Journal Menu

E-Mail Alert

Journal Browser

Highly Accessed

Latest Books

Pharmaceuticals — Open Access Journal

Pharmaceuticals (ISSN 1424-8247; CODEN: PHARH2) is a peer-reviewed open access journal of medicinal chemistry and related drug sciences, published quarterly online by MDPI. The Swiss Chemical Society is a partner of Pharmaceuticals journal and its members receive a discount on the article processing charge. Please visit https://scg.ch/membership for more details.

Open Access free for readers, with article processing charges (APC) paid by authors or their institutions.
High visibility: citations available in PubMed, full-text archived in PubMed Central. Covered by Embase and Scopus. To be indexed in the Emerging Sources Citation Index - ESCI (Web of Science) from Vol. 10 (2017).
CiteScore: 4.20, based on citations in 2017 to articles published 2014-2016.
Rapid publication: manuscripts are peer-reviewed and a first decision provided to authors approximately 16 days after submission; acceptance to publication is undertaken in 5.6 days (median values for papers published in this journal in the second half of 2018).
Recognition of reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Testimonials: See what our authors say about Pharmaceuticals

Full Imprint Information | Download Journal Flyer

Latest Articles

Open AccessArticle

2-Nitroimidazole-Furanoside Derivatives for Hypoxia Imaging—Investigation of Nucleoside Transporter Interaction, ¹⁸F-Labeling and Preclinical PET Imaging

by Florian C. Maier, Anna Schweifer, Vijaya L. Damaraju, Carol E. Cass, Gregory D. Bowden, Walter Ehrlichmann, Manfred Kneilling, Bernd J. Pichler, Friedrich Hammerschmidt and Gerald Reischl

Pharmaceuticals 2019, 12(1), 31; https://doi.org/10.3390/ph12010031 (registering DOI) - 15 February 2019

Abstract

The benefits of PET imaging of tumor hypoxia in patient management has been demonstrated in many examples and with various tracers over the last years. Although, the optimal hypoxia imaging agent has yet to be found, 2-nitroimidazole (azomycin) sugar derivatives—mimicking nucleosides—have proven their potential with [¹⁸F]FAZA ([¹⁸F]fluoro-azomycin-α-arabinoside) as a prominent representative in clinical use. Still, for all of these tracers, cellular uptake by passive diffusion is postulated with the disadvantage of slow kinetics and low tumor-to-background ratios. We recently evaluated [¹⁸F]fluoro-azomycin-β-deoxyriboside (β-[¹⁸F]FAZDR), with a structure more similar to nucleosides than [¹⁸F]FAZA and possible interaction with nucleoside transporters. For a deeper insight, we comparatively studied the interaction of FAZA, β-FAZA, α-FAZDR and β-FAZDR with nucleoside transporters (SLC29A1/2 and SLC28A1/2/3) in vitro, showing variable interactions of the compounds. The highest interactions being for β-FAZDR (IC₅₀ 124 ± 33 µM for SLC28A3), but also for FAZA with the non-nucleosidic α-configuration, the interactions were remarkable (290 ± 44 µM {SLC28A1}; 640 ± 10 µM {SLC28A2}). An improved synthesis was developed for β-FAZA. For a PET study in tumor-bearing mice, α-[¹⁸F]FAZDR was synthesized (radiochemical yield: 15.9 ± 9.0% (n = 3), max. 10.3 GBq, molar activity > 50 GBq/µmol) and compared to β-[¹⁸F]FAZDR and [¹⁸F]FMISO, the hypoxia imaging gold standard. We observed highest tumor-to-muscle ratios (TMR) for β-[¹⁸F]FAZDR already at 1 h p.i. (2.52 ± 0.94, n = 4) in comparison to [¹⁸F]FMISO (1.37 ± 0.11, n = 5) and α-[¹⁸F]FAZDR (1.93 ± 0.39, n = 4), with possible mediation by the involvement of nucleoside transporters. After 3 h p.i., TMR were not significantly different for all 3 tracers (2.5–3.0). Highest clearance from tumor tissue was observed for β-[¹⁸F]FAZDR (56.6 ± 6.8%, 2 h p.i.), followed by α-[¹⁸F]FAZDR (34.2 ± 7.5%) and [¹⁸F]FMISO (11.8 ± 6.5%). In conclusion, both isomers of [¹⁸F]FAZDR showed their potential as PET hypoxia tracers. Differences in uptake behavior may be attributed to a potential variable involvement of transport mechanisms. Full article

▼ Figures

Figure 1

Open AccessReview

Iron in Lung Pathology

by Vida Zhang, Elizabeta Nemeth and Airie Kim

Pharmaceuticals 2019, 12(1), 30; https://doi.org/10.3390/ph12010030 (registering DOI) - 15 February 2019

Abstract

The lung presents a unique challenge for iron homeostasis. The entire airway is in direct contact with the environment and its iron particulate matter and iron-utilizing microbes. However, the homeostatic and adaptive mechanisms of pulmonary iron regulation are poorly understood. This review provides an overview of systemic and local lung iron regulation, as well as the roles of iron in the development of lung infections, airway disease, and lung injury. These mechanisms provide an important foundation for the ongoing development of therapeutic applications. Full article

► Figures

Figure 1

Open AccessReview

Inflammation and Depression: A Nervous Plea for Psychiatry to Not Become Immune to Interpretation

by Jan Pieter Konsman

Pharmaceuticals 2019, 12(1), 29; https://doi.org/10.3390/ph12010029 - 14 February 2019

Abstract

The possibility that inflammation plays a causal role in major depression is an important claim in the emerging field of immunopsychiatry and has generated hope for new treatments. The aims of the present review are first to provide some historical background and to consider the evidence in favor of the claim that inflammation is causally involved in major depression. The second part discusses some of the possibilities allowed for by the use of broad ‘umbrella’ concepts, such as inflammation and stress, in terms of proposing new working hypotheses and potential mechanisms. The third part reviews proposed biomarkers of inflammation and depression and the final part addresses how elements discussed in the preceding sections are used in immunopsychiatry. The ‘umbrella’ concepts of inflammation and stress, as well as insufficiently-met criteria based inferences and reverse inferences are being used to some extent in immunopsychiatry. The field is therefore encouraged to specify concepts and constructs, as well as to consider potential alternative interpretations and explanations for findings obtained. The hope is that pointing out some of the potential problems will allow for a clearer picture of immunopsychiatry’s current strengths and limitations and help the field mature. Full article

Open AccessArticle

Conformation and Cross-Protection in Group B Streptococcus Serotype III and Streptococcus pneumoniae Serotype 14: A Molecular Modeling Study

by Michelle M. Kuttel and Neil Ravenscroft

Pharmaceuticals 2019, 12(1), 28; https://doi.org/10.3390/ph12010028 - 13 February 2019

Abstract

Although the branched capsular polysaccharides of Streptococcus agalactiae serotype III (GBSIII PS) and Streptococcus pneumoniae serotype 14 (Pn14 PS) differ only in the addition of a terminal sialic acid on the GBSIII PS side chains, these very similar polysaccharides are immunogenically distinct. Our simulations of GBSIII PS, Pn14 PS and the unbranched backbone polysaccharide provide a conformational rationale for the different antigenic epitopes identified for these PS. We find that side chains stabilize the proximal

β

dGlc(1→6)

β

dGlcNAc backbone linkage, restricting rotation and creating a well-defined conformational epitope at the branch point. This agrees with the glycotope structure recognized by an anti-GBSIII PS functional monoclonal antibody. We find the same dominant solution conformation for GBSIII and Pn14 PS: aside from the branch point, the backbone is very flexible with a “zig-zag” conformational habit, rather than the helix previously proposed for GBSIII PS. This suggests a common strategy for bacterial evasion of the host immune system: a flexible backbone that is less perceptible to the immune system, combined with conformationally-defined branch points presenting human-mimic epitopes. This work demonstrates how small structural features such as side chains can alter the conformation of a polysaccharide by restricting rotation around backbone linkages. Full article

► Figures

Graphical abstract

Open AccessReview

Neurodegeneration with Brain Iron Accumulation Disorders: Valuable Models Aimed at Understanding the Pathogenesis of Iron Deposition

by Sonia Levi and Valeria Tiranti

Pharmaceuticals 2019, 12(1), 27; https://doi.org/10.3390/ph12010027 - 9 February 2019

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a set of neurodegenerative disorders, which includes very rare monogenetic diseases. They are heterogeneous in regard to the onset and the clinical symptoms, while the have in common a specific brain iron deposition in the region of the basal ganglia that can be visualized by radiological and histopathological examinations. Nowadays, 15 genes have been identified as causative for NBIA, of which only two code for iron-proteins, while all the other causative genes codify for proteins not involved in iron management. Thus, how iron participates to the pathogenetic mechanism of most NBIA remains unclear, essentially for the lack of experimental models that fully recapitulate the human phenotype. In this review we reported the recent data on new models of these disorders aimed at highlight the still scarce knowledge of the pathogenesis of iron deposition. Full article

Open AccessArticle

Curcumin and (−)- Epigallocatechin-3-Gallate Protect Murine MIN6 Pancreatic Beta-Cells Against Iron Toxicity and Erastin-Induced Ferroptosis

by Tugba Kose, Mayra Vera-Aviles, Paul. A. Sharp and Gladys. O. Latunde-Dada

Pharmaceuticals 2019, 12(1), 26; https://doi.org/10.3390/ph12010026 - 6 February 2019

Abstract

Ferroptosis is a form of programmed cell death that is characterized by lipid peroxidation and is inducible by iron and the accumulation of reactive oxygen species (ROS). It is triggered by erastin but inhibited by antioxidants such as -tocopherol, -carotene, polyphenols, and iron chelators such as deferoxamine (DFO), nitrilotriacetic acid (NTA), and ethylenediaminetetraacetic acid (EDTA). This study investigated the protective effects of two polyphenols, curcumin and (−)- epigallocatechin-3-gallate (EGCG), against iron loading and erastin-mediated ferroptosis in MIN6 cells. Cells were treated with polyphenols before exposure to iron-induced oxidative stress comprising of 20 μmol/L of 8-hydroxyquinoline (8HQ) and 50 μmol/L of ferric ammonium citrate, (FAC) (8HQ+FAC) or Fenton reaction substrate (FS) (30 μmol/L of FeSO₄ and 0.5 of mmol/L H₂O₂) and 20 μmol/L erastin. Cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, iron levels were measured by inductively-coupled plasma mass spectrometry (ICP-MS), glutathione and lipid peroxidation were assayed with commercially-available kits. Curcumin and EGCG both significantly protected pancreatic cells againstiron-induced oxidative damage. Moreover, both compounds also protected against erastin-induced ferroptosis in pancreatic cells. The polyphenols enhanced cell viability in erastin-treated MIN6 cells in a dose- and time-dependent manner. Furthermore, MIN6 cells exposed to erastin alone showed elevated levels of iron, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) degradation and lipid peroxidation (p < 0.05) compared to cells that were protected by pre-treatment with curcumin or EGCG. Taken together, the data identify curcumin and EGCG as novel ferroptosis inhibitors, which might exert their protective effects by acting as iron chelators and preventing GSH depletion, GPX4 inactivation, and lipid peroxidation in MIN6 cells. The implications of the findings on the effects of iron overload and ferroptosis represent a potential therapeutic strategy against iron-related diseases. Full article

► Figures

Graphical abstract

Open AccessArticle

Comparative Study of Two Oxidizing Agents, Chloramine T and Iodo-Gen^®, for the Radiolabeling of β-CIT with Iodine-131: Relevance for Parkinson’s Disease

by Ana Claudia R. Durante, Danielle V. Sobral, Ana Claudia C. Miranda, Érika V. de Almeida, Leonardo L. Fuscaldi, Marycel R. F. F. de Barboza and Luciana Malavolta

Pharmaceuticals 2019, 12(1), 25; https://doi.org/10.3390/ph12010025 - 5 February 2019

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to alteration of the integrity of dopaminergic transporters (DATs). In recent years, some radiopharmaceuticals have been used in the clinic to evaluate the integrity of DATs. These include tropane derivatives such as radiolabeled β-CIT and FP-CIT with iodine-123 (¹²³I), and TRODAT-1 with metastable technetium-99 (^99mTc). Radiolabeling of β-CIT with radioactive iodine is based on electrophilic radioiodination using oxidizing agents, such as Chloramine T or Iodo-Gen^®. For the first time, the present work performed a comparative study of the radiolabeling of β-CIT with iodine-131 (¹³¹I), using either Chloramine T or Iodo-Gen^® as oxidizing agents, in order to improve the radiolabeling process of β-CIT and to choose the most advantageous oxidizing agent to be used in nuclear medicine. Both radiolabeling methods were similar and resulted in high radiochemical yield (> 95%), with suitable ¹³¹I-β-CIT stability up to 72 h. Although Chloramine T is a strong oxidizing agent, it was as effective as Iodo-Gen^® for β-CIT radiolabeling with ¹³¹I, with the advantage of briefer reaction time and solubility in aqueous medium. Full article

► Figures

Figure 1

Open AccessArticle

Camphor, Applied Epidermally to the Back, Causes Snout- and Chest-Grooming in Rats: A Response Mediated by Cutaneous TRP Channels

by Débora T. Ishikawa, Robson Cristiano Lillo Vizin, Cristiane Oliveira de Souza, Daniel Carneiro Carrettiero, Andrej A. Romanovsky and Maria Camila Almeida

Pharmaceuticals 2019, 12(1), 24; https://doi.org/10.3390/ph12010024 - 2 February 2019

Abstract

Thermoregulatory grooming, a behavioral defense against heat, is known to be driven by skin-temperature signals. Because at least some thermal cutaneous signals that drive heat defenses are likely to be generated by transient receptor potential (TRP) channels, we hypothesized that warmth-sensitive TRPs drive thermoregulatory grooming. Adult male Wistar rats were used. We showed that camphor, a nonselective agonist of several TRP channels, including vanilloid (V) 3, when applied epidermally to the back (500 mg/kg), caused a pronounced self-grooming response, including paw-licking and snout- and chest-“washing”. By the percentage of time spent grooming, the response was similar to the thermoregulatory grooming observed during exposure to ambient warmth (32 °C). Ruthenium red (a non-selective antagonist of TRP channels, including TRPV3), when administered intravenously at a dose of 0.1 mg/kg, attenuated the self-grooming behavior induced by either ambient warmth or epidermal camphor. Furthermore, the intravenous administration of AMG8432 (40 mg/kg), a relatively selective TRPV3 antagonist, also attenuated the self-grooming response to epidermal camphor. We conclude that camphor causes the self-grooming behavior by acting on TRP channels in the skin. We propose that cutaneous warmth signals mediated by TRP channels, possibly including TRPV3, drive thermoregulatory self-grooming in rats. Full article

► Figures

Figure 1

Open AccessReview

Modulators of Transient Receptor Potential (TRP) Channels as Therapeutic Options in Lung Disease

by Alexander Dietrich

Pharmaceuticals 2019, 12(1), 23; https://doi.org/10.3390/ph12010023 - 1 February 2019

Abstract

The lungs are essential for gas exchange and serve as the gateways of our body to the external environment. They are easily accessible for drugs from both sides, the airways and the vasculature. Recent literature provides evidence for a role of Transient Receptor Potential (TRP) channels as chemosensors and essential members of signal transduction cascades in stress-induced cellular responses. This review will focus on TRP channels (TRPA1, TRPC6, TRPV1, and TRPV4), predominantly expressed in non-neuronal lung tissues and their involvement in pathways associated with diseases like asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), lung fibrosis, and edema formation. Recently identified specific modulators of these channels and their potential as new therapeutic options as well as strategies for a causal treatment based on the mechanistic understanding of molecular events will also be evaluated. Full article

► Figures

Graphical abstract

Open AccessCorrection

Correction: Mateusz, S., et al. Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia. Pharmaceuticals 2018, 11, 128

by Mateusz Szudzik, Rafał R. Starzyński, Aneta Jończy, Rafał Mazgaj, Małgorzata Lenartowicz and Paweł Lipiński

Pharmaceuticals 2019, 12(1), 22; https://doi.org/10.3390/ph12010022 - 29 January 2019

Abstract

The authors wish to make the following corrections to this paper [¹]: the term “liposomal” should be replaced with the term “sucrosomial” in the following places [...]

Full article

Open AccessArticle

On the Absolute Stereochemistry of Tolterodine: A Circular Dichroism Study

by Marcin Górecki, Valerio Zullo, Anna Iuliano and Gennaro Pescitelli

Pharmaceuticals 2019, 12(1), 21; https://doi.org/10.3390/ph12010021 - 26 January 2019

Abstract

Tolterodine (1) is a potent muscarinic receptor antagonist used in the treatment of overactive urinary bladder (OAB) syndrome. Tolterodine is chiral and it was patented, and is currently marketed, as the l-tartrate salt of the (R)-enantiomer. However, the existing literature does not offer an ultimate proof of a stereoselective mode of action of 1. A second open stereochemical issue concerns the absolute configuration (AC) of 1. Neither the original patents nor subsequent studies have established the AC of 1 in an unambiguous way, although the AC of the l-tartrate salt of 1 was assigned by X-ray diffractometry. Finally, neither electronic nor vibrational circular dichroism (ECD and VCD) spectra of 1 are reported so far. We performed a thorough ECD/VCD study of 1 in different solvents and at variable temperatures. Solvent and temperature dependence highlighted the existence of moderate flexibility which was confirmed by molecular modelling. ECD calculations with time-dependent density functional theory (TDDFT) accurately reproduced the experimental spectra and allowed us to confirm the AC of 1 in an independent way. Full article

► Figures

Graphical abstract

Open AccessArticle

Identification of Potential Inhibitors from Pyriproxyfen with Insecticidal Activity by Virtual Screening

by Ryan da Silva Ramos, Josivan da Silva Costa, Rai Campos Silva, Glauber Vilhena da Costa, Alex Bruno Lobato Rodrigues, Érica de Menezes Rabelo, Raimundo Nonato Picanço Souto, Carlton Anthony Taft, Carlos Henrique Tomich de Paula da Silva, Joaquín Maria Campos Rosa, Cleydson Breno Rodrigues dos Santos and Williams Jorge da Cruz Macêdo

Pharmaceuticals 2019, 12(1), 20; https://doi.org/10.3390/ph12010020 - 25 January 2019

Abstract

Aedes aegypti is the main vector of dengue fever transmission, yellow fever, Zika, and chikungunya in tropical and subtropical regions and it is considered to cause health risks to millions of people in the world. In this study, we search to obtain new molecules with insecticidal potential against Ae. aegypti via virtual screening. Pyriproxyfen was chosen as a template compound to search molecules in the database Zinc_Natural_Stock (ZNSt) with structural similarity using ROCS (rapid overlay of chemical structures) and EON (electrostatic similarity) software, and in the final search, the top 100 were selected. Subsequently, in silico pharmacokinetic and toxicological properties were determined resulting in a total of 14 molecules, and these were submitted to the PASS online server for the prediction of biological insecticide and acetylcholinesterase activities, and only two selected molecules followed for the molecular docking study to evaluate the binding free energy and interaction mode. After these procedures were performed, toxicity risk assessment such as LD₅₀ values in mg/kg and toxicity class using the PROTOX online server, were undertaken. Molecule ZINC00001624 presented potential for inhibition for the acetylcholinesterase enzyme (insect and human) with a binding affinity value of −10.5 and −10.3 kcal/mol, respectively. The interaction with the juvenile hormone was −11.4 kcal/mol for the molecule ZINC00001021. Molecules ZINC00001021 and ZINC00001624 had excellent predictions in all the steps of the study and may be indicated as the most promising molecules resulting from the virtual screening of new insecticidal agents. Full article

► Figures

Figure 1

Open AccessArticle

TRPV1 Inhibits the Ventilatory Response to Hypoxia in Adult Rats, but Not the CO₂-Drive to Breathe

by Luis Gustavo A. Patrone, Jaime B. Duarte, Kênia Cardoso Bícego, Alexandre A. Steiner, Andrej A. Romanovsky and Luciane H. Gargaglioni

Pharmaceuticals 2019, 12(1), 19; https://doi.org/10.3390/ph12010019 - 24 January 2019

Abstract

Receptors of the transient receptor potential (TRP) channels superfamily are expressed in many tissues and have different physiological functions. However, there are few studies investigating the role of these channels in cardiorespiratory control in mammals. We assessed the role of central and peripheral [...] Read more.

{\dot{V}}_{E}

), heart rate (HR), mean arterial pressure (MAP) and body temperature (Tb) of male Wistar rats before and after intraperitoneal (AMG9810 [2.85 µg/kg, 1 mL/kg]) or intracebroventricular (AMG9810 [2.85 µg/kg, 1 µL] or AMG7905 [28.5 μg/kg, 1 µL]) injections of TRPV1 antagonists. Central or peripheral injection of TRPV1 antagonists did not change cardiorespiratory parameters or Tb during room air and hypercapnic conditions. However, the hypoxic ventilatory response was exaggerated by both central and peripheral injection of AMG9810. In addition, the peripheral antagonist blunted the drop in Tb induced by hypoxia. Therefore, the current data provide evidence that TRPV1 channels exert an inhibitory modulation on the hypoxic drive to breathe and stimulate the Tb reduction during hypoxia. Full article

► Figures

Figure 1

Open AccessArticle

[¹⁷⁷Lu]Lu-PSMA-617 Salivary Gland Uptake Characterized by Quantitative In Vitro Autoradiography

by Roswitha Tönnesmann, Philipp T. Meyer, Matthias Eder and Ann-Christin Baranski

Pharmaceuticals 2019, 12(1), 18; https://doi.org/10.3390/ph12010018 - 24 January 2019

Abstract

Irradiation of salivary glands remains the main dose-limiting side effect of therapeutic PSMA-inhibitors, especially when using alpha emitters. Thus, further advances in radiopharmaceutical design and therapy strategies are needed to reduce salivary gland uptake, thereby allowing the administration of higher doses and potentially resulting in improved response rates and better tumor control. As the uptake mechanism remains unknown, this work investigates the salivary gland uptake of [¹⁷⁷Lu]Lu-PSMA-617 by autoradiography studies on pig salivary gland tissue and on PSMA-overexpressing LNCaP cell membrane pellets. Displacement studies were performed with non-labeled PSMA-617 and 2-PMPA, respectively. The uptake of [¹⁷⁷Lu]Lu-PSMA-617 in glandular areas was determined to be partly PSMA-specific, with a high non-specific uptake fraction. The study emphasizes that [¹⁷⁷Lu]Lu-PSMA-617 accumulation in pig salivary glands can be attributed to a combination of both specific and non-specific uptake mechanisms. The observation is of high impact for future design of novel radiopharmaceuticals addressing the dose-limiting salivary gland irradiation of current alpha endoradiotherapy in prostate cancer. Full article

► Figures

Graphical abstract

Open AccessArticle

L-Ferritin: One Gene, Five Diseases; from Hereditary Hyperferritinemia to Hypoferritinemia—Report of New Cases

by Beatriz Cadenas, Josep Fita-Torró, Mar Bermúdez-Cortés, Inés Hernandez-Rodriguez, José Luis Fuster, María Esther Llinares, Ana María Galera, Julia Lee Romero, Santiago Pérez-Montero, Cristian Tornador and Mayka Sanchez

Pharmaceuticals 2019, 12(1), 17; https://doi.org/10.3390/ph12010017 - 23 January 2019

Abstract

Ferritin is a multimeric protein composed of light (L-ferritin) and heavy (H-ferritin) subunits that binds and stores iron inside the cell. A variety of mutations have been reported in the L-ferritin subunit gene (FTL gene) that cause the following five diseases: (1) hereditary hyperferritinemia with cataract syndrome (HHCS), (2) neuroferritinopathy, a subtype of neurodegeneration with brain iron accumulation (NBIA), (3) benign hyperferritinemia, (4) L-ferritin deficiency with autosomal dominant inheritance, and (5) L-ferritin deficiency with autosomal recessive inheritance. Defects in the FTL gene lead to abnormally high levels of serum ferritin (hyperferritinemia) in HHCS and benign hyperferritinemia, while low levels (hypoferritinemia) are present in neuroferritinopathy and in autosomal dominant and recessive L-ferritin deficiency. Iron disturbances as well as neuromuscular and cognitive deficits are present in some, but not all, of these diseases. Here, we identified two novel FTL variants that cause dominant L-ferritin deficiency and HHCS (c.375+2T > A and 36_42delCAACAGT, respectively), and one previously reported variant (Met1Val) that causes dominant L-ferritin deficiency. Globally, genetic changes in the FTL gene are responsible for multiple phenotypes and an accurate diagnosis is useful for appropriate treatment. To help in this goal, we included a diagnostic algorithm for the detection of diseases caused by defects in FTL gene. Full article

► Figures

Figure 1

Open AccessReview

Can the Efficacy of [¹⁸F]FDG-PET/CT in Clinical Oncology Be Enhanced by Screening Biomolecular Profiles?

by Hazel O’Neill, Vinod Malik, Ciaran Johnston, John V Reynolds and Jacintha O’Sullivan

Pharmaceuticals 2019, 12(1), 16; https://doi.org/10.3390/ph12010016 - 23 January 2019

Abstract

Positron Emission Tomography (PET) is a functional imaging modality widely used in clinical oncology. Over the years the sensitivity and specificity of PET has improved with the advent of specific radiotracers, increased technical accuracy of PET scanners and incremental experience of Radiologists. However, significant limitations exist—most notably false positives and false negatives. Additionally, the accuracy of PET varies between cancer types and in some cancers, is no longer considered a standard imaging modality. This review considers the relative influence of macroscopic tumour features such as size and morphology on 2-Deoxy-2-[¹⁸F]fluoroglucose ([¹⁸F]FDG) uptake by tumours which, though well described in the literature, lacks a comprehensive assessment of biomolecular features which may influence [¹⁸F]FDG uptake. The review aims to discuss the potential influence of individual molecular markers of glucose transport, glycolysis, hypoxia and angiogenesis in addition to the relationships between these key cellular processes and their influence on [¹⁸F]FDG uptake. Finally, the potential role for biomolecular profiling of individual tumours to predict positivity on PET imaging is discussed to enhance accuracy and clinical utility. Full article

► Figures

Graphical abstract

Open AccessArticle

Micellisation Mechanism and Behaviour of Soluplus^{^{^®}}–Furosemide Micelles: Preformulation Studies of an Oral Nanocarrier-Based System

by Julia F. Alopaeus, Ellen Hagesæther and Ingunn Tho

Pharmaceuticals 2019, 12(1), 15; https://doi.org/10.3390/ph12010015 - 19 January 2019

Abstract

In this study, self-assembling Soluplus^{^®} micelles were examined for inherent properties. Through calorimetric analysis, the critical micelle concentration (CMC) could be determined at 25 and 37 °C, and the influence of three media (Milli-Q water, phosphate-buffered saline (PBS) with a pH of 7.4 and 0.1 M HCl) on the lower critical solution temperature (LCST) was detected. Furthermore, the solubilisation of a poorly soluble drug, furosemide, into the Soluplus^{^®} micelles was studied. The concentration-dependent properties of the micellar system were assessed through an examination of the micellar size, polydispersity, morphology, viscosity and solubilising properties, which were all found to be affected by the concentration, but temperature, pH and the composition of the test medium were also found to have an effect. Homogeneity in the estimated micellar size and morphology was shown for monophasic micelle dispersions in lower concentrations and with a shift towards more complex structures or aggregates in higher concentrations. The micelles were further investigated in terms of drug release and biocompatibility with mucus-producing HT29-MTX cells, where no biocompatibility issues were found. In this research, the implications for oral drug delivery are discussed and valuable preformulation information is provided on the micellar properties of a Soluplus^{^®} drug system in a liquid or semi-solid form. Full article

► Figures

Graphical abstract

Open AccessArticle

Structural and In Vitro Functional Comparability Analysis of Altebrel™, a Proposed Etanercept Biosimilar: Focus on Primary Sequence and Glycosylation

by Ramin Fazel, Yudong Guan, Behrouz Vaziri, Christoph Krisp, Laura Heikaus, Amirhossein Saadati, Siti Nurul Hidayah, Manasi Gaikwad and Hartmut Schlüter

Pharmaceuticals 2019, 12(1), 14; https://doi.org/10.3390/ph12010014 - 17 January 2019

Abstract

The demand for reliable comparability studies of biosimilars grows with their increased market share. These studies focus on physicochemical, structural, functional and clinical properties to ensure that a biosimilar has no significant differences to the originator product and can be released into the market without extensive clinical trials. In the current study, Enbrel^® (etanercept, the originator) and Altebrel™ (the proposed biosimilar) underwent direct comparison. “Bottom-up” mass spectrometric analysis was used for primary sequence analysis, evaluation of N/O-glycosylation sites and quantification of methionine oxidation. N/O-glycans were analyzed after permethylation derivatization and the effect of N-glycans on in-vitro functionality of etanercept was assayed. Three enzyme peptide mapping resulted in complete identification of the primary structure. It was confirmed that total ion chromatograms are valuable datasets for the analysis of the primary structure of biodrugs. New N/O-glycan structures were identified and all the N-glycans were quantified. Finally, investigation of the functional properties of N-deglycosylated and non-modified etanercept samples using surface plasmon resonance analysis and in-vitro bioassay showed that N-glycosylation has no significant effect on its in-vitro functionality. Analysis of etanercept and its biosimilar, revealed a high similarity in terms of glycosylation, primary structure and in-vitro functionality. Full article

► Figures

Graphical abstract

Open AccessArticle

Cholecystokinin-2 Receptor Targeting with Novel C-terminally Stabilized HYNIC-Minigastrin Analogs Radiolabeled with Technetium-99m

by Maximilian Klingler, Christine Rangger, Dominik Summer, Piriya Kaeopookum, Clemens Decristoforo and Elisabeth von Guggenberg

Pharmaceuticals 2019, 12(1), 13; https://doi.org/10.3390/ph12010013 - 15 January 2019

Abstract

The high overexpression of cholecystokinin-2 receptors (CCK2R) in tumors, such as medullary thyroid carcinoma, allows for highly specific diagnostic and therapeutic targeting with radiolabeled peptide probes derived from natural ligands for the receptor. Based on the ideal imaging characteristics, high availability and low cost of technetium-99m (^99mTc)-labeled radiopharmaceuticals we have developed two hydrazinonicotinic acid (HYNIC) conjugated minigastrin analogs allowing labeling at high specific activity. The CCK2R targeting peptide conjugates show specific amino acid substitutions in the C-terminal receptor-specific sequence with the aim to increase stability and tumor targeting. The CCK2R affinity and the cell uptake of the new radioligands were analyzed using A431 human epidermoid carcinoma cells stably transfected with human CCK2R and mock transfected cells. Metabolic studies in BALB/c mice revealed a high resistance against enzymatic degradation for both radioligands. Biodistribution studies in tumor-xenografted athymic BALB/c nude mice at 1 h and 4 h p.i. showed that the two ^99mTc-labeled compounds showed varying uptake in receptor expressing organs, stomach and pancreas (1.3–10.4% IA/g), as well as kidneys, the main route of excretion (7.8–19.9% IA/g). The tumor uptake in A431-CCK2R xenografts was 24.75 ± 4.38% IA/g for [^99mTc]Tc-HYNIC-MGS5 and 42.48 ± 6.99% IA/g for [^99mTc]Tc-HYNIC-MGS11 at 4 h p.i., whereas the tumor-to-kidney ratio was comparable (2.6–3.3). On demand availability and potential application for radioguided surgery of a ^99mTc-labeled minigastrin analog support the further evaluation of these highly promising new compounds. Full article

► Figures

Figure 1

Open AccessArticle

Optimization of the Automated Synthesis of [¹¹C]mHED—Administered and Apparent Molar Activities

by Chrysoula Vraka, Verena Pichler, Neydher Berroterán-Infante, Tim Wollenweber, Anna Pillinger, Maximilian Hohensinner, Lukas Fetty, Dietrich Beitzke, Xiang Li, Cecile Philippe, Katharina Pallitsch, Markus Mitterhauser, Marcus Hacker and Wolfgang Wadsak

Pharmaceuticals 2019, 12(1), 12; https://doi.org/10.3390/ph12010012 - 14 January 2019

Abstract

The tracer [¹¹C]meta-Hydroxyephedrine ([¹¹C]mHED) is one of the most applied PET tracers for cardiac imaging, whose radiosynthesis was already reported in 1990. While not stated in the literature, separation difficulties and an adequate formulation of the product are well known challenges in its production. Furthermore, the precursor (metaraminol) is also a substrate for the norepinephrine transporter, and can therefore affect the image quality. This study aims at optimizing the synthetic process of [¹¹C]mHED and investigating the effect of the apparent molar activity (sum of mHED and metaraminol) in patients and animals. The main optimization was the improved separation through reverse phase-HPLC by a step gradient and subsequent retention of the product on a weakly-cationic ion exchange cartridge. The µPET/µCT was conducted in ten rats (ischemic model) and the apparent molar activity was correlated to the VOI- and SUV-ratio of the myocardium/intra-ventricular blood pool. Moreover, nine long-term heart transplanted and five Morbus Fabry patients underwent PET and MRI imaging for detection of changes in the sympathetic innervation. In summary, the fully-automated synthesis and optimized purification method of [¹¹C]mHED is easily applicable and reproducible. Moreover, it was shown that the administered apparent molar activities had a negligible effect on the imaging quality. Full article

► Figures