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A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing
19 Nov 2013 04:45 pm
New England Journal of Medicine, Volume 0, Issue 0, Ahead of Print.
A golden approach to ion channel inhibition
09 Dec 2013 10:43 am
Publication date: September 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 9
Author(s): Gavin E. Jarvis , Andrew J. Thompson
Drugs are often used in combination and, for pharmacologists, the manner of their interactions can cast
light on drug mechanisms and biological processes. Here we provide simplified descriptions of commonly
used analytical methods for analysing drug combinations and describe a new and practical experimental
solution to address the mechanistic question: ‘Do two channel-blocking drugs bind at the same site?’ We
define two simple mathematical models that describe the effects of two channel blockers acting
simultaneously at either the same (Syntopic Model) or different (Allotopic Model) binding sites within a
channel pore. We find that the optimum concentrations of two drugs for distinguishing between the two
models are related to the mathematical Golden Ratio.
A rising star: pharmacological development in China
09 Dec 2013 10:43 am
Publication date: October 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 10
Author(s): Joanna Schaffhausen
AKAP signaling complexes: pointing towards the next generation of therapeutic targets?
09 Dec 2013 10:43 am
Publication date: December 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 12
Author(s): Jessica L. Esseltine , John D. Scott
A-kinase anchoring proteins (AKAPs) streamline signal transduction by localizing signaling enzymes with
their substrates. Great strides have been made in elucidating the role of these macromolecular signaling
complexes as new binding partners and novel AKAPs are continually being uncovered. The mechanics and
dynamics of these multi-enzyme assemblies suggest that AKAP complexes are viable targets for
therapeutic intervention. This review will highlight recent advances in AKAP research focusing on local
signaling events that are perturbed in disease.
Amygdala FAAH and anandamide: mediating protection and recovery from stress
09 Dec 2013 10:43 am
Publication date: November 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 11
Author(s): Ozge Gunduz-Cinar , Matthew N. Hill , Bruce S. McEwen , Andrew Holmes
A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing
interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis
and degradation upon neuronal activation, the ECB N -arachidonoylethanolamide (anandamide, AEA) is
actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress
rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key
anxiety-mediating region – the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of
FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy
and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues
deficient fear extinction in rodent models by enhancing AEA–CB1 (cannabinoid type 1) receptor signaling
and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by
pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic
stress.
An interview with David Sabatini
09 Dec 2013 10:43 am
Publication date: July 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 7
An interview with Gavril Pasternak
09 Dec 2013 10:43 am
Publication date: August 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 8
An interview with Vishva M. Dixit
09 Dec 2013 10:43 am
Publication date: November 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 11
Assessment of endothelial and neurovascular function in human skin microcirculation
09 Dec 2013 10:43 am
Publication date: July 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 7
Author(s): Matthieu Roustit , Jean-Luc Cracowski
Peripheral microvascular dysfunction has been described in many physiological and pathological
conditions. Owing to its accessibility, the cutaneous microcirculation provides a unique index of
microvascular function. Skin microvascular function has therefore been proposed as a prognostic marker or
for evaluating the effect of drugs on the microcirculation. Various reactivity tests, coupled with techniques
measuring skin blood flux, are used to non-invasively explore both endothelial and neurovascular
microvascular functioning in humans. We review the advantages and limitations of the main reactivity tests,
including post-occlusive reactive hyperemia, local thermal hyperemia, pressure-induced vasodilation, and
iontophoresis of vasodilators, combined with measurement techniques such as laser Doppler and laser
speckle contrast imaging. Recent advances in our comprehension of the physiological pathways underlying
these reactivity tests, as well as technological developments in microcirculation imaging, have provided
reliable and reproducible tools for studying the microcirculation.
Autoimmune disease: Parkinson's drug promotes myelin repair
15 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 905 (2013). doi:10.1038/nrd4181
Author: Sarah Crunkhorn
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is characterized
by immune cell infiltration and inflammation, which cause neuronal demyelination and degeneration.
Accordingly, MS therapy largely involves the long-term use of disease-modifying injectable
immunosuppressants or immunomodulators, but these are
Biophysics of cell membrane lipids in cancer drug resistan Implications for drug transport
and drug delivery with nanoparticles
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Chiranjeevi Peetla , Sivakumar Vijayaraghavalu , Vinod Labhasetwar
In this review, we focus on the biophysics of cell membrane lipids, particularly when cancers develop
acquired drug resistance, and how biophysical changes in resistant cell membrane influence drug transport
and nanoparticle-mediated drug delivery. Recent advances in membrane lipid research show the varied
roles of lipids in regulating membrane P-glycoprotein function, membrane trafficking, apoptotic pathways,
drug transport, and endocytic functions, particularly endocytosis, the primary mechanism of cellular uptake
of nanoparticle-based drug delivery systems. Since acquired drug resistance alters lipid biosynthesis,
understanding the role of lipids in cell membrane biophysics and its effect on drug transport is critical for
developing effective therapeutic and drug delivery approaches to overcome drug resistance. Here we
discuss novel strategies for (a) modulating the biophysical properties of membrane lipids of resistant cells to
facilitate drug transport and regain endocytic function and (b) developing effective nanoparticles based on
their biophysical interactions with membrane lipids to enhance drug delivery and overcome drug
resistance.
Graphical abstract
Bone disorders: Targeting NOX4 knocks down osteoporosis
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 904 (2013). doi:10.1038/nrd4182
Author: Charlotte Harrison
A recent paper published in the Journal of Clinical Investigation has shown that NADPH oxidase 4 (NOX4)
— an enzyme that is involved in the production of reactive oxygen species (ROS) — could be a therapeutic
target for disorders characterized by bone loss, such
Building better drugs: developing and regulating engineered therapeutic proteins
09 Dec 2013 10:43 am
Publication date: October 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 10
Author(s): Chava Kimchi-Sarfaty , Tal Schiller , Nobuko Hamasaki-Katagiri , Mansoor A. Khan , Chen
Yanover , Zuben E. Sauna
Most native proteins do not make optimal drugs and thus a second- and third-generation of therapeutic
proteins, which have been engineered to improve product attributes or to enhance process characteristics,
are rapidly becoming the norm. There has been unprecedented progress, during the past decade, in the
development of platform technologies that further these ends. Although the advantages of engineered
therapeutic proteins are considerable, the alterations can affect the safety and efficacy of the drugs. We
discuss both the key technological innovations with respect to engineered therapeutic proteins and
advancements in the underlying basic science. The latter would permit the design of science-based criteria
for the prediction and assessment of potential risks and the development of appropriate risk management
plans. This in turn holds promise for more predictable criteria for the licensure of a class of products that are
extremely challenging to develop but represent an increasingly important component of modern medical
practice.
CG173: Neuropathic pain - pharmacological management
20 Nov 2013 12:01 am
The summary of the published clinical guideline on Neuropathic pain - pharmacological management. It
links to the published guidance and key documents.
Can nanomedicines kill cancer stem cells?
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Yi Zhao , Daria Y. Alakhova , Alexander V. Kabanov
Most tumors are heterogeneous and many cancers contain small population of highly tumorigenic and
intrinsically drug resistant cancer stem cells (CSCs). Like normal stem cell, CSCs have the ability to selfrenew and differentiate to other tumor cell types. They are believed to be a source for drug resistance,
tumor recurrence and metastasis. CSCs often overexpress drug efflux transporters, spend most of their
time in non-dividing G 0 cell cycle state, and therefore, can escape the conventional chemotherapies. Thus,
targeting CSCs is essential for developing novel therapies to prevent cancer relapse and emerging of drug
resistance. Nanocarrier-based therapeutic agents (nanomedicines) have been used to achieve longer
circulation times, better stability and bioavailability over current therapeutics. Recently, some groups have
successfully applied nanomedicines to target CSCs to eliminate the tumor and prevent its recurrence.
These approaches include 1) delivery of therapeutic agents (small molecules, siRNA, antibodies) that affect
embryonic signaling pathways implicated in self-renewal and differentiation in CSCs, 2) inhibiting drug efflux
transporters in an attempt to sensitize CSCs to therapy, 3) targeting metabolism in CSCs through
nanoformulated chemicals and field-responsive magnetic nanoparticles and carbon nanotubes, and 4)
disruption of multiple pathways in drug resistant cells using combination of chemotherapeutic drugs with
amphiphilic Pluronic block copolymers. Despite clear progress of these studies the challenges of targeting
CSCs by nanomedicines still exist and leave plenty of room for improvement and development. This review
summarizes biological processes that are related to CSCs, overviews the current state of anti-CSCs
therapies, and discusses state-of-the-art nanomedicine approaches developed to kill CSCs.
Graphical abstract
Cancer drug discovery by repurposing: teaching new tricks to old dogs
09 Dec 2013 10:43 am
Publication date: September 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 9
Author(s): Subash C. Gupta , Bokyung Sung , Sahdeo Prasad , Lauren J. Webb , Bharat B. Aggarwal
Progressively increasing failure rates, high cost, poor bioavailability, poor safety, limited efficacy, and a
lengthy design and testing process associated with cancer drug development have necessitated alternative
approaches to drug discovery. Exploring established non-cancer drugs for anticancer activity provides an
opportunity rapidly to advance therapeutic strategies into clinical trials. The impetus for development of
cancer therapeutics from non-cancer drugs stems from the fact that different diseases share common
molecular pathways and targets in the cell. Common molecular origins of diverse diseases have been
discovered through advancements in genomics, proteomics, and informatics technologies, as well as
through the development of analytical tools that allow researchers simultaneously to screen large numbers
of existing drugs against a particular disease target. Thus, drugs originally identified as antitussive,
sedative, analgesic, antipyretic, antiarthritic, anesthetic, antidiabetic, muscle relaxant, immunosuppressant,
antibiotic, antiepileptic, cardioprotective, antihypertensive, erectile function enhancing, or angina relieving
are being repurposed for cancer. This review describes the repurposing of these drugs for cancer
treatment.
Cancer nanotechnology: The impact of passive and active targeting in the era of modern
cancer biology
08 Dec 2013 12:32 pm
Publication date: Available online 22 November 2013
Source:Advanced Drug Delivery Reviews
Author(s): Nicolas Bertrand , Jun Wu , Xiaoyang Xu , Nazila Kamaly , Omid C. Farokhzad
Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has
experienced an exponential growth since early 2000's. The path to the commercialization of oncology drugs
is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies
may contribute to the success of cancer drug development. The pace at which pharmaceutical companies
have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is
now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology
can meaningfully contribute to create differentiated products and improve clinical outcome. This review
describes the lessons learned since the commercialization of the first-generation nanomedicines including
DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles
that are under various stages of development, including BIND-014 and MM-398. It highlights the
opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized
medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced
permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential
“retention” in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral
targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance
our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.
Graphical abstract
Carbon nanotubes as optical biomedical sensors
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Sebastian Kruss , Andrew J. Hilmer , Jingqing Zhang , Nigel F. Reuel , Bin Mu , Michael S.
Strano
Biosensors are important tools in biomedical research. Moreover, they are becoming an essential part of
modern healthcare. In the future, biosensor development will become even more crucial due to the demand
for personalized-medicine, point-of care devices and cheaper diagnostic tools. Substantial advances in
sensor technology are often fueled by the advent of new materials. Therefore, nanomaterials have
motivated a large body of research and such materials have been implemented into biosensor devices.
Among these new materials carbon nanotubes (CNTs) are especially promising building blocks for
biosensors due to their unique electronic and optical properties. Carbon nanotubes are rolled-up cylinders
of carbon monolayers (graphene). They can be chemically modified in such a way that biologically relevant
molecules can be detected with high sensitivity and selectivity. In this review article we will discuss how
carbon nanotubes can be used to create biosensors. We review the latest advancements of optical carbon
nanotube based biosensors with a special focus on near-infrared (NIR)-fluorescence, Raman-scattering and
fluorescence quenching.
Graphical abstract
Carbon nanotubes as vaccine scaffolds
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): David A. Scheinberg , Michael R. McDevitt , Tao Dao , J. Justin Mulvey , Evan Feinberg , Simone
Alidori
Carbon nanotubes display characteristics that are potentially useful in their development as scaffolds for
vaccine compositions. These features include stability in vivo, lack of intrinsic immunogenicity, low toxicity,
and the ability to be appended with multiple copies of antigens. In addition, the particulate nature of carbon
nanotubes and their unusual properties of rapid entry into antigen-presenting cells, such as dendritic cells,
make them especially useful as carriers of antigens. Early attempts demonstrating carbon nanotube-based
vaccines can be used in both infectious disease settings and cancer are promising.
Graphical abstract
Carbon nanotubes as vectors for gene therapy: Past achievements, present challenges and
future goals
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Katie Bates , Kostas Kostarelos
Promising therapeutic and prophylactic effects have been achieved following advances in the gene therapy
research arena, giving birth to the new generation of disease-modifying therapeutics. The greatest
challenge that gene therapy vectors still face is the ability to deliver sufficient genetic payloads in order to
enable efficient gene transfer into target cells. A wide variety of viral and non-viral gene therapy vectors
have been developed and explored over the past 10 years, including carbon nanotubes. In this review we
will address the application of carbon nanotubes as non-viral vectors in gene therapy with the aim to give a
perspective on the past achievements, present challenges and future goals. A series of important topics
concerning carbon nanotubes as gene therapy vectors will be addressed, including the benefits that carbon
nanotubes offer over other non-viral delivery systems. Furthermore, a perspective is given on what the ideal
genetic cargo to deliver using carbon nanotubes is and finally the geno-pharmacological impact of carbon
nanotube-mediated gene therapy is discussed.
Graphical abstract
Carbon nanotubes for biomedical imaging: The recent advances
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Hua Gong , Rui Peng , Zhuang Liu
This article reviews the latest progresses regarding the applications of carbon nanotubes (CNTs), including
single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs), as multifunctional
nano-probes for biomedical imaging. Utilizing the intrinsic band-gap fluorescence of semi-conducting singlewalled carbon nanotubes (SWNTs), fluorescence imaging in the near infrared II (NIR-II) region with
enhanced tissue penetration and spatial resolution has shown great promise in recent years. Raman
imaging based on the resonance Raman scattering of SWNTs has also been explored by a number of
groups for in vitro and in vivo imaging of biological samples. The strong absorbance of CNTs in the NIR
region can be used for photoacoustic imaging, and their photoacoustic signals can be dramatically
enhanced by adding organic dyes, or coating with gold shells. Taking advantages of metal nanoparticle
impurities attached to nanotubes, CNTs can also serve as a T2-contrast agent in magnetic resonance (MR)
imaging. In addition, when labeled with radioactive isotopes, many groups have developed nuclear imaging
with functionalized CNTs. Therefore CNTs are unique imaging probes with great potential in biomedical
multimodal imaging.
Graphical abstract
Carbon nanotubes for delivery of small molecule drugs
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Bin Sheng Wong , Sia Lee Yoong , Anna Jagusiak , Tomasz Panczyk , Han Kiat Ho , Wee Han
Ang , Giorgia Pastorin
In the realm of drug delivery, carbon nanotubes (CNTs) have gained tremendous attention as promising
nanocarriers, owing to their distinct characteristics, such as high surface area, enhanced cellular uptake
and the possibility to be easily conjugated with many therapeutics, including both small molecules and
biologics, displaying superior efficacy, enhanced specificity and diminished side effects. While most CNTbased drug delivery system (DDS) had been engineered to combat cancers, there are also emerging
reports that employ CNTs as either the main carrier or adjunct material for the delivery of various nonanticancer drugs. In this review, the delivery of small molecule drugs is expounded, with special attention
paid to the current progress of in vitro and in vivo research involving CNT-based DDSs, before finally
concluding with some consideration on inevitable complications that hamper successful disease
intervention with CNTs.
Graphical abstract
Carbon nanotubes in hyperthermia therapy
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Ravi Singh , Suzy V. Torti
Thermal tumor ablation therapies are being developed with a variety of nanomaterials, including single- and
multiwalled carbon nanotubes. Carbon nanotubes (CNTs) have attracted interest due to their potential for
simultaneous imaging and therapy. In this review, we highlight in vivo applications of carbon nanotubemediated thermal therapy (CNMTT) and examine the rationale for use of this treatment in recurrent tumors
or those resistant to conventional cancer therapies. Additionally, we discuss strategies to localize and
enhance the cancer selectivity of this treatment and briefly examine issues relating the toxicity and long
term fate of CNTs.
Graphical abstract
Carbon nanotubes in medicine & biology — Therapy and diagnostics
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Hanene Ali‐ Boucetta , Kostas Kostarelos
Carbon nanotubes in medicine and biology — Safety and toxicology
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Cyrill Bussy , Kostas Kostarelos
Carbon nanotubes in neuroregeneration and repair
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Alessandra Fabbro , Maurizio Prato , Laura Ballerini
In the last decade, we have experienced an increasing interest and an improved understanding of the
application of nanotechnology to the nervous system. The aim of such studies is that of developing future
strategies for tissue repair to promote functional recovery after brain damage. In this framework, carbon
nanotube based technologies are emerging as particularly innovative tools due to the outstanding physical
properties of these nanomaterials together with their recently documented ability to interface neuronal
circuits, synapses and membranes. This review will discuss the state of the art in carbon nanotube
technology applied to the development of devices able to drive nerve tissue repair; we will highlight the
most exciting findings addressing the impact of carbon nanotubes in nerve tissue engineering, focusing in
particular on neuronal differentiation, growth and network reconstruction.
Graphical abstract
Challenging resistance mechanisms to therapies for metastatic melanoma
09 Dec 2013 10:43 am
Publication date: December 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 12
Author(s): Lucio Tentori , Pedro Miguel Lacal , Grazia Graziani
Melanoma is the most aggressive form of skin cancer and, if spread outside the epidermis, has a dismal
prognosis. Before the approval of the anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)
monoclonal antibody ipilimumab and the BRAF inhibitors vemurafenib and dabrafenib, no other agents had
demonstrated better results in terms of overall survival than the DNA-methylating compound dacarbazine
(or its oral analog temozolomide). However, most patients with metastatic melanoma do not obtain longlasting clinical benefit from ipilimumab and responses to BRAF inhibitors are short lived. Thus, combination
therapies with inhibitors of DNA repair (e.g., poly(ADP-ribose) polymerase [PARP] inhibitors), novel
immunomodulators (monoclonal antibodies against programmed death-1 [PD-1] or its ligand PD-L1),
targeted therapies (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase [ERK]
kinase [MEK] or phosphatidylinositol 3-kinase [PI3K]/AKT/mammalian target of rapamycin [mTOR]
inhibitors) or antiangiogenic agents are currently being investigated to improve the efficacy of antimelanoma
therapies. This review discusses the implications of simultaneously targeting key regulators of melanoma
cell proliferation/survival and immune responses to counteract resistance.
Charles Hugh-Jones
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 900 (2013). doi:10.1038/nrd4190
Drug developers can identify new opportunities and get insight into their failures when they mine their inhouse clinical trial data. But to gain maximum insight, companies would do well to pool and share their data
sets, argues Charles Hugh-Jones, Chief Medical Officer in North America at Sanofi. To this end, he and his
collaborators from the CEO Roundtable on Cancer are preparing to launch Project Data Sphere, a nonprofit platform designed to share the comparator arm data from dozens of cancer clinical trials. Hugh-Jones
talks to Asher Mullard about the need for, and the promise of, data sharing.
Chemical predictive modelling to improve compound quality
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 948 (2013). doi:10.1038/nrd4128
Authors: John G. Cumming, Andrew M. Davis, Sorel Muresan, Markus Haeberlein & Hongming Chen
The 'quality' of small-molecule drug candidates, encompassing aspects including their potency, selectivity
and ADMET (absorption, distribution, metabolism, excretion and toxicity) characteristics, is a key factor
influencing the chances of success in clinical trials. Importantly, such characteristics are under the control of
chemists during the identification
Comparison of pethidine and tramadol for pain relief after a caesarean: a randomised
controlled trial
08 Dec 2013 01:45 pm
Publication date: 5 December 2013
Source:The Lancet, Volume 382, Supplement 4
Author(s): Khaled I Abu El-Aish , Haly S Zourob
Background Appropriate analgesia for pain after caesarean is important to aid a mother's recovery.
Pethidine and tramadol are used for analgesia during obstetrical procedures, but they have not been
compared for relief of post-caesarean pain. We therefore compared the analgesic efficacies and adverse
effects of pethidine and tramadol in women after a caesarean. Methods In a randomised, unmasked,
parallel-group controlled trial, we enrolled women (aged 18–41 years) who were undergoing either elective
or emergency lower-segment caesarean under general anaesthetic at Al Helal Al Emirati Hospital, Rafah,
Gaza Strip, occupied Palestinian territory. Using a manually generated allocation sequence that was
independently managed by medical staff, we randomly assigned women to receive a single dose (100 mg)
of pethidine or tramadol intramuscularly immediately after the caesarean. We used a visual analogue scale
(VAS; range 0–10, 0=no pain and 10=pain as bad as it could be) to record the pain 1 h after the start of the
analgesia and then at 6 h, 12 h, and 24 h (primary outcome). The secondary outcomes were nausea and
vomiting scores (NVS 0–3; 0=no nausea or vomiting and 3=severe, unresponsive to antiemetic drugs),
sedation scores (SS 0–3; 0=patient awake and 3=severe sedation, patient difficult to rouse, unrousable),
and time to pass first flatus. Another secondary outcome was the use of other analgesic drugs during 24 h.
Data were analysed with SPSS (version 13.0). We compared the groups using the Mann-Whitney U test,
student's t test, or χ2. The study was approved by the Ministry of Health and Helsinki Committee, Gaza
Strip. Women provided verbal informed consent before their participation in the trial and consent to undergo
a caesarean. Findings We screened 258 women and enrolled 232 (mean age 29·5 years [SD 7·3]); 26
women were excluded because they had spinal or epidural anaesthesia. 116 women were allocated to each
of the two treatment groups. Greater analgesia was achieved with pethidine at 1 h and 6 h than with
tramadol (VAS: 1 h, mean score 2·91 vs 5·10, p=0·003; 6 h, 2·97 vs 3·52, p=0·049). No differences were
noted in the proportion of patients in the pethidine and tramadol groups with NVS 0 at 1 h, 6 h, 12 h, and 24
h after caesarean (102 [88%] of 116 vs 99 [85%] of 116, p=0·555; 108 [93%] vs 105 [91%], p=0·633; 111
[96%] vs 112 [97%], p=1·00; and 114 [98%] vs 113 [97%], p=1·00, respectively). Mean time to first passage
of flatus was 12·6 h (SD 5·0) and 13·3 h (5·1) in the pethidine and tramadol groups, respectively (p=0·376).
More patients in the tramadol group had slight sedation (SS 1) than did those in the pethidine group at 12 h
and 24 h (16 [14%] vs five [4%], p=0·014; and seven [6%] vs one [<1%], p=0·036, respectively). The total
intake of other non-narcotic analgesic drugs was greater in the tramadol group than in the pethidine group
(99 [85%] of 116 vs 87 [75%] of 116 patients; p=0·048). Interpretation Pethidine was more effective than
was tramadol for post-caesarean pain relief. We therefore recommend that it is used to relieve pain after a
caesarean. Funding None.
Computational biology: Structural insights into allosteric GPCR drugs
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 906 (2013). doi:10.1038/nrd4188
Author: Charlotte Harrison
Dror et al. used computational modelling to garner information on how ligands bind to the allosteric binding
site on G protein-coupled receptors (GPCRs). The authors determined conformations of the M2 muscarinic
acetylcholine receptor in combination with several structurally diverse allosteric ligands, which revealed they
Computational methods for drug design and discovery: focus on China
09 Dec 2013 10:43 am
Publication date: October 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 10
Author(s): Mingyue Zheng , Xian Liu , Yuan Xu , Honglin Li , Cheng Luo , Hualiang Jiang
In the past decades, China's computational drug design and discovery research has experienced fast
development through various novel methodologies. Application of these methods spans a wide range, from
drug target identification to hit discovery and lead optimization. In this review, we firstly provide an overview
of China's status in this field and briefly analyze the possible reasons for this rapid advancement. The
methodology development is then outlined. For each selected method, a short background precedes an
assessment of the method with respect to the needs of drug discovery, and, in particular, work from China
is highlighted. Furthermore, several successful applications of these methods are illustrated. Finally, we
conclude with a discussion of current major challenges and future directions of the field.
Contents page + Editorial Board
09 Dec 2013 10:43 am
Publication date: December 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 12
Delivery of inhalation drugs to children for asthma and other respiratory diseases
08 Dec 2013 12:32 pm
Publication date: Available online 21 November 2013
Source:Advanced Drug Delivery Reviews
Author(s): Philip Chi Lip Kwok , Hak-Kim Chan
Infants and children constitute a patient group that has unique requirements in pulmonary drug delivery.
Since their lungs develop continuously until they reach adulthood, the airways undergo changes in
dimensions and number. Computational models have been devised on the growth dynamics of the airways
during childhood, as well as the particle deposition mechanisms in these growing lungs. The models
indicate that total aerosol deposition in the body decreases with age, while deposition in the lungs increases
with age. This has been observed on paediatric subjects in in vivo studies. Issues unique to children in
pulmonary drug delivery include their lower tidal volume, highly variable breathing patterns, air leaks from
facemasks, and the off-label or unlicensed use of pharmaceutical products due to lack of clinical data for
this age group. The aerosol devices used are essentially those developed for adult patients that have been
adapted to paediatric use. Facemasks should be used with nebulisers and spacers for infants and young
children. An idealised throat that mimic the average particle deposition in paediatric throats has been
designed to obtain more clinically relevant aerosol dispersion data in vitro. More effort should be spent on
studying particle deposition in the paediatric lung and developing products specific for this subpopulation to
meet their needs.
Graphical abstract
Design production and characterization of drug delivery systems by Lab-on-a-Chip
technology
08 Dec 2013 12:32 pm
Publication date: 15 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 11–12
Author(s): Stefania Mazzitelli , Claudio Nastruzzi
Design, fabrication and characterization of drug delivery systems based on lab-on-a-chip
technology
08 Dec 2013 12:32 pm
Publication date: 15 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 11–12
Author(s): Nam-Trung Nguyen , Seyed Ali Mousavi Shaegh , Navid Kashaninejad , Dinh-Tuan Phan
Lab-on-a-chip technology is an emerging field evolving from the recent advances of micro- and
nanotechnologies. The technology allows the integration of various components into a single microdevice.
Microfluidics, the science and engineering of fluid flow in microscale, is the enabling underlying concept for
lab-on-a-chip technology. The present paper reviews the design, fabrication and characterization of drug
delivery systems based on this amazing technology. The systems are categorized and discussed according
to the scales at which the drug is administered. Starting with the fundamentals on scaling laws of mass
transfer and basic fabrication techniques, the paper reviews and discusses drug delivery devices for
cellular, tissue and organism levels. At the cellular level, a concentration gradient generator integrated with
a cell culture platform is the main drug delivery scheme of interest. At the tissue level, the synthesis of
smart particles as drug carriers using lab-on-a-chip technology is the main focus of recent developments. At
the organism level, microneedles and implantable devices with fluid-handling components are the main
drug delivery systems. For drug delivery to a small organism that can fit into a microchip, devices similar to
those of cellular level can be used.
Graphical abstract
Determinants of carbon nanotube toxicity
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Sophie Lanone , Pascal Andujar , Ali Kermanizadeh , Jorge Boczkowski
In the last few years questions have been raised regarding the potential toxicity of carbon nanotubes
(CNTs) to humans and environment. It is believed that the physico-chemical characteristics of these
materials are key determinants of CNT interaction with living organisms, and hence determine their toxicity.
As for other nanomaterials, the most important of these characteristics are the length, diameter, surface
area, tendency to agglomerate, bio-durability, presence and nature of catalyst residues as well as chemical
functionalization of the CNT. This review highlights the recent advancements in the understanding of the
CNT properties which are essential in determining CNT toxicity. Hence the focus is on CNT dimensions,
surface properties, bio-durability and corona formation as these fields have evolved greatly in recent years.
A deeper understanding of these events and their underlying mechanisms could provide a molecular
explanation of the biological and physiological responses following CNT administration and therefore help in
the development of safe by design materials.
Graphical abstract
Do Pharmacogenetics Have a Role in the Dosing of Vitamin K Antagonists?
19 Nov 2013 04:45 pm
New England Journal of Medicine, Volume 0, Issue 0, Ahead of Print.
Does Improving Handoffs Reduce Medical Error Rates?
04 Dec 2013 12:00 am
In 1965, the American Medical Association declared that “An intern’s duties and responsibilities are not
discharged on a ‘nine-to-five’ basis. While an acceptable internship provides for a reasonable amount of
free time, [the intern’s] thought for and contact with his patients should be on a ‘round-the-clock’ basis.” In
the intervening 45 years, the advent of the hospitalist movement fragmented inpatient and outpatient care,
payment by diagnosis reduced length of stay, hospitalization rates per capita increased by 15%, and more
than 1000 new drug applications were approved. In short, inpatient care is now more fragmented, more
frantic, and more complicated than in the 1960s. At the same time, the science of sleep and cognition
matured enough to make the risks of working while fatigued unequivocally clear, and the influx of women
into medical training made it increasingly difficult to sustain the fiction that house staff have no obligations
outside the hospital. The medical establishment reacted accordingly by restricting work hours of house staff.
Thus, in 2013 not only is the “round the clock” internship a relic of the past, but in Europe internships are
approaching the “nine to five” standard, with work-hours restricted to 48 hours a week.
Drug allergy
15 Oct 2014 01:00 am
This is the clinical guideline in development on using Drug allergy.
Drugging cancer genomes
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 889 (2013). doi:10.1038/nrd4184
Authors: Paul Workman & Bissan Al-Lazikani
A recent landmark analysis compared genome-wide mutations and associated 'omics' features for 3,281
tumours across 12 human cancer types. There is a clear need for objective target assessment and
prioritization by the drug discovery community to make the best use of such vast amounts of data.
Editorial Board
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Efficacy of antipsychotic drugs for schizophrenia
08 Dec 2013 01:45 pm
Publication date: 7–13 December 2013
Source:The Lancet, Volume 382, Issue 9908
Author(s): Philippe D Vincent , Edouard Kouassi
Efficacy of antipsychotic drugs for schizophrenia – Authors' reply
08 Dec 2013 01:45 pm
Publication date: 7–13 December 2013
Source:The Lancet, Volume 382, Issue 9908
Author(s): Stefan Leucht , Andrea Cipriani , John R Geddes , Georgia Salanti , John M Davis
Endocannabinoid signaling in cancer: a rather complex puzzle
09 Dec 2013 10:43 am
Publication date: August 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 8
Author(s): Mauro Maccarrone
Endowing carbon nanotubes with biological and biomedical properties by chemical
modifications
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Alessia Battigelli , Cécilia Ménard-Moyon , Tatiana Da Ros , Maurizio Prato , Alberto Bianco
The scope of nanotechnology is gaining importance in biology and medicine. Carbon nanotubes (CNTs)
have emerged as a promising tool due to their unique properties, high specific surface area, and capacity to
cross biological barriers. These properties offer a variety of opportunities for applications in nanomedicine,
such as diagnosis, disease treatment, imaging, and tissue engineering. Nevertheless, pristine CNTs are
insoluble in water and in most organic solvents; thereby functionalization of their surface is necessary to
increase biocompatibility. Derivatization of CNTs also gives the possibility to conjugate different biological
and bioactive molecules including drugs, proteins, and targeting ligands. This review focuses on the
chemical modifications of CNTs that have been developed to impart specific properties for biological and
medical purposes. Biomolecules can be covalently grafted or non-covalently adsorbed on the nanotube
surface. In addition, the inner core of CNTs can be exploited to encapsulate drugs, nanoparticles, or
radioactive elements.
Graphical abstract
Europe drug regulator wins appeal over release of trial data
06 Dec 2013 11:36 am
The European Union’s highest court has overturned a decision by a lower court that stopped the European
drug regulator releasing clinical trial data it holds on two drugs.The US drug company AbbVie...
Exploiting nanotechnology to overcome tumor drug resistan Challenges and opportunities
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Ameya R. Kirtane , Stephen M. Kalscheuer , Jayanth Panyam
Tumor cells develop resistance to chemotherapeutic drugs through multiple mechanisms. Overexpression
of efflux transporters is an important source of drug resistance. Efflux transporters such as P-glycoprotein
reduce intracellular drug accumulation and compromise drug efficacy. Various nanoparticle-based
approaches have been investigated to overcome efflux-mediated resistance. These include the use of
formulation excipients that inhibit transporter activity and co-delivery of the anticancer drug with a specific
inhibitor of transporter function or expression. However, the effectiveness of nanoparticles can be
diminished by poor transport in the tumor tissue. Hence, adjunct therapies that improve the intratumoral
distribution of nanoparticles may be vital to the successful application of nanotechnology to overcome tumor
drug resistance. This review discusses the mechanisms of tumor drug resistance and highlights the
opportunities and challenges in the use of nanoparticles to improve the efficacy of anticancer drugs against
resistant tumors.
Graphical abstract
Exploiting pluripotent stem cell technology for drug discovery, screening, safety, and
toxicology assessments
08 Dec 2013 12:32 pm
Publication date: Available online 2 December 2013
Source:Advanced Drug Delivery Reviews
Author(s): Jered V. McGivern , Allison D. Ebert
In order for the pharmaceutical industry to maintain a constant flow of novel drugs and therapeutics into the
clinic, compounds must be thoroughly validated for safety and efficacy in multiple biological and
biochemical systems. Pluripotent stem cells, because of their ability to develop into any cell type in the body
and recapitulate human disease, may be an important cellular system to add to the drug development
repertoire. This review will discuss some of the benefits of using pluripotent stem cells for drug discovery
and safety studies as well as some of the recent applications of stem cells in drug screening studies. We
will also address some of the hurdles that need to be overcome in order to make stem cell-based
approaches an efficient and effective tool in the quest to produce clinically successful drug compounds.
Graphical abstract
From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists
09 Dec 2013 10:43 am
Publication date: October 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 10
Author(s): Guy A. Higgins , Edward M. Sellers , Paul J. Fletcher
The recent US Food and Drug Administration (FDA) approval of the serotonin (5-hydroxytryptamine, 5-HT)
5-HT 2C receptor agonist lorcaserin for the treatment of obesity represents a new therapeutic drug class
available to the clinic. Preclinical evidence supports the potential for this drug class to treat other related
conditions such as substance abuse. In the present article we review this evidence and further suggest that
overlapping neurobiological systems may contribute to an anti-addictive and anti-obesity profile. The
availability of selective 5-HT 2C agonists provides an opportunity to evaluate their potential as treatments
for nicotine dependence or psychostimulant abuse, conditions for which there is significant medical need
but only limited available treatment options.
Gardasil administration to hr-HPV-positive women and their partners
09 Dec 2013 10:43 am
Publication date: September 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 9
Author(s): Salvatore Gizzo , Marco Noventa , Giovanni Battista Nardelli
Genotoxicity and carcinogenicity risk of carbon nanotubes
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Shinya Toyokuni
Novel materials are often commercialized without a complete assessment of the risks they pose to human
health because such assessments are costly and time-consuming; additionally, sometimes the
methodology needed for such an assessment does not exist. Carbon nanotubes have the potential for
widespread application in engineering, materials science and medicine. However, due to the needle-like
shape and high durability of multiwalled carbon nanotubes (MWCNTs), concerns have been raised that they
may induce asbestos-like pathogenicity when inhaled. Indeed, experiments in rodents supported this
hypothesis. Notably, the genetic alterations in MWCNT-induced rat malignant mesothelioma were similar to
those induced by asbestos. Single-walled CNTs (SWCNTs) cause mitotic disturbances in cultured cells, but
thus far, there has been no report that SWCNTs are carcinogenic. This review summarizes the recent
noteworthy publications on the genotoxicity and carcinogenicity of CNTs and explains the possible
molecular mechanisms responsible for this carcinogenicity. The nanoscale size and needle-like rigid
structure of CNTs appear to be associated with their pathogenicity in mammalian cells, where carbon atoms
are major components in the backbone of many biomolecules. Publishing adverse events associated with
novel materials is critically important for alerting people exposed to such materials. CNTs still have a bright
future with superb economic and medical merits. However, appropriate regulation of the production,
distribution and secondary manufacturing processes is required, at least to protect the workers.
Graphical abstract
Glucocorticoid receptor signaling in health and disease
09 Dec 2013 10:43 am
Publication date: September 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 9
Author(s): Mahita Kadmiel , John A. Cidlowski
Glucocorticoids are steroid hormones regulated in a circadian and stress-associated manner to maintain
various metabolic and homeostatic functions that are necessary for life. Synthetic glucocorticoids are widely
prescribed drugs for many conditions including asthma, chronic obstructive pulmonary disease (COPD),
and inflammatory disorders of the eye. Research in the past few years has begun to unravel the profound
complexity of glucocorticoid signaling and has contributed remarkably to improved therapeutic strategies.
Glucocorticoids signal through the glucocorticoid receptor (GR), a member of the superfamily of nuclear
receptors, in both genomic and non-genomic ways in almost every tissue in the human body. In this review,
we provide an update on glucocorticoid receptor signaling and highlight the role of GR signaling in
physiological and pathophysiological conditions in the major organ systems in the human body.
Gold-nanoparticle-based biosensors for detection of enzyme activity
09 Dec 2013 10:43 am
Publication date: September 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 9
Author(s): Eliza Hutter , Dusica Maysinger
Optimal enzyme activity is essential for maintenance of physiological homeostasis. A variety of both nongenetic and genetic disruptions can excessively activate or silence intrinsic enzyme activities, with
pathological outcomes. Many pharmacological agents are activators and inhibitors of enzymes. It is
essential, therefore, in the development of drugs as enzyme activators and inhibitors, that enzyme activities
be accurately measured under physiological and pathological conditions. Different biochemical assays have
been developed for this purpose, some of which are based on nanostructured materials. This review
focuses on gold nanoparticle (GNP)-based structures for the sensing and measurement of enzyme
activities in biological specimens. Here we provide an overview and critical analysis of such assays, identify
their advantages and limitations, and discuss interesting features of GNPs to be exploited for future
applications in pharmacology.
Guidance: Pharmaceutical Price Regulation Scheme 2014
03 Dec 2013 09:30 am
The 2014 Pharmaceutical Price Regulation Scheme ( PPRS ) will provide assurance on almost all of the
branded medicines bill for the NHS. The bill will stay flat over the first 2 years of the scheme and will grow
slowly after that. The industry will make payments to the Department of Health if NHS spending on branded
medicines exceeds the allowed growth rate.
The PPRS is a voluntary agreement to control the prices of branded drugs sold to the NHS. It is negotiated
between the Department of Health, acting on behalf of the UK government and Northern Ireland, and the
branded pharmaceutical industry, represented by the ABPI .
Hemotoxicity of carbon nanotubes
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Cyrill Bussy , Laura Methven , Kostas Kostarelos
Carbon nanotubes may enter into the bloodstream and interact with blood components indirectly via
translocation following unintended exposure or directly after an intended administration for biomedical
purposes. Once introduced into systemic circulation, nanotubes will encounter various proteins,
biomolecules or cells which have specific roles in the homeostasis of the circulatory system. It is therefore
essential to determine whether those interactions will lead to adverse effects or not. Advances in the
understanding of how carbon nanotubes interact with blood proteins, the complement system, red blood
cells and the hemostatic system are reviewed in this article. While many studies on carbon nanotube health
risk assessment and their biomedical applications have appeared in the last few years, reports on the
hemocompatibility of these nanomaterials remain surprisingly limited. Yet, defining the hemotoxicological
profile is a mandatory step toward the development of clinically-relevant medications or contrast agents
based on carbon nanotubes.
Graphical abstract
Histone lysine demethylases as targets for anticancer therapy
15 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 917 (2013). doi:10.1038/nrd4154
Authors: Jonas W. Højfeldt, Karl Agger & Kristian Helin
It has recently been demonstrated that the genes controlling the epigenetic programmes that are required
for maintaining chromatin structure and cell identity include genes that drive human cancer. This
observation has led to an increased awareness of chromatin-associated proteins as potentially interesting
drug targets. The
How to fix a broken clock
09 Dec 2013 10:43 am
Publication date: November 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 11
Author(s): Analyne M. Schroeder , Christopher S. Colwell
Fortunate are those who rise out of bed to greet the morning light well rested with the energy and
enthusiasm to drive a productive day. Others, however, depend on hypnotics for sleep and require
stimulants to awaken lethargic bodies. Sleep/wake disruption is a common occurrence in healthy individuals
throughout their lifespan and is also a comorbid condition to many diseases (neurodegenerative) and
psychiatric disorders (depression and bipolar). There is growing concern that chronic disruption of the
sleep/wake cycle contributes to more serious conditions including diabetes (type 2), cardiovascular disease,
and cancer. A poorly functioning circadian system resulting in misalignments in the timing of clocks
throughout the body may be at the root of the problem for many people. In this article we discuss
environmental (light therapy) and lifestyle changes (scheduled meals, exercise, and sleep) as interventions
to help fix a broken clock. We also discuss the challenges and potential for future development of
pharmacological treatments to manipulate this key biological system.
Illuminating somatostatin analog action at neuroendocrine tumor receptors
09 Dec 2013 10:43 am
Publication date: December 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 12
Author(s): Jean Claude Reubi , Agnes Schonbrunn
Somatostatin analogs for the diagnosis and therapy of neuroendocrine tumors (NETs) have been used in
clinical applications for more than two decades. Five somatostatin receptor subtypes have been identified
and molecular mechanisms of somatostatin receptor signaling and regulation have been elucidated. These
advances increased understanding of the biological role of each somatostatin receptor subtype, their
distribution in NETs, as well as agonist-specific regulation of receptor signaling, internalization, and
phosphorylation, particularly for the sst 2 receptor subtype, which is the primary target of current
somatostatin analog therapy for NETs. Various hypotheses exist to explain differences in patient
responsiveness to somatostatin analog inhibition of tumor secretion and growth as well as differences in the
development of tumor resistance to therapy. In addition, we now have a better understanding of the action
of both first generation (octreotide, lanreotide, Octreoscan) and second generation (pasireotide) FDAapproved somatostatin analogs, including the biased agonistic character of some agonists. The increased
understanding of somatostatin receptor pharmacology provides new opportunities to design more
sophisticated assays to aid the future development of somatostatin analogs with increased efficacy.
In this issue
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 887 (2013). doi:10.1038/nrd4192
Reducing attrition rates remains a major challenge in drug development, with the probability of a drug
candidate successfully completing Phase II trials currently estimated at only 34%. The physicochemical
properties of small-molecule drug candidates are one important factor influencing the chance of success
and, importantly,
In vitro models of tumor vessels and matrix: Engineering approaches to investigate
transport limitations and drug delivery in cancer
08 Dec 2013 12:32 pm
Publication date: Available online 2 December 2013
Source:Advanced Drug Delivery Reviews
Author(s): Bo Ri Seo , Peter DelNero , Claudia Fischbach
Tumor–stroma interactions have emerged as critical determinants of drug efficacy. However, the underlying
biological and physicochemical mechanisms by which the microenvironment regulates therapeutic response
remain unclear, due in part to a lack of physiologically relevant in vitro platforms to accurately interrogate
tissue-level phenomena. Tissue-engineered tumor models are beginning to address this shortcoming. By
allowing selective incorporation of microenvironmental complexity, these platforms afford unique access to
tumor-associated signaling and transport dynamics. This review will focus on engineering approaches to
study drug delivery as a function of tumor-associated changes of the vasculature and extracellular matrix
(ECM). First, we review current biological understanding of these components and discuss their impact on
transport processes. Then, we evaluate existing microfluidic, tissue engineering, and materials science
strategies to recapitulate vascular and ECM characteristics of tumors, and finish by outlining challenges and
future directions of the field that may ultimately improve anti-cancer therapies.
Graphical abstract
International Union of Pharmacology. LXXXIX. Update on the Extended Family of
Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine
Receptors [IUPHAR Nomenclature Report]
11 Nov 2013 12:38 pm
Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a
system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large
family of leukocyte chemoattractant receptors that regulates immune system development and function, in
large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major
overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk
R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145–176]. Since
then, several new receptors have been discovered, and major advances have been made for the others in
many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New
and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other
areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug
Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and
plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are
now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical
chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as
chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and
soluble chemokine-binding proteins have been described. Here, we review this extended family of
chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels,
including an update on drug development. We also introduce a new nomenclature for atypical chemokine
receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of
the International Union of Pharmacology and the Human Genome Nomenclature Committee.
Learning from the 2012–2013 class of breakthrough therapies
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 891 (2013). doi:10.1038/nrd4196
Author: Asher Mullard
The expedited US regulatory pathway for 'breakthrough therapies' has already yielded its first two approvals
and more than 26 designations, for 30 candidates in 22 indications.
Market watch: Defining and quantifying the use of personalized medicines
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 896 (2013). doi:10.1038/nrd4177
Authors: Sean X. Hu, Murray L. Aitken, Arnold M. Epstein, Mark R. Trusheim & Ernst R. Berndt
Despite the great attention given to personalized medicines, the pace at which they are being added to the
pharmacopaeia and adopted into clinical practice has been limited. Quantifying the use of personalized
medicines in multiple geographical regions over time would help monitor the extent to
Matching structure with function: the GAIN domain of Adhesion-GPCR and PKD1-like
proteins
09 Dec 2013 10:43 am
Publication date: August 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 8
Author(s): Simone Prömel , Tobias Langenhan , Demet Araç
Elucidation of structural information can greatly facilitate the understanding of molecular function. A recent
example is the description of the G-protein-coupled receptor (GPCR) autoproteolysis-inducing (GAIN)
domain, an evolutionarily ancient fold present in Adhesion-GPCRs (aGPCRs) and polycystic kidney disease
1 (PKD1)-like proteins. In the past, the peculiar autoproteolytic capacity of both membrane protein families
at the conserved GPCR proteolysis site (GPS) had not been described in detail. The physiological
performance of aGPCRs and PKD1-like proteins is thought to be regulated through the GPS, but it is
debated how. A recent report provides pivotal details by discovery and analysis of the GAIN domain
structure that incorporates the GPS motif. Complementary studies have commenced to analyze
physiological requirements of the GAIN domain for aGPCR function, indicating that it serves as the linchpin
for multiple receptor signals. Structural analysis and functional assays now allow for the dissection of the
biological duties conferred through the GAIN domain.
Mechanisms of carbon nanotube-induced toxicity: Focus on pulmonary inflammation
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Kunal Bhattacharya , Fernando Torres Andón , Ramy El-Sayed , Bengt Fadeel
Carbon nanotubes have gained tremendous interest in a wide range of applications due to their unique
physical, chemical, and electronic properties. Needless to say, close attention to the potential toxicity of
carbon nanotubes is of paramount importance. Numerous studies have linked exposure of carbon
nanotubes to the induction of inflammation, a complex protective response to harmful stimuli including
pathogens, damaged or dying cells, and other irritants. However, inflammation is a double-edged sword as
chronic inflammation can lead to destruction of tissues thus compromising the homeostasis of the organism.
Here, we provide an overview of the process of inflammation, the key cells and the soluble mediators
involved, and discuss research on carbon nanotubes and inflammation, including recent studies on the
activation of the so-called inflammasome complex in macrophages resulting in secretion of proinflammatory cytokines. Moreover, recent work has shown that inflammatory cells i.e. neutrophils and
eosinophils are capable of enzymatic degradation of carbon nanotubes, with mitigation of the proinflammatory and pro-fibrotic effects of nanotubes thus underscoring that inflammation is both good and
bad.
Graphical abstract
Mechanisms of dopamine transporter regulation in normal and disease states
09 Dec 2013 10:43 am
Publication date: September 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 9
Author(s): Roxanne A. Vaughan , James D. Foster
The dopamine (DA) transporter (DAT) controls the spatial and temporal dynamics of DA neurotransmission
by driving reuptake of extracellular transmitter into presynaptic neurons. Many diseases such as
depression, bipolar disorder, Parkinson's disease (PD), and attention deficit hyperactivity disorder (ADHD)
are associated with abnormal DA levels, implicating DAT as a factor in their etiology. Medications used to
treat these disorders and many addictive drugs target DAT and enhance dopaminergic signaling by
suppressing transmitter reuptake. We now understand that the transport and binding properties of DAT are
regulated by complex and overlapping mechanisms that provide neurons with the ability to modulate DA
clearance in response to physiological demands. These processes are controlled by endogenous signaling
pathways and affected by exogenous transporter ligands, demonstrating their importance for normal
neurotransmission, drug abuse, and disease treatments. Increasing evidence supports the disruption of
these mechanisms in DA disorders, implicating dysregulation of transport in disease etiologies and
suggesting these processes as potential points for therapeutic manipulation of DA availability.
Medical genetic inspirations for anticancer drug repurposing
09 Dec 2013 10:43 am
Publication date: Available online 4 December 2013
Source:Trends in Pharmacological Sciences
Author(s): Zhong-Yi Wang , Yuan Quan , Hong-Yu Zhang
Metabolic targets for cancer therapy
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 963 (2013). doi:10.1038/nrd4191
Author: Lorenzo Galluzzi, Oliver Kepp, Matthew G. Vander Heiden & Guido Kroemer
Nature Reviews Drug Discovery12, 829–846 (2013)There were some inaccuracies in the following
sentence on p839 of the article: “Along similar lines, the pharmacological or genetic inhibition of
phosphoglycerate mutase 1 (PGAM1) reduces tumour growth in vitro
Miniaturized pre-clinical cancer models as research and diagnostic tools
08 Dec 2013 12:32 pm
Publication date: Available online 1 December 2013
Source:Advanced Drug Delivery Reviews
Author(s): Maria Håkanson , Edna Cukierman , Mirren Charnley
Cancer is one of the most common causes of death worldwide. Consequently, important resources are
directed towards bettering treatments and outcomes. Cancer is difficult to treat due to its heterogeneity,
plasticity and frequent drug resistance. New treatment strategies should strive for personalized approaches.
These should target neoplastic and/or activated microenvironmental heterogeneity and plasticity without
triggering resistance and spare host cells. In this review, the putative use of increasingly physiologically
relevant microfabricated cell-culturing systems intended for drug development is discussed. There are two
main reasons for the use of miniaturized systems. First, scaling down model size allows for high control of
microenvironmental cues enabling more predictive outcomes. Second, miniaturization reduces reagent
consumption, thus facilitating combinatorial approaches with little effort and enables the application of
scarce materials, such as patient-derived samples. This review aims to give an overview of the state-of-theart of such systems while predicting their application in cancer drug development.
Graphical abstract
Modulation of oxidative stress as an anticancer strategy
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 931 (2013). doi:10.1038/nrd4002
Authors: Chiara Gorrini, Isaac S. Harris & Tak W. Mak
The regulation of oxidative stress is an important factor in both tumour development and responses to
anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the
metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are
Molecular modeling in structural nano-toxicology: Interactions of nano-particles with nanomachinery of cells
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Naveena Yanamala , Valerian E. Kagan , Anna A. Shvedova
Over the past two decades, nanotechnology has emerged as a key player in various disciplines of science
and technology. Some of the most exciting applications are in the field of biomedicine – for theranostics (for
combined diagnostic and therapeutic purposes) as well as for exploration of biological systems. A detailed
understanding of the molecular interactions between nanoparticles and biological nano-machinery –
macromolecules, membranes, and intracellular organelles – is crucial for obtaining adequate information on
mechanisms of action of nanomaterials as well as a perspective on the long term effects of these materials
and their possible toxicological outcomes. This review focuses on the use of structure-based computational
molecular modeling as a tool to understand and to predict the interactions between nanomaterials and
nano-biosystems. We review major approaches and provide examples of computational analysis of the
structural principles behind such interactions. A rationale on how nanoparticles of different sizes, shape,
structure and chemical properties can affect the organization and functions of nano-machinery of cells is
also presented.
Graphical abstract
Multidrug resistan Physiological principles and nanomedical solutions
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Sijumon Kunjachan , Błażej Rychlik , Gert Storm , Fabian Kiessling , Twan Lammers
Multidrug resistance (MDR) is a pathophysiological phenomenon employed by cancer cells which limits the
prolonged and effective use of chemotherapeutic agents. MDR is primarily based on the over-expression of
drug efflux pumps in the cellular membrane. Prominent examples of such efflux pumps, which belong to the
ATP-binding cassette (ABC) superfamily of proteins, are Pgp (P-glycoprotein) and MRP (multidrug
resistance-associated protein), nowadays officially known as ABCB1 and ABCC1. Over the years, several
strategies have been evaluated to overcome MDR, based not only on the use of low-molecular-weight MDR
modulators, but also on the implementation of 1–100(0) nm-sized drug delivery systems. In the present
manuscript, after introducing the most important physiological principles of MDR, we summarize prototypic
nanomedical strategies to overcome multidrug resistance, including the use of carrier materials with intrinsic
anti-MDR properties, the use of nanomedicines to modify the mode of cellular uptake, and the coformulation of chemotherapeutic drugs together with low- and high-molecular-weight MDR inhibitors within a
single drug delivery system. While certain challenges still need to be overcome before such constructs and
concepts can be widely applied in the clinic, the insights obtained and the progress made strongly suggest
that nanomedicine formulations hold significant potential for improving the treatment of multidrug-resistant
malignancies.
Graphical abstract
Multiphase flow microfluidics for the production of single or multiple emulsions for drug
delivery
08 Dec 2013 12:32 pm
Publication date: 15 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 11–12
Author(s): Chun-Xia Zhao
Considerable effort has been directed towards developing novel drug delivery systems. Microfluidics,
capable of generating monodisperse single and multiple emulsion droplets, executing precise control and
operations on these droplets, is a powerful tool for fabricating complex systems (microparticles,
microcapsules, microgels) with uniform size, narrow size distribution and desired properties, which have
great potential in drug delivery applications. This review presents an overview of the state-of-the-art
multiphase flow microfluidics for the production of single emulsions or multiple emulsions for drug delivery.
The review starts with a brief introduction of the approaches for making single and multiple emulsions,
followed by presentation of some potential drug delivery systems (microparticles, microcapsules and
microgels) fabricated in microfluidic devices using single or multiple emulsions as templates. The design
principles, manufacturing processes and properties of these drug delivery systems are also discussed and
compared. Furthermore, drug encapsulation and drug release (including passive and active controlled
release) are provided and compared highlighting some key findings and insights. Finally, site-targeting
delivery using multiphase flow microfluidics is also briefly introduced.
Graphical abstract
NIH denies march-in rights on Norvir patent
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 898 (2013). doi:10.1038/nrd4198
Author: Charlotte Harrison
The US National Institutes of Health (NIH) has refused to override AbbVie's patents on the HIV drug Norvir
(ritonavir) under so-called march-in rights. The decision means that the cost of Norvir in the United States
will remain higher than in several other high-income countries.March-in
Nanocarriers for delivery of platinum anticancer drugs
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Hardeep S. Oberoi , Natalia V. Nukolova , Alexander V. Kabanov , Tatiana K. Bronich
Platinum based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in
widespread clinical use especially for management of tumors of the ovary, testes, and the head and neck.
However, several dose limiting toxicities associated with platinum drug use, partial anti-tumor response in
most patients, development of drug resistance, tumor relapse, and many other challenges have severely
limited the patient quality of life. These limitations have motivated an extensive research effort towards
development of new strategies for improving platinum therapy. Nanocarrier-based delivery of platinum
compounds is one such area of intense research effort beginning to provide encouraging preclinical and
clinical results and may allow the development of the next generation of platinum chemotherapy. This
review highlights current understanding on the pharmacology and limitations of platinum compounds in
clinical use, and provides a comprehensive analysis of various platinum–polymer complexes, micelles,
dendrimers, liposomes and other nanoparticles currently under investigation for delivery of platinum drugs.
Graphical abstract
Nanomedicine therapeutic approaches to overcome cancer drug resistance
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Janet L. Markman , Arthur Rekechenetskiy , Eggehard Holler , Julia Y. Ljubimova
Nanomedicine is an emerging form of therapy that focuses on alternative drug delivery and improvement of
the treatment efficacy while reducing detrimental side effects to normal tissues. Cancer drug resistance is a
complicated process that involves multiple mechanisms. Here we discuss the major forms of drug
resistance and the new possibilities that nanomedicines offer to overcome these treatment obstacles. Novel
nanomedicines that have a high ability for flexible, fast drug design and production based on tumor genetic
profiles can be created making drug selection for personal patient treatment much more intensive and
effective. This review aims to demonstrate the advantage of the young medical science field, nanomedicine,
for overcoming cancer drug resistance. With the advanced design and alternative mechanisms of drug
delivery known for different nanodrugs including liposomes, polymer conjugates, micelles, dendrimers,
carbon-based, and metallic nanoparticles, overcoming various forms of multi-drug resistance looks
promising and opens new horizons for cancer treatment.
Graphical abstract
Nanopreparations for organelle-specific delivery in cancer
08 Dec 2013 12:32 pm
Publication date: Available online 21 November 2013
Source:Advanced Drug Delivery Reviews
Author(s): Swati Biswas , Vladimir P. Torchilin
To efficiently deliver therapeutics into cancer cells, a number of strategies have been recently investigated.
The toxicity associated with the administration of chemotherapeutic drugs due to their random interactions
throughout the body necessitates the development of drug-encapsulating nanopreparations that
significantly mask, or reduce, the toxic side effects of the drugs. In addition to reduced side effects
associated with drug encapsulation, nanocarriers preferentially accumulate in tumors as a result of its
abnormally leaky vasculature via the Enhanced Permeability and Retention (EPR) effect. However, simple
passive nanocarrier delivery to the tumor site is unlikely to be enough to elicit a maximum therapeutic
response as the drug-loaded carriers must reach the intracellular target sites. Therefore, efficient
translocation of the nanocarrier through the cell membrane is necessary for cytosolic delivery of the cargo.
However, crossing the cell membrane barrier and reaching cytosol might still not be enough for achieving
maximum therapeutic benefit, which necessitates the delivery of drugs directly to intracellular targets, such
as bringing pro-apoptotic drugs to mitochondria, nucleic acid therapeutics to nuclei, and lysosomal enzymes
to defective lysosomes. In this review, we discuss the strategies developed for tumor targeting, cytosolic
delivery via cell membrane translocation, and finally organelle-specific targeting, which may be applied for
developing highly efficacious, truly multifunctional, cancer-targeted nanopreparations.
Graphical abstract
Nanopreparations to overcome multidrug resistance in cancer
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Niravkumar R. Patel , Bhushan S. Pattni , Abraham H. Abouzeid , Vladimir P. Torchilin
Multidrug resistance is the most widely exploited phenomenon by which cancer eludes chemotherapy.
Broad variety of factors, ranging from the cellular ones, such as over-expression of efflux transporters,
defective apoptotic machineries, and altered molecular targets, to the physiological factors such as higher
interstitial fluid pressure, low extracellular pH, and formation of irregular tumor vasculature are responsible
for multidrug resistance. A combination of various undesirable factors associated with biological
surroundings together with poor solubility and instability of many potential therapeutic small & large
molecules within the biological systems and systemic toxicity of chemotherapeutic agents has necessitated
the need for nano-preparations to optimize drug delivery. The physiology of solid tumors presents
numerous challenges for successful therapy. However, it also offers unique opportunities for the use of
nanotechnology. Nanoparticles, up to 400 nm in size, have shown great promise for carrying, protecting and
delivering potential therapeutic molecules with diverse physiological properties. In this review, various
factors responsible for the MDR and the use of nanotechnology to overcome the MDR, the use of spheroid
culture as well as the current technique of producing microtumor tissues in vitro are discussed in detail.
Graphical abstract
Nanotechnology and drug resistance
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Tamara Minko
Nanotechnology and pulmonary delivery to overcome resistance in infectious diseases
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Fernanda Andrade , Diana Rafael , Mafalda Videira , Domingos Ferreira , Alejandro Sosnik ,
Bruno Sarmento
Used since ancient times especially for the local treatment of pulmonary diseases, lungs and airways are a
versatile target route for the administration of both local and systemic drugs. Despite the existence of
different platforms and devices for the pulmonary administration of drugs, only a few formulations are
marketed, partly due to physiological and technological limitations. Respiratory infections represent a
significant burden to health systems worldwide mainly due to intrahospital infections that more easily affect
immune-compromised patients. Moreover, tuberculosis (TB) is an endemic infectious disease in many
developing nations and it has resurged in the developed world associated with the human
immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic. Currently, medicine
faces the specter of antibiotic resistance. Besides the development of new anti-infectious drugs, the
development of innovative and more efficient delivery systems for drugs that went off patent appears as a
promising strategy pursued by the pharmaceutical industry to improve the therapeutic outcomes and to
prolong the utilities of their intellectual property portfolio. In this context, nanotechnology-based drug
delivery systems (nano-DDS) emerged as a promising approach to circumvent the limitations of
conventional formulations and to treat drug resistance, opening the hypothesis for new developments in this
area.
Graphical abstract
Nanotechnology approaches for personalized treatment of multidrug resistant cancers
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Tamara Minko , Lorna Rodriguez-Rodriguez , Vitaly Pozharov
The efficacy of chemotherapy is substantially limited by the resistance of cancer cells to anticancer drugs
that fluctuates significantly in different patients. Under identical chemotherapeutic protocols, some patients
may receive relatively ineffective doses of anticancer agents while other individuals obtain excessive
amounts of drugs that induce severe adverse side effects on healthy tissues. The current review is focused
on an individualized selection of drugs and targets to suppress multidrug resistance. Such selection is
based on the molecular characteristics of a tumor from an individual patient that can potentially improve the
treatment outcome and bring us closer to an era of personalized medicine.
Graphical abstract
Nanotechnology as a therapeutic tool to combat microbial resistance
08 Dec 2013 12:32 pm
Publication date: 30 November 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issues 13–14
Author(s): Robert Y. Pelgrift , Adam J. Friedman
Use of nanoparticles is among the most promising strategies to overcome microbial drug resistance. This
review article consists of three parts. The first part discusses the epidemiology of microbial drug resistance.
The second part describes mechanisms of drug resistance used by microbes. The third part explains how
nanoparticles can overcome this resistance, including the following: Nitric oxide-releasing nanoparticles
(NO NPs), chitosan-containing nanoparticles (chitosan NPs), and metal-containing nanoparticles all use
multiple mechanisms simultaneously to combat microbes, thereby making development of resistance to
these nanoparticles unlikely. Packaging multiple antimicrobial agents within the same nanoparticle also
makes development of resistance unlikely. Nanoparticles can overcome existing drug resistance
mechanisms, including decreased uptake and increased efflux of drug from the microbial cell, biofilm
formation, and intracellular bacteria. Finally, nanoparticles can target antimicrobial agents to the site of
infection, so that higher doses of drug are given at the infected site, thereby overcoming resistance.
Graphical abstract
Neurodegenerative disease: A PERK for the therapy of prion disease
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 906 (2013). doi:10.1038/nrd4185
Author: Charlotte Harrison
The unfolded protein response (UPR), which triggers cellular toxicity, is characteristic of prion disease,
Alzheimer's disease and Parkinson's disease. This paper showed that an inhibitor of PERK (PRKR-like
endoplasmic reticulum kinase), which is a mediator of the UPR pathway, prevented the development of
prion disease
Neurodegenerative disease: Patient stem cells give clues to ALS
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 906 (2013). doi:10.1038/nrd4187
Author: Charlotte Harrison
A nucleotide GGGGCC-repeat expansion in the C9ORF72 gene is found in amyotrophic lateral sclerosis
(ALS), but how this triggers disease is unclear. This paper used induced pluripotent stem cells (iPSCs)
derived from patients with ALS as a model. These cells had enhanced glutamate excitotoxicity
Neurodegenerative disease: Tau immunotherapy targets transcellular propagation
15 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 904 (2013). doi:10.1038/nrd4179
Author: Monica Hoyos Flight
Extracellular deposition of amyloid-β and intracellular aggregates of tau are pathological hallmarks of
Alzheimer's disease. To date, most attempts at developing immunotherapies to treat Alzheimer's disease
have focused on targeting amyloid-β, but a study published in Neuron suggests that antibodies against
extracellular tau that
Neurological disorders: Chloride extrusion alleviates neuropathic pain
29 Nov 2013 12:00 am
Nature Reviews Drug Discovery 12, 906 (2013). doi:10.1038/nrd4183
Author: Alexandra Flemming
The potassium-chloride co-transporter KCC2 is expressed in neurons of the central nervous system (CNS),
where it is responsible for maintaining low Cl− concentrations. Loss of activity of KCC2 is a key mechanism
underlying several neurological and psychiatric disorders, including epilepsy, schizophrenia and chronic
Neuroregulation of cutaneous microcirculation: the shadow of Sir Thomas Lewis
09 Dec 2013 10:43 am
Publication date: November 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 11
Author(s): János Szolcsányi
Peroxidase-mediated biodegradation of carbon nanotubes in vitro and in vivo
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Gregg P. Kotchey , Yong Zhao , Valerian E. Kagan , Alexander Star
As a result of their unique electronic, optical, and mechanical properties, carbon nanotubes (CNTs) have
been implemented in therapeutic and imaging applications. In an idealized situation, CNTs would be
disposed of after they transport their theranostic payloads. Biodegradation represents an attractive pathway
for the elimination of CNT carriers post-delivery and may be integral in catalyzing the release of the cargo
from the delivery vehicle. Accordingly, recent research efforts have focused on peroxidase-driven
biodegradation of CNTs. In this review, we not only summarize recent efforts to biodegrade CNTs in the test
tube, in vitro , and in vivo , but also attempt to explore the fundamental parameters underlying degradation.
Encouraged by the in vivo results obtained to date, we envision a future, where carbon-based nanocontainers, which are specifically designed to target organs/cells, deliver their cargo, and biodegrade via
peroxidase-driven mechanism, will represent an attractive therapeutic delivery option in nanomedicine.
Graphical abstract
Pfizer's open data policy should include trials of off-label uses, say critics
06 Dec 2013 11:36 am
A commitment from the pharmaceutical giant Pfizer to extend access to the data it holds on drug trials in
patients has been criticised for excluding studies of unlicensed uses.On 4 December Pfizer...
Pharmacological tools for the development of traditional Chinese medicine
09 Dec 2013 10:43 am
Publication date: November 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 11
Author(s): Xuan Liu , Wan-Ying Wu , Bao-Hong Jiang , Min Yang , De-An Guo
Pharmacology as a modern science was introduced in China approximately 150 years ago, and has been
used since then to study traditional Chinese medicine (TCM). Pharmacology has experienced its own
development over this time and continues to provide new tools for the study of TCM. In the present review,
three models for the pharmacological study of TCM are considered: (i) chemistry-focused study; (ii) targetdirected study; and (iii) systems-biology-based study. These approaches correspond to recent
developments in pharmacology, and in particular to new tools available to the field. Representative
achievements and the pharmacological tools used to study TCM are reviewed. Pharmacology has played,
and will continue to play, an indispensable role in elucidating the chemical basis, biological targets, and
mechanisms of action of TCM medicines, and in developing a scientific basis for the theory of TCM.
Pharmacology in China: a brief overview
09 Dec 2013 10:43 am
Publication date: October 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 10
Author(s): Ming-Wei Wang , Richard D. Ye , Yizhun Zhu
Pharmacology of carbon nanotubes: Toxicokinetics, excretion and tissue accumulation
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Hanene Ali-Boucetta , Kostas Kostarelos
Carbon nanotubes (CNT) are increasingly being investigated for their use in biomedical applications and
nanomedicine. An emergent need for the understanding of their in vivo biodistribution and pharmacokinetics
is therefore needed to establish the essential properties and criteria for their further development as
targeted CNT delivery systems to specific tissues for diagnostics and therapeutic purposes. Until their
biodistribution and toxicoketic profiles are fully understood, their translation into the clinic will be hindered.
This review will highlight the important factors affecting the biodistribution and pharmacokinetic profile of
CNT and address their toxicokinetics following systemic, pulmonary and dermal exposure.
Graphical abstract
Pharmacovigilance and use of online health information
09 Dec 2013 10:43 am
Publication date: July 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 7
Author(s): Marco Masoni , Maria Renza Guelfi , Antonio Conti , Gian Franco Gensini
Polyclonal immunoglobulin G for autoimmune demyelinating nervous system disorders
09 Dec 2013 10:43 am
Publication date: August 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 8
Author(s): Mathias Buttmann , Srini Kaveri , Hans-Peter Hartung
Demyelinating diseases with presumed autoimmune pathogenesis are characterised by direct or indirect
immune-mediated damage to myelin sheaths, which normally surround nerve fibres to ensure proper
electrical nerve conduction. Parenteral administration of polyclonal IgG purified from multi-donor human
plasma pools may beneficially modulate these misguided immune reactions via several mechanisms that
are outlined in this review. Convincing therapeutic evidence from controlled trials now exists for certain
disorders of the peripheral nervous system, including Guillain–Barré syndrome, chronic inflammatory
demyelinating polyradiculoneuropathy, and multifocal motor neuropathy. In addition, there is evidence for
potential therapeutic benefits of IgG in patients with chronic inflammatory demyelinating diseases of the
central nervous system, including multiple sclerosis and neuromyelitis optica. This review introduces these
disorders, briefly summarises the established treatment options, and discusses therapeutic evidence for the
use of polyclonal immunoglobulins with a particular emphasis on recent clinical trials and meta-analyses.
Polymers in cell encapsulation from an enveloped cell perspective
08 Dec 2013 12:32 pm
Publication date: Available online 22 November 2013
Source:Advanced Drug Delivery Reviews
Author(s): Paul de Vos , Hamideh Aghajani Lazarjani , Denis Poncelet , Marijke M. Faas
In the past two decades, many polymers have been proposed for producing immunoprotective capsules.
Examples include the natural polymers alginate, agarose, chitosan, cellulose, collagen, and xanthan and
synthetic polymers poly(ethylene glycol), polyvinyl alcohol, polyurethane, poly(ether-sulfone),
polypropylene, sodium polystyrene sulfate, and polyacrylate poly(acrylonitrile-sodium methallylsulfonate).
The biocompatibility of these polymers is discussed in terms of tissue responses in both the host and matrix
to accommodate the functional survival of the cells. Cells should grow and function in the polymer network
as adequately as in their natural environment. This is critical when therapeutic cells from scarce cadaveric
donors are considered, such as pancreatic islets. Additionally, the cell mass in capsules is discussed from
the perspective of emerging new insights into the release of so-called danger-associated molecular pattern
molecules by clumps of necrotic therapeutic cells. We conclude that despite two decades of intensive
research, drawing conclusions about which polymer is most adequate for clinical application is still difficult.
This is because of the lack of documentation on critical information, such as the composition of the polymer,
the presence or absence of confounding factors that induce immune responses, toxicity to enveloped cells,
and the permeability of the polymer network. Only alginate has been studied extensively and currently
qualifies for application. This review also discusses critical issues that are not directly related to polymers
and are not discussed in the other reviews in this issue, such as the functional performance of encapsulated
cells in vivo. Physiological endocrine responses may indeed not be expected because of the many barriers
that the metabolites encounter when traveling from the blood stream to the enveloped cells and back to
circulation. However, despite these diffusion barriers, many studies have shown optimal regulation, allowing
us to conclude that encapsulated grafts do not always follow nature's course but are still a possible solution
for many endocrine disorders for which the minute-to-minute regulation of metabolites is mandatory.
Graphical abstract
Potential therapeutic applications of biosurfactants
09 Dec 2013 10:43 am
Publication date: December 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 12
Author(s): Eduardo J. Gudiña , Vivek Rangarajan , Ramkrishna Sen , Lígia R. Rodrigues
Biosurfactants have recently emerged as promising molecules for their structural novelty, versatility, and
diverse properties that are potentially useful for many therapeutic applications. Mainly due to their surface
activity, these molecules interact with cell membranes of several organisms and/or with the surrounding
environments, and thus can be viewed as potential cancer therapeutics or as constituents of drug delivery
systems. Some types of microbial surfactants, such as lipopeptides and glycolipids, have been shown to
selectively inhibit the proliferation of cancer cells and to disrupt cell membranes causing their lysis through
apoptosis pathways. Moreover, biosurfactants as drug delivery vehicles offer commercially attractive and
scientifically novel applications. This review covers the current state-of-the-art in biosurfactant research for
therapeutic purposes, providing new directions towards the discovery and development of molecules with
novel structures and diverse functions for advanced applications.
Protection against chemotherapy-induced alopecia: targeting ATP-binding cassette
transporters in the hair follicle?
09 Dec 2013 10:43 am
Publication date: November 2013
Source:Trends in Pharmacological Sciences, Volume 34, Issue 11
Author(s): Iain S. Haslam , Aaron Pitre , John D. Schuetz , Ralf Paus
Currently, efficacious treatments for chemotherapy-induced alopecia (hair loss) are lacking, and incidences
of permanent hair loss following high-dose chemotherapy are on the increase. In this article, we describe
mechanisms by which the pharmacological defense status of the hair follicle might be enhanced, thereby
reducing the accumulation of cytotoxic cancer drugs and preventing or reducing hair loss and damage. We
believe this could be achieved via the selective increase in ATP-binding cassette (ABC) transporter
expression within the hair follicle epithelium, following application of topical agonists for regulatory nuclear
receptors. Clinical application would require the development of hair follicle-targeted formulations,
potentially utilizing nanoparticle technology. This novel approach has the potential to yield entirely new
therapeutic options for the treatment and management of chemotherapy-induced alopecia, providing
significant psychological and physical benefit to cancer patients.
Pulmonary toxicity of carbon nanotubes and asbestos — Similarities and differences
08 Dec 2013 12:32 pm
Publication date: December 2013
Source:Advanced Drug Delivery Reviews, Volume 65, Issue 15
Author(s): Ken Donaldson , Craig A. Poland , Fiona A. Murphy , Marion MacFarlane , Tatyana Chernova ,
Anja Schinwald
Carbon nanotubes are a valuable industrial product but there is potential for human pulmonary exposure
during production and their fibrous shape raises the possibility that they may have effects like asbestos,
which caused a worldwide pandemic of disease in the20th century that continues into present. CNT may
exist as fibres or as more compact particles and the asbestos-type hazard only pertains to the fibrous forms
of CNT. Exposure to asbestos causes asbestosis, bronchogenic carcinoma, mesothelioma, pleural fibrosis
and pleural plaques indicating that both the lungs and the pleura are targets. The fibre pathogenicity
paradigm was developed in the 1970s–80s and has a robust structure/toxicity relationship that enables the
prediction of the pathogenicity of fibres depending on their length, thickness and biopersistence. Fibres that
are sufficiently long and biopersistent and that deposit in the lungs can cause oxidative stress and
inflammation. They may also translocate to the pleura where they can be retained depending on their
length, and where they cause inflammation and oxidative stress in the pleural tissues. These
pathobiological processes culminate in pathologic change — fibroplasia and neoplasia in the lungs and the
pleura. There may also be direct genotoxic effects of fibres on epithelial cells and mesothelium, contributing
to neoplasia. CNT show some of the properties of asbestos and other types of fibre in producing these
types of effects and more research is needed. In terms of the molecular pathways involved in the interaction
of long biopersistent fibres with target tissue the events leading to mesothelioma have been a particular
area of interest. A variety of kinase pathways important in proliferation are activated by asbestos leading to
pre-malignant states and investigations are under way to determine whether fibrous CNT also affects these
molecular pathways. Current research suggests that fibrous CNT can elicit effects similar to asbestos but
more research is needed to determine whether they, or other nanofibres, can cause fibrosis and cancer in
the long term.
Graphical abstract
Pumped up: reflections on PfATP6 as the target for artemisinins
09 Dec 2013 10:43 am
Publication date: Available online 21 November 2013
Source:Trends in Pharmacological Sciences
Author(s): Sanjeev Krishna , Serena Pulcini , Catherine M. Moore , Beatrix Huei-Yi Teo , Henry M. Staines
Sarco/endoplasmic reticulum Ca2+-ATPases (SERCAs) are increasingly being studied for therapeutic
interventions in the fields of cancer, heart disease, and infection. Our suggestion a decade ago that
artemisinins (the most important antimalarial class) act by inhibiting parasite SERCAs (PfATP6 and
orthologues) expressed in Xenopus oocytes stimulated new directions for research away from conventional
site-of-action studies of the food vacuole of the parasite. There is, however, still no consensus on how
artemisinins act. We have continued to explore the hypothesis that PfATP6 is a key target by confirming
that artemisinins inhibit Plasmodium falciparum PfATP6 when it is expressed in yeast and that it is essential
for survival of pathogenic asexual-stage parasites. These advances are discussed with their implications for
our understanding of how parasites regulate calcium in different stages of asexual development and for the
global challenge posed by artemisinin resistance.
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