis. In conclusion, the current study proposed a thorough screening of important formulation and process variabilities affecting brain-targeting liposomes for further scale-up processes.
Extracted statement — Type of nanocarrier: Liposomes
Research field: Medicinal Chemistry and Pharmaceutics
Title: A Novel Nanoparticle Formulation for Sustained Paclitaxel Delivery
Abstract: PurposeTo develop a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate (GMO) for the delivery of a wide variety of therapeutics including paclitaxel.MethodsChitosan/GMO nanoparticles were prepared by multiple emulsion (o/w/o) solvent evaporation methods. Particle size and surface charge were determined. The morphological characteristics and cellular adhesion were evaluated with surface or transmission electron microscopy methods. The drug loading, encapsulation efficiency, in vitro release and cellular uptake were determined using HPLC methods. The safety and efficacy were evaluated by MTT cytotoxicity assay in human breast cancer cells (MDA-MB-231).ResultsThese studies provide conceptual proof that chitosan/GMO can form polycationic nano-sized particles (400 to 700 nm). The formulation demonstrates high yields (98 to 100%) and similar entrapment efficiencies. The lyophilized powder can be stored and easily be resuspended in an aqueous matrix. The nanoparticles have a hydrophobic inner-core with a hydrophilic coating that exhibits a significant positive charge and sustained release characteristics. This novel nanoparticle formulation shows evidence of mucoadhesive properties; a fourfold increased cellular uptake and a 1000-fold reduction in the IC50 of PTX.ConclusionThese advantages allow lower doses of PTX to achieve a therapeutic effect, thus presumably minimizing the adverse side effects.
Extracted statement — keywords: mucoadhesive
Research field: Medicinal Chemistry and Pharmaceutics
Title: Nanoemulsions: formation, properties and applications
Abstract: Nanoemulsions are kinetically stable liquid-in-liquid dispersions with droplet sizes on the order of 100 nm. Their small size leads to useful properties such as high surface area per unit volume, robust stability, optically transparent appearance, and tunable rheology. Nanoemulsions are finding application in diverse areas such as drug delivery, food, cosmetics, pharmaceuticals, and material synthesis. Additionally, they serve as model systems to understand nanoscale colloidal dispersions. High and low energy methods are used to prepare nanoemulsions, including high pressure homogenization, ultrasonication, phase inversion temperature and emulsion inversion point, as well as recently developed approaches such as bubble bursting method. In this review article, we summarize the major methods to prepare nanoemulsions, theories to predict droplet size, physical conditions and chemical additives which affect droplet stability, and recent applications.
Extracted statement — Type of nanocarrier: Nanoemulsions