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Pharmaceutical Research
Journal Prestige (SJR): 1.077
Citation Impact (citeScore): 3
Number of Followers: 152  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
Published by Springer-Verlag Homepage  [2349 journals]
  • Establishment of a Mucin Secreting Cell Line Cx-03 from an Uterine Carcino
           Sarcoma
    • Authors: R. Bücker; C. Schaefer; A. D. Gruber; J. Hoppe; L. Lazzerini; J. Barinoff; J. Sehouli; Günter Cichon
      Abstract: Purpose The identification of novel cell lines which combine the most important properties of mucosal membranes in terms of drug absorption, transmembrane transport and mucus secretion can help to establish improved and meaningful test systems for pharmacological and infectiological studies. Methods We have established a novel mucus secreting tumor cell line (Cx-03) derived from a female patient who underwent radical hysterectomy after diagnosis of a large malignant carcino sarcoma (Muellerian mixed tumor). Via xenotransplantation in SCID beige mice, recultivation and subcloning a stable cell line was established from primary tumor cells. Results Human origin and novelty of the cell line was determined by karyotype analysis and STR fingerprint. During growth cells produce considerable amounts of a PAS positive viscoelastic mucus. Immunostaining revealed expression of mucins and the mucin modifier CLCA1. We demonstrate in initial electrophysiological experiments that confluent, polarized monolayers of Cx-03 are formed (on PCF-filter supports) that exhibit stable electrical resistance (> 600 Ω cm2). Confluent Cx-03 monolayers express barrier-forming tight junction proteins claudin-1 and -4 which co-localize with zonula occludens protein-1 (ZO-1) at cell-cell contacts. Conclusions Mucus secretion is a rare property among mammalian cell lines. In combination with its ability to form polarized monolayers Cx-03 might contribute as a novel cell based model for drug absorption, transport and barrier studies.
      PubDate: 2018-11-08
      DOI: 10.1007/s11095-018-2533-z
      Issue No: Vol. 36, No. 1 (2018)
       
  • Stearic Acid-Grafted Chitooligosaccharide Nanomicelle System with
           Biocleavable Gadolinium Chelates as a Multifunctional Agent for Tumor
           Imaging and Drug Delivery
    • Authors: Chuhua Xin; Xiuzhong Yao; Bin Du; Weiyu Yang; Liuguo Wang; Lirong Ma; Weiyu Weng
      Abstract: Purpose Theranostic nanoplatforms are promising approaches for diagnosis and treatment. Here, we report a drug-loaded nanomicelle system with biocleavable gadolinium (Gd) chelates as a multifunctional biodegradable agent for simultaneous magnetic resonance imaging (MRI) and drug delivery. Methods Self-assembled nanomicelles based on stearic acid-grafted chitooligosaccharide were utilized as vehicles. Gd chelates, DTPA-Gds, were linked to the nanomicelles via redox-responsive disulfide bonds, and hydrophobic drugs were encapsulated in the micelle cores. MRI and cargo delivery were investigated in orthotopic pancreatic tumor-bearing mice. Results In vivo MRI demonstrated that the biodegradable agent was cleaved by endogenous thiols after intravenous injection, and the released DTPA-Gds were eliminated rapidly. At the same time, the agent resulted in a greater contrast enhancement of T1-weighted MR signal intensity at the tumor region than Magnevist®, and the tumor boundaries were clearly defined for at least 2 h. In addition, the agent possessed high drug-loading and tumor-targeting capacities. Loading content and encapsulation efficiency of docetaxel were 3.2% and 99.4%, respectively. Compared with Taxotere®, the commercially available docetaxel injection, the docetaxel-loaded agent significantly increased the drug concentration in tumor tissue in vivo. Conclusion The fabricated multifunctional agent may serve as a biodegradable nanoscale MRI contrast agent and as a drug delivery system for tumor diagnosis and treatment.
      PubDate: 2018-11-08
      DOI: 10.1007/s11095-018-2530-2
      Issue No: Vol. 36, No. 1 (2018)
       
  • New Classes of Polycationic Compounds as Preservatives for Ophthalmic
           Formulations
    • Authors: Dörte von Deylen; Christina Dreher; Oliver Seidelmann; Stephan Reichl
      Abstract: Purpose The purpose of this research work was to develop new polycationic compounds based on pyridine and piperidine structures with high antimicrobial activities against bacteria and fungi. Furthermore, the compounds should offer a lower toxicity than the commonly used preservatives for ophthalmic formulations, such as benzalkonium chloride (BAC) and polyquaternium-1 (PQ1). Methods Two polymers and three dimeric compounds were developed. Minimum inhibitory concentrations were determined for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis. The compounds were characterized regarding their impact on cell viability, cytotoxicity, epithelial integrity and surface tension. MTT and CytoTox-Glo™ assays, permeation studies with mannitol and transepithelial electrical resistance (TEER) measurements were performed on human corneal epithelial or MDCK I cells. BAC and PQ1 were used as references. Results Three polycationic compounds exhibited high antimicrobial activity against the tested microorganisms comparable to that of BAC. Four compounds were tolerated as well as or better than PQ1. In addition, the TEER, permeability and surface tension were only affected by compounds with amphiphilic properties. Conclusion The pyridine- and piperidine-based polycationic compounds are promising candidates as new preservatives for ophthalmic formulations. Their high antimicrobial efficacy and good tolerability indicate a different mechanism of action compared to BAC.
      PubDate: 2018-11-08
      DOI: 10.1007/s11095-018-2536-9
      Issue No: Vol. 36, No. 1 (2018)
       
  • Mycobacterium Tuberculosis and Interactions with the Host Immune System:
           Opportunities for Nanoparticle Based Immunotherapeutics and Vaccines
    • Authors: Raymonde B. Bekale; Su-Mari Du Plessis; Nai-Jen Hsu; Jyoti R. Sharma; Samantha L. Sampson; Muazzam Jacobs; Mervin Meyer; Gene D. Morse; Admire Dube
      Abstract: Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a deadly infectious disease. The thin pipeline of new drugs for TB, the ineffectiveness in adults of the only vaccine available, i.e. the Bacillus Calmette-Guerin vaccine, and increasing global antimicrobial resistance, has reinvigorated interest in immunotherapies. Nanoparticles (NPs) potentiate the effect of immune modulating compounds (IMC), enabling cell targeting, improved transfection of antigens, enhanced compound stability and provide opportunities for synergistic action, via delivery of multiple IMCs. In this review we describe work performed in the application of NPs towards achieving immune modulation for TB treatment and vaccination. Firstly, we present a comprehensive review of M. tuberculosis and how the bacterium modulates the host immune system. We find that current work suggest great promise of NP based immunotherapeutics as novel treatments and vaccination systems. There is need to intensify research efforts in this field, and rationally design novel NP immunotherapeutics based on current knowledge of the mycobacteriology and immune escape mechanisms employed by M. tuberculosis.
      PubDate: 2018-11-08
      DOI: 10.1007/s11095-018-2528-9
      Issue No: Vol. 36, No. 1 (2018)
       
  • Physicochemical Characterization and Pharmacokinetics of
           Agomelatine-Loaded PLGA Microspheres for Intramuscular Injection
    • Authors: Hongjuan Zhang; Chenguang Pu; Qiao Wang; Xinyi Tan; Jingxin Gou; Haibing He; Yu Zhang; Tian Yin; Yanjiao Wang; Xing Tang
      Abstract: Purpose The aim of this study was to design agomelatine loaded long acting injectable microspheres, with an eventual goal of reducing the frequency of administration and improving patient compliance in treatment of depression. Methods AGM-loaded microspheres were prepared by an O/W emulsion solvent evaporation method. The physicochemical properties and in vitro performance of the microspheres were characterized. The pharmacokinetics of different formulations with various particle sizes and drug loadings were evaluated. Results AGM-loaded microspheres with drug loading of 23.7% and particle size of 60.2 μm were obtained. The in vitro release profiles showed a small initial burst release (7.36%) followed by a fast release, a period of lag time and a second accelerated release. Pore formation and pore closure were observed in vitro, indicating that the release of drug from microspheres is dominated by water-filled pores. Pharmacokinetic studies showed that AGM microspheres could release up to 30 days in vivo at a steady plasma concentration. As well, particle size and drug loading could significantly influence the in vivo release of AGM microspheres. Conclusions AGM-loaded microspheres are a promising carrier for the treatment of major depressant disorder.
      PubDate: 2018-11-08
      DOI: 10.1007/s11095-018-2538-7
      Issue No: Vol. 36, No. 1 (2018)
       
  • Pharmaceutical Potential of a Novel Chitosan Derivative Schiff Base with
           Special Reference to Antibacterial, Anti-Biofilm, Antioxidant,
           Anti-Inflammatory, Hemocompatibility and Cytotoxic Activities
    • Authors: Sameh S. Ali; El-Refaie Kenawy; Fatma I. Sonbol; Jianzhong Sun; Marwa Al-Etewy; Asmaa Ali; Liu Huizi; Nessma A. El-Zawawy
      Abstract: Purpose Chitosan and its derivatives possess several unique properties relevant in the field of pharmaceutics and medicinal chemistry. This study aimed to evaluate the pharmaceutical performance of an innovative chitosan derivative, methyl acrylate chitosan bearing p-nitrobenzaldehyde (MA*CS*pNBA) Schiff base. Methods The antibacterial activity of MA*CS*pNBA was tested against multi-drug resistant (MDR) Gram-negative and Gram-positive bacteria using agar-well diffusion method. Anti-biofilm formation was analyzed using a microtitre plate. Antioxidant assays were performed to assess the scavenging activity of MA*CS*pNBA using DPPH, hydrogen peroxide, superoxide together with its reducing power activity. Anti-inflammatory activity was evaluated by albumin denaturation, membrane stabilization, and proteinase inhibition methods. MA*CS*pNBA was tested for its hemolytic efficiency on human erythrocytes. Cytotoxicity of MA*CS*pNBA was evaluated by MTT assay. Results MA*CS*pNBA showed a significant performance as an antibacterial candidate against MDR bacteria, anti-biofilm, antioxidant and anti-inflammatory biomaterial, evidencing hemocompatibility and no cytotoxicity. It exhibited a significant negative correlation with biofilm formation by the MDR-PA-09 strain. Biological activities were found to be significantly concentration-dependent. Conclusions the newly chitosan derivative MA*CS*pNBA showed to be promising for pharmaceutical applications, expanding the treatment ways toward skin burn infections since it allied excellent antibacterial, anti-biofilm, antioxidant, anti-inflammatory, hemocompatibility and absence of cytotoxic activities.
      PubDate: 2018-11-07
      DOI: 10.1007/s11095-018-2535-x
      Issue No: Vol. 36, No. 1 (2018)
       
  • An Overview of 3D Printing Technologies for Soft Materials and Potential
           Opportunities for Lipid-based Drug Delivery Systems
    • Authors: Kapilkumar Vithani; Alvaro Goyanes; Vincent Jannin; Abdul W. Basit; Simon Gaisford; Ben J. Boyd
      Abstract: Purpose Three-dimensional printing (3DP) is a rapidly growing additive manufacturing process and it is predicted that the technology will transform the production of goods across numerous fields. In the pharmaceutical sector, 3DP has been used to develop complex dosage forms of different sizes and structures, dose variations, dose combinations and release characteristics, not possible to produce using traditional manufacturing methods. However, the technology has mainly been focused on polymer-based systems and currently, limited information is available about the potential opportunities for the 3DP of soft materials such as lipids. Methods This review paper emphasises the most commonly used 3DP technologies for soft materials such as inkjet printing, binder jetting, selective laser sintering (SLS), stereolithography (SLA), fused deposition modeling (FDM) and semi-solid extrusion, with the current status of these technologies for soft materials in biological, food and pharmaceutical applications. Result The advantages of 3DP, particularly in the pharmaceutical field, are highlighted and an insight is provided about the current studies for lipid-based drug delivery systems evaluating the potential of 3DP to fabricate innovative products. Additionally, the challenges of the 3DP technologies associated with technical processing, regulatory and material issues of lipids are discussed in detail. Conclusion The future utility of 3DP for printing soft materials, particularly for lipid-based drug delivery systems, offers great advantages and the technology will potentially support patient compliance and drug effectiveness via a personalised medicine approach.
      PubDate: 2018-11-07
      DOI: 10.1007/s11095-018-2531-1
      Issue No: Vol. 36, No. 1 (2018)
       
  • Understanding the Impacts of Surface Compositions on the In-Vitro
           Dissolution and Aerosolization of Co-Spray-Dried Composite Powder
           Formulations for Inhalation
    • Authors: Sharad Mangal; Rongkun Xu; Heejun Park; Dmitry Zemlyanov; Nivedita Shetty; Yu-Wei Lin; David Morton; Hak-Kim Chan; Jian Li; Qi Tony Zhou
      Abstract: Purpose Dissolution behavior of dry powder inhaler (DPI) antibiotic formulations in the airways may affect their efficacy especially for poorly-soluble antibiotics such as azithromycin. The main objective of this study was to understand the effects of surface composition on the dissolution of spray dried azithromycin powders by itself and in combination with colistin. Methods Composite formulations of azithromycin (a poorly water-soluble molecule) and colistin (a water-soluble molecule) were produced by spray drying. The resultant formulations were characterized for particle size, morphology, surface composition, solid-state properties, solubility and dissolution. Results The results demonstrate that surfaces composition has critical impacts on the dissolution of composite formulations. Colistin was shown to increase the solubility of azithromycin. For composite formulations with no surface colistin, azithromycin released at a similar dissolution rate as the spray-dried azithromycin alone. An increase in surface colistin concentration was shown to accelerate the dissolution of azithromycin. The dissolution of colistin from the composite formulations was significantly slower than the spray-dried pure colistin. In addition, FTIR spectrum showed intermolecular interactions between azithromycin and colistin in the composite formulations, which could contribute to the enhanced solubility and dissolution of azithromycin. Conclusions Our study provides fundamental understanding of the effects of surface concentration of colistin on azithromycin dissolution of co-spray-dried composite powder formulations.
      PubDate: 2018-11-07
      DOI: 10.1007/s11095-018-2527-x
      Issue No: Vol. 36, No. 1 (2018)
       
  • An Expandable Mechanopharmaceutical Device (2): Drug Induced Granulomas
           Maximize the Cargo Sequestering Capacity of Macrophages in the Liver
    • Authors: Phillip Rzeczycki; Gi Sang Yoon; Rahul K. Keswani; Sudha Sud; Jason Baik; Mikhail D. Murashov; Ingrid L. Bergin; Kathleen A. Stringer; Gus R. Rosania
      Abstract: Purpose Drug-induced liver injuries (DILI) comprise a significant proportion of adverse drug reactions leading to hospitalizations and death. One frequent DILI is granulomatous inflammation from exposure to harmful metabolites that activate inflammatory pathways of immune cells of the liver, which may act as a barrier to isolate the irritating stimulus and limit tissue damage. Methods Paralleling the accumulation of CFZ precipitates in the liver, granulomatous inflammation was studied to gain insight into its effect on liver structure and function. A structural analog that does not precipitate within macrophages was also studied using micro-analytical approaches. Depleting macrophages was used to inhibit granuloma formation and assess its effect on drug bioaccumulation and toxicity. Results Granuloma-associated macrophages showed a distinct phenotype, differentiating them from non-granuloma macrophages. Granulomas were induced by insoluble CFZ cargo, but not by the more soluble analog, pointing to precipitation being a factor driving granulomatous inflammation. Granuloma-associated macrophages showed increased activation of lysosomal master-regulator transcription factor EB (TFEB). Inhibiting granuloma formation increased hepatic necrosis and systemic toxicity in CFZ-treated animals. Conclusions Granuloma-associated macrophages are a specialized cell population equipped to actively sequester and stabilize cytotoxic chemotherapeutic agents. Thus, drug-induced granulomas may function as drug sequestering “organoids” –an induced, specialized sub-compartment– to limit tissue damage.
      PubDate: 2018-11-07
      DOI: 10.1007/s11095-018-2541-z
      Issue No: Vol. 36, No. 1 (2018)
       
  • An Expandable Mechanopharmaceutical Device (3): a Versatile Raman Spectral
           Cytometry Approach to Study the Drug Cargo Capacity of Individual
           Macrophages
    • Authors: Vernon LaLone; Márcio A. Mourão; Theodore J. Standiford; Krishnan Raghavendran; Kerby Shedden; Kathleen A. Stringer; Gus R. Rosania
      Abstract: Purpose To improve cytometric phenotyping abilities and better understand cell populations with high interindividual variability, a novel Raman-based microanalysis was developed to characterize macrophages on the basis of chemical composition, specifically to measure and characterize intracellular drug distribution and phase separation in relation to endogenous cellular biomolecules. Methods The microanalysis was developed for the commercially-available WiTec alpha300R confocal Raman microscope. Alveolar macrophages were isolated and incubated in the presence of pharmaceutical compounds nilotinib, chloroquine, or etravirine. A Raman data processing algorithm was specifically developed to acquire the Raman signals emitted from single-cells and calculate the signal contributions from each of the major molecular components present in cell samples. Results Our methodology enabled analysis of the most abundant biochemicals present in typical eukaryotic cells and clearly identified “foamy” lipid-laden macrophages throughout cell populations, indicating feasibility for cellular lipid content analysis in the context of different diseases. Single-cell imaging revealed differences in intracellular distribution behavior for each drug; nilotinib underwent phase separation and self-aggregation while chloroquine and etravirine accumulated primarily via lipid partitioning. Conclusions This methodology establishes a versatile cytometric analysis of drug cargo loading in macrophages requiring small numbers of cells with foreseeable applications in toxicology, disease pathology, and drug discovery.
      PubDate: 2018-11-06
      DOI: 10.1007/s11095-018-2540-0
      Issue No: Vol. 36, No. 1 (2018)
       
  • Evaluation of a Potential Clinical Significant Drug-Drug Interaction
           between Digoxin and Bupropion in Cynomolgus Monkeys
    • Authors: Yang Shen; Yang Yu; Wei Lai; Shuai Li; Zixuan Xu; Jiejing Jin; Xia Yan; Han Xing; Xijing Chen; Aizhen Xiong; Chunhua Xia; Jiake He; Kui Hong
      Abstract: Purpose A three-period digoxin-bupropion drug-drug interaction study was performed in cynomolgus monkeys to assess the effect of bupropion and its metabolites on digoxin disposition. Methods Monkeys were administered either an i.v. infusion (0.1 mg/kg) or an oral dose of digoxin (0.2 mg/kg) as control. In single-dosing period, monkeys received an i.v. infusion of bupropion at 1.5 mg/kg together with an infusion or oral dosing of digoxin, respectively. During multiple-dosing period, bupropion was orally administered q.d. at 7.72 mg/kg for 12-day. Then it was co-administered with an i.v. infusion or oral dosing of digoxin, respectively. Renal expression of OATP4C1 and P-gp was examined. Results Bupropion significantly increased i.v. digoxin CLrenal0-48h by 1 fold in single-dosing period. But it had no effect on the systemic disposition of digoxin. In multiple-dosing period, bupropion significantly increased oral digoxin CLrenal0-48h, CLtotal0-48h, CLnon-renal0-48h and decreased its plasma exposure. Bupropion and its metabolites did not alter creatinine clearance. OATP4C1 was located at the basolateral membrane of proximal tubule cells, while P-gp was on the apical membrane. Conclusions The effect of multiple dosing with bupropion on the pharmacokinetics of digoxin is more pronounced. The magnitude of increase in digoxin CLrenal0-48h contributed to the decrease in AUC of digoxin in some extent, but certainly is not the major driving force. The lack of systemic exposure after a single dose but a significant decrease in exposure mediated by an increase in the digoxin CLnon-renal0-48h with repeated dosing is likely to be the more clinically relevant.
      PubDate: 2018-11-06
      DOI: 10.1007/s11095-018-2525-z
      Issue No: Vol. 36, No. 1 (2018)
       
  • A Review of the Emerging Role of Silk for the Treatment of the Eye
    • Authors: Simon H. Tran; Clive G. Wilson; F. Philipp Seib
      Abstract: Silk is a remarkable biopolymer with a long history of medical use. Silk fabrications have a robust track record for load-bearing applications, including surgical threads and meshes, which are clinically approved for use in humans. The progression of top-down and bottom-up engineering approaches using silk as the basis of a drug delivery or cell-loaded matrix helped to re-ignite interest in this ancient material. This review comprehensively summarises the current applications of silk for tissue engineering and drug delivery, with specific reference to the eye. Additionally, the review also covers emerging trends for the use of silk as a biologically active biopolymer for the treatment of eye disorders. The review concludes with future capabilities of silk to contribute to advanced, electronically-enhanced ocular drug delivery concepts.
      PubDate: 2018-11-05
      DOI: 10.1007/s11095-018-2534-y
      Issue No: Vol. 35, No. 12 (2018)
       
  • Formulating Inhalable Dry Powders Using Two-Fluid and Three-Fluid Nozzle
           Spray Drying
    • Authors: Donglei Leng; Kaushik Thanki; Camilla Foged; Mingshi Yang
      Abstract: Purpose The spray drying process is widely applied for pharmaceutical particle engineering. The purpose of this study was to investigate advantages and disadvantages of two-fluid nozzle and three-fluid nozzle spray drying processes to formulate inhalable dry powders. Methods Budesonide nanocomposite microparticles (BNMs) were prepared by co-spray drying of budesonide nanocrystals suspended in an aqueous mannitol solution by using a two-fluid nozzle spray drying process. Budesonide-mannitol microparticles (BMMs) were prepared by concomitant spray drying of a budesonide solution and an aqueous mannitol solution using a spray drier equipped with a three-fluid nozzle. The resulting dry powders were characterized by using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and Raman microscopy. A Next Generation Impactor was used to evaluate the aerodynamic performance of the dry powders. Results XRPD and DMA results showed that budesonide remained crystalline in the BNMs, whereas budesonide was amorphous in the BMMs. Spray drying of mannitol into microparticles resulted in a crystalline transformation of mannitol, evident from XRPD, DSC and Raman spectroscopy analyses. Both BMMs and BNMs displayed a faster dissolution rate than bulk budesonide. The yield of BNMs was higher than that of BMMs. The mass ratio between budesonide and mannitol was preserved in the BNMs, whereas the mass ratio in the BMMs was higher than the theoretical ratio. Conclusions Spray drying is an enabling technique for preparation of budesonide amorphous solid dispersions and nanocrystal-embedded microparticles. Two-fluid nozzle spray drying is superior to three-fluid nozzle spray drying in terms of yield.
      PubDate: 2018-11-01
      DOI: 10.1007/s11095-018-2509-z
      Issue No: Vol. 35, No. 12 (2018)
       
  • Topical Drug Delivery to the Posterior Segment of the Eye: Addressing the
           Challenge of Preclinical to Clinical Translation
    • Authors: Gerard A. Rodrigues; David Lutz; Jie Shen; Xiaoda Yuan; Hong Shen; James Cunningham; Hongwen M. Rivers
      Abstract: Topical delivery of therapeutics to the posterior segment of the eye remains the “holy grail” of ocular drug delivery. As an example, anti–vascular endothelial growth factor biologics, such as ranibizumab, aflibercept, and bevacizumab, are delivered by intravitreal injection to treat neovascular age-related macular degeneration and, although these drugs have revolutionized treatment of the disease, less invasive alternatives to intravitreal injection are desired. Multiple reports in the literature have demonstrated topical delivery of both small and large molecules to the back of the eye in small animal models. Despite this progress, successful translation to larger species, and ultimately humans, has yet to be demonstrated. Selection of animal models with relevant ocular anatomy and physiology, along with appropriate experimental design, is critical to enable more relevant feasibility assessments and increased probability of successful translation.
      PubDate: 2018-10-29
      DOI: 10.1007/s11095-018-2519-x
      Issue No: Vol. 35, No. 12 (2018)
       
  • Transport of Pregabalin Via L-Type Amino Acid Transporter 1 (SLC7A5) in
           Human Brain Capillary Endothelial Cell Line
    • Authors: Yu Takahashi; Tomohiro Nishimura; Kei Higuchi; Saki Noguchi; Yuma Tega; Toshiki Kurosawa; Yoshiharu Deguchi; Masatoshi Tomi
      Abstract: Purpose The anti-epileptic drug pregabalin crosses the blood-brain barrier (BBB) in spite of its low lipophilicity. This study was performed to determine whether L-type amino acid transporters (LAT1/SLC7A5 and LAT2/SLC7A8) contribute to the uptake of pregabalin. Methods Pregabalin uptake by LATs-transfected HEK293 cells or hCMEC/D3 cells, an in vitro human BBB model, was measured by LC-MS/MS analysis. Expression of LAT1 mRNA in hCMEC/D3 cells was determined by quantitative RT-PCR analysis. Results Overexpression of LAT1, but not LAT2, in HEK293 cells significantly increased the cellular uptake of pregabalin, and the LAT1-mediated uptake was saturable with a Km of 0.288 mM. LAT1-mediated amino acid uptake was inhibited specifically and almost completely in the presence of 1 mM pregabalin. The uptake of pregabalin by hCMEC/D3 cells was sodium-independent, saturable (Km = 0.854 mM), and strongly inhibited by large amino acids at 1 mM, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, a specific system L inhibitor, at 1 mM and by JPH203, a LAT1-selective inhibitor, at 10 μM. Pregabalin uptake in hCMEC/D3 cells was also decreased by 75% by the silencing of LAT1 gene using LAT1 siRNA. Conclusions Our results indicate that LAT1, but not LAT2, recognizes pregabalin as a substrate. It is suggested that LAT1 mediates pregabalin transport at the BBB.
      PubDate: 2018-10-29
      DOI: 10.1007/s11095-018-2532-0
      Issue No: Vol. 35, No. 12 (2018)
       
  • Correction to: Application of a Novel ‘Make and Test in Parallel’
           Strategy to Investigate the Effect of Formulation on the Pharmacokinetics
           of GDC-0810 in Healthy Subjects
    • Authors: Sravanthi Cheeti; Hao Helen Hou; Eric Nelson; Helen Walker; Buyun Chen; Roland Morley; Mary Gates; Luna Musib; Sandhya Girish; Srikumar Sahasranaman; Lichuan Liu
      Abstract: The Publisher regrets the typesetting mistake of retaining incorrect text in the Figure 1 caption. The correct text for the caption is “Molecular Structure of GDC-0810 NMG Salt”. The original article has been corrected.
      PubDate: 2018-10-26
      DOI: 10.1007/s11095-018-2529-8
      Issue No: Vol. 35, No. 12 (2018)
       
  • Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic
           Cation Transporter 1 (OCT1) and 2 (OCT2)
    • Authors: Peng Zhu; Zhi Ye; Dong Guo; Zongping Xiong; Shiqiong Huang; Jun Guo; Wei Zhang; James E. Polli; Honghao Zhou; Qing Li; Yan Shu
      Abstract: Purpose The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs) together are regarded as an organic cation transport system critical to the disposition and response of many organic cationic drugs. Patient response to the analgesic morphine, a characterized substrate for human OCT1, is highly variable. This study was aimed to examine whether there is any organic cation transporter-mediated drug and drug interaction (DDI) between morphine and commonly co-administrated drugs. Methods The uptake of morphine and its inhibition by six drugs which are commonly co-administered with morphine in the clinic were assessed in human embryonic kidney 293 (HEK293) cells stably expressing OCT1, OCT2 and MATE1. The in vivo interaction between morphine and the select irinotecan was determined by comparing the disposition of morphine in the absence versus presence of irinotecan treatment in mice. Results The uptake of morphine in the stable HEK293 cells expressing human OCT1 and OCT2 was significantly increased by 3.56 and 3.04 fold, respectively, than that in the control cells, with no significant uptake increase in the cells expressing human MATE1. All of the six drugs examined, including amitriptyline, fluoxetine, imipramine, irinotecan, ondansetron, and verapamil, were inhibitors of OCT1/2-mediated morphine uptake. The select irinotecan significantly increased the plasma concentrations and decreased hepatic and renal accumulation of morphine in mice. Conclusions Morphine is a substrate of OCT1 and OCT2. Clinician should be aware that the disposition of and thus the response to morphine may be altered by co-administration of an OCT1/2 inhibitor, such as irinotecan.
      PubDate: 2018-10-25
      DOI: 10.1007/s11095-018-2526-y
      Issue No: Vol. 35, No. 12 (2018)
       
  • The Extended Clearance Concept Following Oral and Intravenous Dosing:
           Theory and Critical Analyses
    • Authors: Leslie Z. Benet; Christine M. Bowman; Shufang Liu; Jasleen K. Sodhi
      Abstract: Purpose To derive the theoretical basis for the extended clearance model of organ elimination following both oral and IV dosing, and critically analyze the approaches previously taken. Methods We derived from first principles the theoretical basis for the extended clearance concept of organ elimination following both oral and IV dosing and critically analyzed previous approaches. Results We point out a number of critical characteristics that have either been misinterpreted or not clearly presented in previously published treatments. First, the extended clearance concept is derived based on the well-stirred model. It is not appropriate to use alternative models of hepatic clearance. In analyzing equations, clearance terms are all intrinsic clearances, not total drug clearances. Flow and protein binding parameters should reflect blood measurements, not plasma values. In calculating the AUCR-factor following oral dosing, the AUC terms do not include flow parameters. We propose that calculations of AUCR may be a more useful approach to evaluate drug-drug and pharmacogenomic interactions than evaluating rate-determining steps. Through analyses of cerivastatin and fluvastatin interactions with cyclosporine we emphasize the need to characterize volume of distribution changes resulting from transporter inhibition/induction that can affect rate constants in PBPK models. Finally, we note that for oral doses, prediction of systemic and intrahepatic drug-drug interactions do not require knowledge of fu,H or Kp,uu for substrates/victims. Conclusions The extended clearance concept is a powerful tool to evaluate drug-drug interactions, pharmacogenomic and disease state variance but evaluating the AUCR-factor may provide a more valuable approach than characterizing rate-determining steps.
      PubDate: 2018-10-22
      DOI: 10.1007/s11095-018-2524-0
      Issue No: Vol. 35, No. 12 (2018)
       
  • Editorial, IAPC-6 Meeting
    • Authors: Kin Tam; Tonglei Li; Zoran Mandić
      PubDate: 2018-10-18
      DOI: 10.1007/s11095-018-2510-6
      Issue No: Vol. 35, No. 11 (2018)
       
  • Progress in Inherited Retinal Disease Drug Discovery and Development: A
           Foundation’s Perspective
    • Authors: Benjamin Yerxa
      Abstract: Ophthalmic drug discovery and development has enjoyed a recent renaissance, with a major shift away from reformulating old systemic drugs for ocular use to de novo discovery of drugs for specific ocular disease targets. This shift, coupled with a revolution in molecular biology and genetic sequencing, has uncovered an unprecedented number and variety of novel targets for therapeutic intervention in eye disease. With such a treasure chest of new science to pursue, it also creates a new challenge for translating the lab-based discoveries through the translational “valley of death” into full scale industry-led development of new, approved therapeutics to treat eye disease. This is in fact a daunting task, as the cost of drug development continues to increase and many of the new therapeutic targets are based on smaller, orphan diseases with very high unmet medical needs. This perspective focuses on the role of a nonprofit foundation, The Foundation Fighting Blindness, in fueling and supporting the advancement of new therapies for blinding inherited retinal degenerative diseases into approved therapeutics. The new collaborative model is changing the way breakthrough drugs are coming to market for patients, and innovative funding models are required to match the innovative science.
      PubDate: 2018-10-18
      DOI: 10.1007/s11095-018-2514-2
      Issue No: Vol. 35, No. 11 (2018)
       
 
 
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