Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 1, 2007
Contents
Molecular Imaging in Drug Development
Executive Editor: M. Kassiou
Editorial Pp. 1
Copper Chelation Chemistry and its Role in Copper
Radiopharmaceuticals Pp. 3-16
T.J. Wadas, E.H. Wong, G.R. Weisman and C.J. Anderson
[Abstract] [Full
text article]
Targeted In Vivo Imaging of Angiogenesis:
Present Status and Perspectives Pp. 17-31
Y.S. Choe and K.-H. Lee
[Abstract] [Full
text article]
PET and SPECT Imaging of the Opioid System: Receptors,
Radioligands and Avenues for Drug Discovery and Development
Pp. 33-49
J.R. Lever
[Abstract] [Full
text article]
Imaging Sigma Receptors: Applications in Drug Development
Pp. 51-72
T.L. Collier, R.N. Waterhouse and M. Kassiou
[Abstract] [Full
text article]
Ganeral Articles
Exacerbations of Asthma and Chronic Obstructive Pulmonary
Disease (COPD): Focus on Virus Induced Exacerbations
Pp. 73-97
P. Mallia, M. Contoli, G. Caramori, A. Pandit, S.L. Johnston
and A. Papi
[Abstract] [Full
text article]
Controlled Delivery of Peptides and Proteins
Pp. 99-117
I.T. Degim and N. Çelebi
[Abstract] [Full
text article]
Aminoglycoside-Induced Ototoxicity Pp. 119-126
E. Selimoglu
[Abstract] [Full
text article]
Abstracts
[Back
to top]
Editorial: Molecular Imaging in Drug Development
Molecular imaging refers to the use of non-invasive
imaging techniques to detect signals that originate from molecules,
often in the form of an injected tracer, and observe their
interaction with a specific cellular target in vivo.
This technique is capable of measuring the biodistribution
of minute concentrations of radio-labelled biomolecules in
vivo and quantifying the molecular kinetic processes
in which they participate. This technique can provide a wealth
of information, which can facilitate the drug development
process and the planning of therapy. This issue of Current
Pharmaceutical Design highlights the capabilities of PET and
SPECT in pre-clinical and clinical research and acknowledges
the efforts from each contributor in putting this issue together.
T.J. Wadas and co-workers [1] at the Mallinckrodt Institute
of Radiology and the University of New Hampshire outline the
use of copper isotopes in particular 64Cu in diagnostic
imaging and radiotherapy. However, significant developments
are required in the development of ligands that can form a
stable complex with 64Cu for delivery into living
systems. These advances are highlighted in this review.
Y.S. Choe and K-H Lee [2] from the Samsung Medical Center
review applications of targeted imaging of angiogenesis using
molecular imaging and suitable radiotracers based on potential
targets which include integrins, extracellular matrix, VEGF,
activated endothelial cells and MMPs. Specific imaging of
angiogenesis will help define the pathophysiology in living
subjects and identify those patients likely to respond to
antiangiogenic or angiogenic therapies and enable the efficacies
of these therapies to be assessed.
J. Lever [3] from the University of Missouri outlines the
use of opioid receptors as drug targets and focuses on the
status and use of radiotracers for imaging opioid receptors
using molecular imaging. Selected studies are discussed to
illustrate the power of molecular imaging for facilitating
opioid drug discovery and development.
T.L. Collier and co-workers [4] at Siemens Biomarker Solutions,
Columbia University of Physicians and Surgeons and the University
of Sydney outline the biological function and therapeutic
potential of sigma receptors. Sigma receptors have recently
been the target of drug development related to psychiatric
disorders, cognitive enhancers, neuroprotective and antiamnesic
actions. This review highlights what is known about these
enigmatic sites and the use of molecular imaging in studying
these receptors.
References
[1] Wadas TJ, Wong EH, Weisman GR, Anderson CJ. Copper Chelation
Chemistry and Its Role in Copper Radiopharmaceuticals. Curr
Pham Des 2007; 13(1): 3-16.
[2] Choe YS, Lee K.-H. Targeted In Vivo Imaging of
Angiogenesis: Present Status and Perspectives. Curr Pham Des
2007; 13(1): 17-31.
[3] Lever JR. PET and SPECT Imaging of the Opioid System:
Receptors, Radioligands and Avenues for Drug Discovery and
Development. Curr Pham Des 2007; 13(1): 33-49.
[4] Collier TL, Waterhouse RN, Kassiou M. Imaging Sigma Receptors:
Applications in Drug Development. Curr Pham Des 2007; 13(1):
51-72.
Associate Professor Michael Kassiou, PhD, FRACI,
CChem
Schools of Medical Radiation Sciences and Chemistry
Brain and Mind Research Institute
University of Sydney
Australia
E-mail: mkassiou@med.usyd.edu.au
[Back to top]
Copper Chelation Chemistry and its Role in Copper Radiopharmaceuticals
T.J. Wadas, E.H. Wong, G.R. Weisman and C.J. Anderson
[Full
text article]
Molecular imaging is an important scientific discipline
that plays a major role in clinical medicine and pharmaceutical
development. While several imaging modalities including X-ray
computed tomography (CT) and magnetic resonance imaging (MRI)
generate high-resolution anatomical images, positron emission
tomography (PET) and single photon emission computed tomography
(SPECT) offer insight into the physiological processes that
occur within a living organism. Of these two nuclear medicine
imaging techniques, PET has advantages with respect to sensitivity
and resolution, and this has led to the production and development
of many positron emitting radionuclides that include non-traditional
radionuclides of the transition metals. Copper-64 (t1/2
= 12.7 h, β+:
17.4%, Eβ+max
= 656 keV; β-:
39%, Eβ-max
= 573 keV) has emerged as an important positron emitting radionuclide
that has the potential for use in diagnostic imaging and radio-therapy.
However, 64Cu must be delivered to the living system
as a stable complex that is attached to a biological targeting
molecule for effective imaging and therapy. Therefore, significant
research has been devoted to the development of ligands that
can stably chelate 64Cu. This review discusses
the necessary characteristics of an effective 64Cu
chelator, while highlighting the development and evaluation
of 64Cu-complexes attached to biologically-targeted
ligands.
[Back to top]
Targeted In Vivo Imaging of Angiogenesis:
Present Status and Perspectives
Y.S. Choe and K.-H. Lee
[Full
text article]
Angiogenesis, the process whereby new capillaries are formed
by outgrowth from existing microvessels, is required for tumor
growth and metastasis, and is also necessary for natural healing
after ischemic injury. Because angiogenesis, excessive or
deficient, underlies many pathological situations, there is
a need for the development of noninvasive imaging to allow
monitoring of angiogenesis related molecular events. Furthermore,
specific imaging of angiogenesis would help define the pathophysiology
of angiogenesis in living subjects, identify those patients
likely to respond to anti-angiogenic or angiogenic therapies,
and enable the efficacies of these molecular therapies to
be assessed. Herein, we review the targeted imaging of angiogenesis
using nuclear medicine modalities (positron emission tomography;
PET and single photon emission computed tomography; SPECT)
and suitable radiotracers based on potential targets including
integrin, extracellular matrix, VEGF and its receptors, activated
endothelial cells, and matrix metalloproteinases.
[Back to top]
PET and SPECT Imaging of the Opioid System: Receptors,
Radioligands and Avenues for Drug Discovery and Development
J.R. Lever
[Full
text article]
As we celebrate the bicentennial of the isolation of morphine
by Sertürner, opioids continue to dominate major sectors
of the analgesic market worldwide. The pharmaceutical industry
stands to benefit greatly from molecular imaging in preclinical
and early clinical trials of new or improved opioid drugs.
At this juncture, it seems fitting to summarize the past twenty
or so years of research on molecular imaging of the opioid
system from the viewpoint of drug discovery and development.
Opioid receptors were first imaged in human volunteers by
positron emission tomography (PET) in 1984. Now, quantitative
PET imaging of the major opioid receptor types (μ,
δ,
κ)
is possible in the brain and peripheral organs of healthy
persons and patient populations. Radioligands are under development
for single photon emission computed tomography (SPECT) of
opioid receptors as well. These functional, nuclear imaging
techniques can trace the fate of radio-labeled molecules directly,
but non-invasively, and allow precise pharmacokinetic and
pharmacodynamic measurements. Molecular imaging provides unique
data that can aid in selecting the best drug candidates, determining
optimal dosing regimens, clearing regulatory hurdles and lowering
risks of failure. Using a historical perspective, this review
touches on opioid receptors as drug targets, and focuses on
the status and use of radiotracers for opioid receptor PET
and SPECT. Selected studies are discussed to illustrate the
power of molecular imaging for facilitating opioid drug discovery
and development.
[Back to top]
Imaging Sigma Receptors: Applications in Drug Development
T.L. Collier, R.N. Waterhouse and M. Kassiou
[Full
text article]
Sigma receptors have been implicated in a myriad of cellular
functions, biological processes and diseases. While the precise
biological functions of sigma receptors have not been elucidated,
recent work has shed some light on to these enigmatic systems.
Sigma receptors have recently been a target of drug development
related to psychiatric and neurological disorders.
Sigma ligands have also been shown to modulate endothelial
cell proliferation and can control angiogenesis which makes
them a promising target for oncology applications. Other areas
currently being investigated include treatment of gastrointestinal,
cardiovascular, endocrine and immune system disorders.
Of interest is that the human sigma-1 receptor gene contains
a steroid binding component, and several gonadal steroids,
including progesterone, testosterone and dehydroepiandrosterone
(DHEA), interact with sigma-1 receptors. Of the steroids examined
thus far, progesterone binds with the highest affinity to
human sigma-1 receptors, with a reported affinity (Ki) as
high as 30 nM while the other steroids exhibit lower affinity.
For this and other reasons, sigma-1 receptors have been proposed
as a link between the central nervous system and the endocrine
and reproductive systems.
Taken together, the above information highlights an important
yet largely unexplored but promising area of research to examine
the biological function and therapeutic potential of sigma
receptors. This review provides an overview of the current
knowledge of these sites with a focus on specific areas where
in vivo sigma receptor imaging is currently being
investigated.
[Back to top]
Exacerbations of Asthma and Chronic Obstructive Pulmonary
Disease (COPD): Focus on Virus Induced Exacerbations
P. Mallia, M. Contoli, G. Caramori, A. Pandit, S.L. Johnston
and A. Papi
[Full
text article]
Asthma and chronic obstructive pulmonary disease (COPD) are
the 2 most prevalent chronic airway diseases. Much of the
morbidity, mortality and health care costs of the diseases
are associated with acute exacerbations, which are episodes
of increased symptoms and airflow obstruction. Over the last
decade evidence has emerged implicating virus respiratory
tract infections as a major cause of exacerbations of both
asthma and COPD. Current therapies are not very effective
in the prevention or treatment of virus-induced exacerbations
and exacerbations are therefore a major unmet medical need.
The development of new and novel treatments requires a better
understanding of the molecular and cellular mechanisms linking
virus infection with exacerbations of asthma and COPD. This
article provides an overview of current knowledge regarding
the mechanisms of virus-induced exacerbations in both asthma
and COPD. It will also review existing treatments and future
treatments that are in advanced stages of development.
[Back to top]
Controlled Delivery of Peptides and Proteins
I.T. Degim and N. Çelebi
[Full
text article]
The final aim/target of Pharmaceutical Sciences is to design
successful dosage forms for effective therapy, considering
individual patient needs and compliance. Development of new
drug entities, particularly using peptides and proteins, is
growing in importance and attracting increased interest, as
they are specifically effective at a comparably low dose.
These very potent and specific peptides and proteins can now
be produced in large quantities due to increased knowledge
and advancements in biotechnological and pharmaceutical applications.
A number of peptide and protein products are now available
on the market, and numerous studies investigating them have
been published in the literature.
Although many peptide/protein like products are generally
designed for parenteral administration, some other noninvasive
routes have also been used. For example, desmopressin is delivered
nasally and deoxyribonuclease by inhalation. Although peptides
and proteins are generally orally inactive, cyclosporine is
an exception.
In order to design and develop long-acting, more effective
peptide/protein drugs, the controlled release mechanisms and
effective parameters need to be understood and clarified.
Therefore, we review herein various peptide/protein delivery
systems, including biodegradable and nondegradable microspheres,
microcapsules, nanocapsules, injectable implants, diffusion-controlled
hydrogels and other hydrophilic systems, microemulsions and
multiple emulsions, and the use of iontophoresis or electroporation,
and discuss the results of recent researches.
[Back to top]
Aminoglycoside-Induced Ototoxicity
E. Selimoglu
[Full
text article]
It has long been known that the major irreversible toxicity
of aminoglycosides is ototoxicity. Among them, streptomycin
and gentamicin are primarily vestibulotoxic, whereas amikacin,
neomycin, dihydrosterptomycin, and kanamicin are primarily
cochleotoxic. Cochlear damage can produce permanent hearing
loss, and damage to the vestibular apparatus results in dizziness,
ataxia, and/or nystagmus. Aminoglycosides appear to generate
free radicals within the inner ear, with subsequent permanent
damage to sensory cells and neurons, resulting in permanent
hearing loss. Two mutations in the mitochondrial 12S ribosomal
RNA gene have been previously reported to predispose carriers
to aminoglycoside-induced ototoxicity. As aminoglycosides
are indispensable agents both in the treatment of infections
and Meniere’s disease, a great effort has been made
to develop strategies to prevent aminoglycoside ototoxicity.
Anti-free radical agents, such as salicylate, have been shown
to attenuate the ototoxic effects of aminoglycosides. In this
paper, incidence, predisposition, mechanism, and prevention
of aminoglycoside-induced ototoxicity is discussed in the
light of literature data.
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