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Journal Cover Pharmaceutical Research
  [SJR: 1.189]   [H-I: 163]   [147 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
   Published by Springer-Verlag Homepage  [2355 journals]
  • Access to the CNS: Biomarker Strategies for Dopaminergic Treatments
    • Authors: Willem Johan van den Brink; Semra Palic; Isabelle Köhler; Elizabeth Cunera Maria de Lange
      Abstract: Despite substantial research carried out over the last decades, it remains difficult to understand the wide range of pharmacological effects of dopaminergic agents. The dopaminergic system is involved in several neurological disorders, such as Parkinson’s disease and schizophrenia. This complex system features multiple pathways implicated in emotion and cognition, psychomotor functions and endocrine control through activation of G protein-coupled dopamine receptors. This review focuses on the system-wide effects of dopaminergic agents on the multiple biochemical and endocrine pathways, in particular the biomarkers (i.e., indicators of a pharmacological process) that reflect these effects. Dopaminergic treatments developed over the last decades were found to be associated with numerous biochemical pathways in the brain, including the norepinephrine and the kynurenine pathway. Additionally, they have shown to affect peripheral systems, for example the hypothalamus-pituitary-adrenal (HPA) axis. Dopaminergic agents thus have a complex and broad pharmacological profile, rendering drug development challenging. Considering the complex system-wide pharmacological profile of dopaminergic agents, this review underlines the needs for systems pharmacology studies that include: i) proteomics and metabolomics analysis; ii) longitudinal data evaluation and mathematical modeling; iii) pharmacokinetics-based interpretation of drug effects; iv) simultaneous biomarker evaluation in the brain, the cerebrospinal fluid (CSF) and plasma; and v) specific attention to condition-dependent (e.g., disease) pharmacology. Such approach is considered essential to increase our understanding of central nervous system (CNS) drug effects and substantially improve CNS drug development.
      PubDate: 2018-02-15
      DOI: 10.1007/s11095-017-2333-x
      Issue No: Vol. 35, No. 3 (2018)
  • Progesterone PLGA/mPEG-PLGA Hybrid Nanoparticle Sustained-Release System
           by Intramuscular Injection
    • Authors: Bin Xie; Yang Liu; Yuting Guo; Enbo Zhang; Chenguang Pu; Haibing He; Tian Yin; Xing Tang
      Abstract: Purpose To prepare sustained-release PLGA/mPEG-PLGA hybrid nanoparticles of progesterone (PRG), and evaluate the descending required administration dosage in vivo. Methods PRG hybrid nanoparticles (PRG H-NPs) based on PLGA/mPEG-PLGA were compared with PRG nanoparticles (PRG-NPs) of pure PLGA as the matrix and PRG-oil solutions. Nanoparticles (NPs) were formed by the method of nanoemulsion, and the pharmacokinetics of the sustained-release PRG H-NPs in male Sprague dawley (SD) rats were investigated. The rats were randomly divided into four groups, each group received: single dose of PRG H-NPs (14.58 mg/kg, i.m.) and PRG-NPs (14.58 mg/kg, i.m.), repeated dosing for 7 days of PRG-oil (2.08 mg/kg, i.m.) solution (Oil-L) and a higher dosage of PRG-oil (6.24 mg/kg, i.m.) solution (Oil-H), respectively. Results In the pharmacokinetic test, the PRG H-NPs exhibited a comparatively good sustained-release effect against the PRG-NPs without mPEG-PLGA and PRG-oil solution. The pharmacokinetic parameters of the PRG H-NPs, PRG-NPs, Oil-L and Oil-H were AUC0–t(ng·h·mL−1) 8762.1, 1546.1, 1914.5, and 12,138.9, t1/2 (h)52.7, 44.1, 8.4 and 44.6 respectively. Conclusions Owing to the modification of PEG, PRG H-NPs can act as safe delivery platforms for sustained-release of drugs with a lower dosage required.
      PubDate: 2018-02-14
      DOI: 10.1007/s11095-018-2357-x
      Issue No: Vol. 35, No. 3 (2018)
  • Enhanced Tumor Diagnostic and Therapeutic Effect of Mesoporous Silica
           Nanoparticle-Mediated Pre-targeted Strategy
    • Authors: Gaochao Lv; Ke Li; Ling Qiu; Ying Peng; Xueyu Zhao; Xi Li; Qingzhu Liu; Shanshan Wang; Jianguo Lin
      Abstract: Purpose Improving the targeting efficiency of imaging agents or anticancer drugs has become essential in the current primary mission to enhance the diagnostic or therapeutic effects. To improve the tumor diagnosis and therapy effect, a promising drug-delivery and targeting strategy was established based on the bioorthogonal chemistry. Method The delivery system was composed of the pre-targeting carrier Biotin-MSNs-DBCO nanoparticles and the azido cargoes. The fluorescence probe 1-(3-azidopropyl) fluorescein (FITC-N3) and ruthenium N-heterocyclic carbene complex N3-S-S-NHC-Ru were synthesized and served as the tumor imaging and therapy probes, respectively. The cell imaging and viability was investigated by the Biotin-MSNs-DBCO pre-targeted for 4 h in colonic carcinoma (HeLa) cells. Results For the tumor cell imaging, Biotin-MSNs-DBCO could react with FITC-N3 rapidly and completely in 20 min with 93% yields. The fluorescence intensity of tumor cells was obviously increased by the Biotin-MSNs-DBCO pre-targeted. The cytotoxicity of the ruthenium complex N3-S-S-NHC-Ru was significantly improved appropriately three times with the IC50 (half inhibitory concentration) value of 6.68 ± 1.29 μM and enhancement of the mitochondrial dysfunction. Conclusions The pre-targeting nanoparticle Biotin-MSNs-DBCO could selectively capture the azido compounds in tumor cells, which provided a site-specific target for the cargoes and then resulted in an enhancement of diagnostic or therapeutic effects.
      PubDate: 2018-02-14
      DOI: 10.1007/s11095-017-2338-5
      Issue No: Vol. 35, No. 3 (2018)
  • Pregnancy- Associated Changes in Pharmacokinetics and their Clinical
    • Authors: Gideon Koren; Gali Pariente
      Abstract: Purpose To critically review pregnancy-induced pharmacokinetic changes and their clinical application. Methods Structured review of Pubmed, MBASE and published books. Results For many drugs, advanced pregnancy is associated with lower maternal serum concentrations. As most drug concentrations are not measured routinely, such changes are not evident to the clinician. Moreover, even for drug concentrations measured clinically, one cannot interpret lower total drug levels as evidence of lower fraction of free drug, which is the pharmacologically- active component, due to lower protein binding of many drugs in late pregnancy. Higher fractions of free drug will lead to higher rate of hepatic metabolism, especially for high extraction medications, leading to lower total drug concentrations.. Pregnancy- induced larger volume of distribution will lead to lower peak of drugs and hence may impact the achievement therapeutic levels. To further complicate matters, the adherence of many women decreases during pregnancy, mostly due to fears of adverse fetal effects. These dynamic and complex processes make changes in recommendations for dose schedule very challenging and in many cases not practical. Conclusions Indeed, there are presently no pregnancy- targeted dose schedules, similar to existing dose changes, for example, in renal failure. Similar to the recent increased attention given to pharmacokinetic changes in pregnancy, well designed studies should compare dose-effect relationships in women receiving medications in different stages of pregnancy, to women receiving the same drug before, and/or after pregnancy. Whenever possible, women with chronic conditions can serve as their own controls and decrease the uncertainty created by inter- patient variability. Measuring drug effects in parallel to drug concentrations, will allow pharmacokinetic- pharmacodynamic modelling, leading to evidence-based decisions regarding changes in dose schedules during gestation.
      PubDate: 2018-02-12
      DOI: 10.1007/s11095-018-2352-2
      Issue No: Vol. 35, No. 3 (2018)
  • Carbon Dioxide-Generating PLG Nanoparticles for Controlled Anti-Cancer
           Drug Delivery
    • Authors: Hyeon Jin Jang; Eun Ju Jeong; Kuen Yong Lee
      Abstract: Purpose Poly(D,L-lactide-co-glycolide) (PLG) nanoparticles containing doxorubicin and mineralized calcium carbonate were fabricated and their anti-tumor efficacy was tested using a neuroblastoma-bearing mouse model. Methods PLG nanoparticles were prepared by a double emulsion (water-in-oil-in-water; W/O/W) method. Calcium carbonate was mineralized within the PLG nanoparticles during the emulsion process. Rabies virus glycoprotein (RVG) peptide was chemically introduced to the surface of the PLG nanoparticles as a targeting moiety against neuroblastoma. The cytotoxicity and cellular uptake characteristics of these nanoparticles were investigated in vitro. Moreover, their therapeutic efficacy was evaluated using a tumor-bearing mouse model. Results Mineralized calcium carbonate in PLG nanoparticles was ionized at acidic pH and generated carbon dioxide gas, which resultantly accelerated the release of doxorubicin from the nanoparticles. RVG peptide-modified, gas-generating PLG nanoparticles showed a significantly enhanced targeting ability to neuroblastoma and an increased therapeutic efficacy in vivo as compared with free doxorubicin. Conclusions Targeting ligand-modified polymer nanoparticles containing both anti-cancer drug and mineralized calcium carbonate could be useful for cancer treatment.
      PubDate: 2018-02-09
      DOI: 10.1007/s11095-018-2359-8
      Issue No: Vol. 35, No. 3 (2018)
  • Fabrication of 3-O-sn-Phosphatidyl-L-serine Anchored PLGA Nanoparticle
           Bearing Amphotericin B for Macrophage Targeting
    • Authors: Pankaj K. Singh; Anil K. Jaiswal; Vivek K. Pawar; Kavit Raval; Animesh Kumar; Himangsu K. Bora; Anuradha Dube; Manish K. Chourasia
      Abstract: ABSTRACT Purpose To fabricate, characterize and evaluate 3-O-sn-Phosphatidyl-L-serine (PhoS) anchored PLGA nanoparticles for macrophage targeted therapeutic intervention of VL. Materials and Methods PLGA-AmpB NPs were prepared by well-established nanoprecipitation method and decorated with Phos by thin film hydration method. Physico-chemical characterization of the formulation was done by Zetasizer nano ZS and atomic force microscopy. Results The optimized formulation (particle size, 157.3 ± 4.64 nm; zeta potential, − 42.51 ± 2.11 mV; encapsulation efficiency, ∼98%) showed initial rapid release up to 8 h followed by sustained release until 72 h. PhoS generated ‘eat-me’ signal driven augmented macrophage uptake, significant increase in in-vitro (with ∼82% parasite inhibition) and in-vivo antileishmanial activity with preferential accumulation in macrophage rich organs liver and spleen were found. Excellent hemo-compatibility justified safety profile of developed formulation in comparison to commercial formulations. Conclusion The developed PhoS-PLGA-AmpB NPs have improved efficacy, and necessary stability which promisingly put itself as a better alternative to available commercial formulations for optimized treatment of VL.
      PubDate: 2018-02-09
      DOI: 10.1007/s11095-017-2293-1
      Issue No: Vol. 35, No. 3 (2018)
  • Correction to: Effects of Moisture-Induced Crystallization on the Aerosol
           Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations
    • Authors: Nivedita Shetty; Lingfei Zeng; Sharad Mangal; Haichen Nie; Matthew R. Rowles; Rui Guo; Youngwoo Han; Joon Hyeong Park; Qi Zhou
      Abstract: Page 4, right column, under section heading “In-Vitro Aerosol Performance”, line 11.
      PubDate: 2018-02-08
      DOI: 10.1007/s11095-018-2354-0
      Issue No: Vol. 35, No. 3 (2018)
  • Targeting Suppressive Oligonucleotide to Lymph Nodes Inhibits Toll-like
           Receptor-9-Mediated Activation of Adaptive Immunity
    • Authors: Chunsong Yu; Myunggi An; Evan Jones; Haipeng Liu
      Abstract: Purpose This paper aims to investigate the immunoinhibitory properties of a lymph nodes-targeting suppressive oligonucleotide (ODN) for the potential treatment of autoimmune diseases or chronic inflammation. Methods Synthetic suppressive ODN engineered with an albumin-binding diacyl lipid at the 5′-terminal (lipo-ODN) was synthesized. In vitro and in vivo experiments were designed to compare the immune suppressive properties of lipo-ODN and unmodified ODN. Cellular uptake and distribution, inhibition of Toll-like receptor (TLR) activation, lymph nodes (LN) draining, and the suppression of antigen-specific immune responses in an ovalbumin protein model was investigated. Results Compared to unmodified ODN, lipid functionalized suppressive ODN demonstrated enhanced cellular uptake and TLR-9 specific immune suppression in TLR reporter cells. Additionally, injection of a low dose of lipid-modified suppressive ODN, but not the unconjugated ODN, accumulated in the draining LNs and exhibited potent inhibition of antigen-specific CD8+ T cell and B cell responses in vivo. Conclusions Targeting suppressive ODN to antigen presenting cells (APCs) in the local LNs is an effective approach to amplify the immune modulation mediated by ODN containing repetitive TTAGGG motif. This approach might be broadly applicable to target molecular adjuvants to the key immune cells in the LNs draining from disease site, providing a simple strategy to improve the efficacy of many molecular immune modulators.
      PubDate: 2018-02-08
      DOI: 10.1007/s11095-018-2344-2
      Issue No: Vol. 35, No. 3 (2018)
  • Novel Core-Interlayer-Shell DOX/ZnPc Co-loaded MSNs@ pH-Sensitive
    • Authors: Jinyuan Ma; Hongjie Wu; Yang Li; Zehua Liu; Guihua Liu; Yuxin Guo; Zhenqing Hou; Qingliang Zhao; Dengyue Chen; Xuan Zhu
      Abstract: Purpose This work was intended to develop novel doxorubicin (DOX)/zinc (II) phthalocyanine (ZnPc) co-loaded mesoporous silica (MSNs)@ calcium phosphate (CaP)@PEGylated liposome nanoparticles (NPs) that could efficiently achieve collaborative anticancer therapy by the combination of photodynamic therapy (PDT) and chemotherapy. The interlayer of CaP could be utilized to achieve pH-triggered controllable drug release, promote the cellular uptake, and induce cell apoptosis to further enhance the anticancer effects. Methods MSNs were first synthesized as core particles in which the pores were diffusion-filled with DOX, then the cores were coated by CaP followed by the liposome encapsulation with ZnPc to form the final DOX/ZnPc co-loaded MSNs@CaP@PEGylated liposome. Results A core-interlayer-shell MSNs@CaP@PEGylated liposomes was developed as a multifunctional theranostic nanoplatform. In vitro experiment indicated that CaP could not only achieve pH-triggered controllable drug release, promote the cellular uptake of the NPs, but also generate high osmotic pressure in the endo/lysosomes to induce cell apoptosis. Besides, the chemotherapy using DOX and PDT effect was achieved by the photosensitizer ZnPc. Furthermore, the MSNs@CaP@PEGylated liposomes showed outstanding tumor-targeting ability by enhanced permeability and retention (EPR) effect. Conclusions The novel prepared MSNs@CaP@PEGylated liposomes could serve as a promising multifunctional theranostic nanoplatform in anticancer treatment by synergic chemo-PDT and superior tumor-targeting ability.
      PubDate: 2018-02-08
      DOI: 10.1007/s11095-017-2295-z
      Issue No: Vol. 35, No. 3 (2018)
  • Submicron Protein Particle Characterization using Resistive Pulse Sensing
           and Conventional Light Scattering Based Approaches
    • Authors: Gregory V. Barnett; Julia M. Perhacs; Tapan K. Das; Sambit R. Kar
      Abstract: Purpose Characterizing submicron protein particles (approximately 0.1–1μm) is challenging due to a limited number of suitable instruments capable of monitoring a relatively large continuum of particle size and concentration. In this work, we report for the first time the characterization of submicron protein particles using the high size resolution technique of resistive pulse sensing (RPS). Methods Resistive pulse sensing, dynamic light scattering and size-exclusion chromatography with in-line multi-angle light scattering (SEC-MALS) are performed on protein and placebo formulations, polystyrene size standards, placebo formulations spiked with silicone oil, and protein formulations stressed via freeze-thaw cycling, thermal incubation, and acid treatment. Results A method is developed for monitoring submicron protein particles using RPS. The suitable particle concentration range for RPS is found to be approximately 4 × 107-1 × 1011 particles/mL using polystyrene size standards. Particle size distributions by RPS are consistent with hydrodynamic diameter distributions from batch DLS and to radius of gyration profiles from SEC-MALS. RPS particle size distributions provide an estimate of particle counts and better size resolution compared to light scattering. Conclusion RPS is applicable for characterizing submicron particles in protein formulations with a high degree of size polydispersity. Data on submicron particle distributions provide insights into particles formation under different stresses encountered during biologics drug development.
      PubDate: 2018-02-08
      DOI: 10.1007/s11095-017-2306-0
      Issue No: Vol. 35, No. 3 (2018)
  • Lipids in the Stomach – Implications for the Evaluation of Food Effects
           on Oral Drug Absorption
    • Authors: Mirko Koziolek; Frédéric Carrière; Christopher J. H. Porter
      Abstract: Food effects on oral drug bioavailability can have significant impact on the provision of safe and reliable oral pharmacotherapy. A mechanistic understanding of the events that contribute to the occurrence of food effects is therefore critical. An increased oral bioavailability is often seen for poorly water-soluble drugs after co-administration with lipids, including lipids in food, and is commonly explained by the ability of lipids to enhance drug solubility in intestinal luminal fluids. In contrast, the impact of lipids on drug solubilisation in the stomach has received less attention. This is in spite of the fact that lipid digestion is initiated in the stomach by human gastric lipase and that gastric events also initiate emulsification of lipids in the gastrointestinal tract. The stomach therefore acts to ‘pre-process’ lipids for subsequent events in the intestine and may significantly affect downstream events at intestinal drug absorption sites. In this article, the mechanisms by which lipids are processed in the stomach are reviewed and the potential impact of these processes on drug absorption discussed. Attention is also focused on in vitro methods that are used to assess gastric processing of lipids and their application to better understand food effects on drug release and absorption.
      PubDate: 2018-02-08
      DOI: 10.1007/s11095-017-2289-x
      Issue No: Vol. 35, No. 3 (2018)
  • Correction to: The Race of 10 Synthetic RNAi-Based Drugs to the
           Pharmaceutical Market
    • Authors: Ricardo Titze-de-Almeida; Catherine David; Simoneide Souza Titze-de-Almeida
      Abstract: The published article contains an error in Figure 5. The term “Atu027” should be substituted by “Patisiran” in figure and legend.
      PubDate: 2018-02-07
      DOI: 10.1007/s11095-017-2335-8
      Issue No: Vol. 35, No. 3 (2018)
  • Non-profit Drug Research and Development at a Crossroads
    • Authors: Szymon Jarosławski; Mondher Toumi; Pascal Auquier; Claude Dussart
      Abstract: In wealthy nations, non-profit drug R&D has been proposed to reduce the prices of medicines. We sought to review the ethical and economic issues concerning non-profit drug R&D companies, and the possible impact that their pricing strategy may have on the innovation efforts from for-profit companies targeting the same segment of the pharmaceutical market. There are two possible approaches to pricing drugs developed by non-profit R&D programs: pricing that maximises profits and “affordable” pricing that reflects the cost of manufacturing and distribution, plus a margin that ensures sustainability of the drug supply. Overall, the non-profits face ethical challenges - due to the lack of resources, they are unable to independently commercialize their products on a large scale; however, the antitrust law does not permit them to impose prices on potential licensees. Also, reduced prices for the innovative products may result in drying the for-profit R&D in the area.
      PubDate: 2018-02-07
      DOI: 10.1007/s11095-018-2351-3
      Issue No: Vol. 35, No. 3 (2018)
  • Sweetening Inhaled Antibiotic Treatment for Eradication of Chronic
           Respiratory Biofilm Infection
    • Authors: Ching-Yee Loo; Wing-Hin Lee; Gianluca Lauretani; Santo Scalia; David Cipolla; Daniela Traini; Paul Young; Hui Xin Ong
      Abstract: Purpose The failure of chronic therapy with antibiotics to clear persistent respiratory infection is the key morbidity and mortality factor for patients with chronic lung diseases, primarily due to the presence of biofilm in the lungs. It is hypothesised that carbon sources, such as mannitol, could stimulate the metabolic activity of persister cells within biofilms and restore their susceptibility to antibiotics. The aims of the current study are to: (1) establish a representative in vitro model of Pseudomonas aeruginosa biofilm lung infection, and (2) investigate the effects of nebulised mannitol on antibiotic efficacy, focusing on ciprofloxacin, in the eradication of biofilm. Method Air interface biofilm was cultured onto Snapwell inserts incorporated into a modified pharmacopeia deposition apparatus, the Anderson Cascade Impactor (ACI). Three different formulations including mannitol only, ciprofloxacin only and combined ciprofloxacin and mannitol were nebulised onto the P. aeruginosa biofilm using the modified ACI. Antibacterial effectiveness was evaluated using colony-forming units counts, biofilm penetration and scanning electron microscopy. Results Nebulised mannitol promotes the dispersion of bacteria from the biofilm and demonstrated a synergistic enhancement of the antibacterial efficacy of ciprofloxacin compared to delivery of antibiotic alone. Conclusions The combination of ciprofloxacin and mannitol may provide an important new strategy to improve antibiotic therapy for the treatment of chronic lung infections. Furthermore, the development of a representative lung model of bacterial biofilm could potentially be used as a platform for future new antimicrobial pre-clinical screening.
      PubDate: 2018-02-07
      DOI: 10.1007/s11095-018-2350-4
      Issue No: Vol. 35, No. 3 (2018)
  • Exploring Molecular Speciation and Crystallization Mechanism of Amorphous
           2-Phenylamino Nicotinic Acid
    • Authors: Arjun Kalra; Joseph W. Lubach; Eric J. Munson; Tonglei Li
      Abstract: Purpose Molecular understanding of phase stability and transition of the amorphous state helps in formulation and manufacturing of poorly-soluble drugs. Crystallization of a model compound, 2-phenylamino nicotinic acid (2PNA), from the amorphous state was studied using solid-state analytical methods. Our previous report suggests that 2PNA molecules mainly develop intermolecular –COOH∙∙∙pyridine N (acid-pyridine) interactions in the amorphous state. In the current study, the molecular speciation is explored with regard to the phase transition from the amorphous to the crystalline state. Methods Using spectroscopic techniques, the molecular interactions and structural evolvement during the recrystallization from the glassy state were investigated. Results The results unveiled that the structurally heterogeneous amorphous state contains acid-pyridine aggregates – either as hydrogen-bonded neutral molecules or as zwitterions – as well as a population of carboxylic acid dimers. Phase transition from the amorphous state results in crystal structures composed of carboxylic acid dimer (acid-acid) synthon or acid-pyridine chains depending on the crystallization conditions employed. Conclusions The study underlines the structural evolvement, as well as its impact on the metastability, of amorphous samples from local, supramolecular assemblies to long-range intermolecular ordering through crystallization.
      PubDate: 2018-02-07
      DOI: 10.1007/s11095-018-2346-0
      Issue No: Vol. 35, No. 3 (2018)
  • Pharmacological Treatment of Attention Deficit Hyperactivity Disorder
           During Pregnancy and Lactation
    • Authors: Asher Ornoy
      Abstract: Introduction Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral problem found in 2–5% of adults. Stimulants and drugs that affect the dopaminergic, noradrenergic and/or serotonergic systems are effective treatment and are increasingly prescribed to women at child bearing age. It is consequently important that reliable information on the safety of these drugs in pregnancy is available so that appropriate therapeutic choices can be made. Results The data on stimulants (methylphenidate and amphetamines) are generally showing that there is no increase in the rate of major congenital anomalies. There are very little data on the use of atomoxetine and guanfacine in pregnancy. There are no data on the use of clonidine for ADHD but the data on its use as an antihypertensive drug have not revealed any serious adverse effect. Bupropion, when used as an antidepressant, does not seem to increase the rate of congenital anomalies. There are practically no data on the possible long-term neurodevelopmental effects of any of these drugs. Most of them are secreted in human milk, but the concentrations in infant’s blood, except for clonidine and amphetamines, have been very low. Breast feeding with clonidine and amphetamines is therefore contraindicated, but there seems to be no safety concerns for the other drugs. Conclusion The drugs used for the treatment of ADHD are apparently not teratogenic, but due to paucity of data, especially on the long-term neurodevelopmental outcome, the treating physician should reconsider the need of treatment during pregnancy. If needed, methylphenidate, amphetamines and bupropion are preferred drugs.
      PubDate: 2018-02-06
      DOI: 10.1007/s11095-017-2323-z
      Issue No: Vol. 35, No. 3 (2018)
  • Drugs in Lactation
    • Authors: Philip O. Anderson
      Abstract: One impediment to breastfeeding is the lack of information on the use of many drugs during lactation, especially newer ones. The principles of drug passage into breastmilk are well established, but have often not been optimally applied prospectively. Commonly used preclinical rodent models for determining drug excretion into milk are very unreliable because of marked differences in milk composition and transporters compared to those of humans. Measurement of drug concentrations in humans remains the gold standard, but computer modeling is promising. New FDA labeling requirements present an opportunity to apply modeling to preclinical drug development in place of conventional animal testing for drug excretion into breastmilk, which should improve the use of medications in nursing mothers.
      PubDate: 2018-02-06
      DOI: 10.1007/s11095-017-2287-z
      Issue No: Vol. 35, No. 3 (2018)
  • Two-Pore Minimum Physiologically-based Pharmacokinetic Model to Describe
           the Disposition of Therapeutic Monoclonal IgG Antibody in Humans
    • Authors: Deni Hardiansyah; Chee Meng Ng
      Abstract: Purpose The aim of this study was to develop a two-pore minimum physiologically-based pharmacokinetic (mPBPK) model in describing the pharmacokinetic (PK) of therapeutic monoclonal antibody (TMAb) in human subjects. Methods PK data used in this study were endogenous/exogenous native IgG and two TMAbs (palivizumab and Motavizumab-YTE) in normal volunteer or familial hypercatabolic hypoproteinemia (FIHH) patient. Several important components were implemented to overcome the limitations of the early mPBPK model, e.g. two-pore model to describe the transcapillary transport of IgG from vascular to interstitial space. Six mPBPK models with different osmotic reflection coefficient (OFC) of transcapillary transport, endocytosis rates (ETR) and plasma clearance for the TMAbs/IgG were tested and the best model was selected using AICc values. Results The final model consisted of different OFC and ETR values for native IgG and TMAbs, supporting the hypothesis that the dynamics in the endosomal space had an important role in the compliant FcRn salvage mechanism to determine the clearance of TMAbs. The estimated FcRn concentration of FIHH subjects was 2.72 μmol/l. The final two-pore mPBPK model has a better performance for native IgG than previously developed mPBPK model. Conclusions The final two-pore mPBPK model not only overcome the limitations of the early mPBPK model but also has a better performance to describe the disposition of the IgG antibody in human subjects.
      PubDate: 2018-02-06
      DOI: 10.1007/s11095-017-2292-2
      Issue No: Vol. 35, No. 3 (2018)
  • Dihydroceramide Desaturase 1 Inhibitors Reduce Amyloid-β Levels in
           Primary Neurons from an Alzheimer’s Disease Transgenic Model
    • Authors: Lara Ordóñez-Gutiérrez; Irene Benito-Cuesta; José Luis Abad; Josefina Casas; Gemma Fábrias; Francisco Wandosell
      Abstract: ABSTRACT Purpose The induction of autophagy has recently been explored as a promising therapeutic strategy to combat Alzheimer’s disease. Among many other factors, there is evidence that ceramides/dihydroceramides act as mediators of autophagy, although the exact mechanisms underlying such effects are poorly understood. Here, we describe how two dihydroceramide desaturase inhibitors (XM461 and XM462) trigger autophagy and reduce amyloid secretion by neurons. Methods Neurons isolated from wild-type and APP/PS1 transgenic mice were exposed to the two dihydroceramide desaturase inhibitors to assess their effect on these cell’s protein and lipid profiles. Results Both dihydroceramide desaturase inhibitors increased the autophagic vesicles in wild-type neurons, reflected as an increase in LC3-II, and this was correlated with the accumulation of dihydroceramides and dihydrosphingomyelins. Exposing APP/PS1 transgenic neurons to these inhibitors also produced a 50% reduction in amyloid secretion and/or production. The lipidomic defects triggered by these dihydroceramide desaturase inhibitors were correlated with a loss of S6K activity, witnessed by the changes in S6 phosphorylation, which strongly suggested a reduction of mTORC1 activity. Conclusions The data obtained strongly suggest that dihydroceramide desaturase 1 activity may modulate autophagy and mTORC1 activity in neurons, inhibiting amyloid secretion and S6K activity. As such, it is tantalizing to propose that dihydroceramide desaturase 1 may be an important therapeutic target to combat amyloidosis.
      PubDate: 2018-02-06
      DOI: 10.1007/s11095-017-2312-2
      Issue No: Vol. 35, No. 3 (2018)
  • Topically Applied Ceramides Interact with the Stratum Corneum Lipid Matrix
           in Compromised Ex Vivo Skin
    • Authors: Tineke Berkers; Dani Visscher; Gert S. Gooris; Joke A. Bouwstra
      Abstract: Purpose To determine whether formulations containing ceramides (including a ceramide with a long hydroxyl acyl chain linked to a linoleate, CER EOS) and fatty acids are able to repair the skin barrier by normalizing the lipid organization in stratum corneum (SC). Methods The formulations were applied on a skin barrier repair model consisting of ex vivo human skin from which SC was removed by stripping. The effect of formulations on the lipid organization and conformational ordering in the regenerated SC were analyzed using Fourier transform infrared spectroscopy and small angle X-ray diffraction. Results Application of the formulation containing only one ceramide on regenerating SC resulted in a higher fraction of lipids adopting an orthorhombic organization. A similar fraction of lipids forming an orthorhombic organization was observed after application of a formulation containing two ceramides and a fatty acid on regenerating SC. No effects on the lamellar lipid organization were observed. Conclusions Application of a formulation containing either a single ceramide or two ceramides and a fatty acid on regenerating SC, resulted in a denser lateral lipid packing of the SC lipids in compromised skin. The strongest effect was observed after application of a formulation containing a single ceramide.
      PubDate: 2018-02-06
      DOI: 10.1007/s11095-017-2288-y
      Issue No: Vol. 35, No. 3 (2018)
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