Current Drug Discovery Technologies
ISSN: 1570-1638
Current Drug Discovery Technologies
Volume 6, Number 1, March 2009
Contents
Discovery of Medically Significant Lantibiotics Pp.
1-18
Clare Piper, Paul D. Cotter, R. Paul Ross and Colin
Hill
[Abstract] [Full
Text Article] [PMID:
19275538 PubMed - indexed for MEDLINE]
The Kdo Biosynthetic Pathway Toward OM Biogenesis
as Target in Antibacterial Drug Design and Development Pp.
19-33
Laura Cipolla, Alessandra Polissi, Cristina Airoldi,
Paolo Galliani, Paola Sperandeo and Francesco Nicotra
[Abstract] [Full
Text Article]
[PMID: 19275539 PubMed - indexed for MEDLINE]
Ghrelin and Growth Hormone Secretagogues, Physiological
and Pharmacological Aspect Pp. 34-42
Fernando Cordido, Maria Luisa Isidro, Rosa Nemiña
and Susana Sangiao-Alvarellos
[Abstract] [Full
Text Article] [PMID:
19275540 PubMed - indexed for MEDLINE]
Development of Multifunctional Nanoparticles for Targeted
Drug Delivery and Noninvasive Imaging of Therapeutic Effect
Pp. 43-51
Hari Krishna Sajja, Michael P. EastHui Mao, Y.
Andrew Wang, Shuming Nie and Lily Yang
[Abstract] [Full
Text Article] [PMID:
19275541 PubMed - indexed for MEDLINE]
Sculpted Amphiphilic Liposomal Particles for Modifiable
Medicinal Applications Pp. 52-58
Dipak K. Sarker
[Abstract] [Full
Text Article] [PMID:
19275542 PubMed - indexed for MEDLINE]
The Role of the RhoA/rho-kinase Pathway in Pulmonary
Hypertension Pp. 59-71
Bobby D. Nossaman and Philip J. Kadowitz
[Abstract] [Full
Text Article] [PMID:
19275543 PubMed - indexed for MEDLINE]
Using Pharmacologic Data to Plan Clinical Treatments
for Patients with Peritoneal Surface Malignancy Pp.
72-81
Kurt Van der Speeten, Oswald Anthony Stuart and
Paul H. Sugarbaker
[Abstract] [Full
Text Article] [PMID:
19275544 PubMed - indexed for MEDLINE]
Abstracts
[Back to top] [PMID:
19275538 PubMed - indexed for MEDLINE]
Discovery of Medically Significant Lantibiotics
Clare Piper, Paul D. Cotter, R. Paul Ross and Colin
Hill
[Full
Text Article]
The emergence of drug-resistant pathogens such as staphylococci
and enterococci in the hospital setting has long
being recognized as a serious clinical problem. Staphylococcus
aureus is the causative agent of many nosocomial infections
from minor skin abscesses to serious, potentially life threatening
diseases such as bone and soft tissue intra-surgical infections,
sepsis and invasive endocarditis, while enterococci are responsible
for nosocomial bacteraemia, surgical wound infections and
endocarditis. The most infamous drug-resistant forms of these
include MRSA (methicillin resistant S. aureus), VISA
(vancomycin insensitive S. aureus), hVISA (heterogenous
vancomycin insensitive S. aureus) and VRE (vancomycin
resistant S. aureus). While enhanced hygiene awareness
is essential to any solution, the identification of effective
novel antimicrobial compounds remains a major goal in eradicating
these and other infections caused by multi-drug resistant
pathogens. In recent years a class of antimicrobial peptides,
the Lantibiotics, have been the focus of an ever increasing
level of attention. This interest has been prompted by an
enhanced appreciation of the mode of action of these peptides
(including, in many cases, the ability to bind lipid II) and
their frequently high levels of antimicrobial activity. Here
we review lantibiotic-related issues in drug discovery, outline
the strategies that have been employed to identify these peptides
and summarize the use of bioengineering to generate enhanced
forms of these peptides as well as the application of the
associated biological machinery to generate novel forms of
existing pharmaceutical compounds. In so doing we highlight
how some, or all, of these approaches have the potential to
result in the development of clinically important drugs.
[Back to top] [PMID:
19275539 PubMed - indexed for MEDLINE]
The Kdo Biosynthetic Pathway Toward OM Biogenesis
as Target in Antibacterial Drug Design and Development
Laura Cipolla, Alessandra Polissi, Cristina
Airoldi, Paolo Galliani, Paola Sperandeo and Francesco Nicotra
[Full
Text Article]
Despite important advances made in the last century, infectious
diseases caused by pathogenic microrganisms are still a major
threat to human health. This is worsened by the occurrence
of new forms of bacterial resistance against antibiotics,
that are the main remedy against infectious diseases, and
their rapid spreading across bacterial species, pose additional
threats to our health. Thus, the necessity to develop new
weapons against pathogenic bacteria is widely recognized as
a major challenge for modern drug research. Traditional antibiotic
discovery procedures have so far focused on inhibiting the
main processes of the bacterial cell (replication, transcription,
translation, and peptidoglycan synthesis).
This review will give an overview of the therapeutic strategies
to cure infectious diseases caused by Gram-negative bacteria
through the development of inhibitors of Kdo biosynthesis.
Kdo is a monsaccharide essential for OM biogenesis, OM being
an essential cellular structure shared by all Gram-negative
bacteria. Hence, inhibitors of its biosynthesis can have a
broad-spectrum antibacterial activity.
[Back to top] [PMID:
19275540 PubMed - indexed for MEDLINE]
Ghrelin and Growth Hormone Secretagogues, Physiological
and Pharmacological Aspect
Fernando Cordido, Maria Luisa Isidro, Rosa
Nemiña and Susana Sangiao-Alvarellos
[Full
Text Article]
The first “growth hormone secretagogues” (GHSs)
were discovered by Bowers et al. in 1977. In 1996
the GHSs receptor (GHS-R 1a) was cloned. The endogenous ligand
for this receptor, ghrelin, was not identified until 1999.
Synthetic molecules termed GHSs are substances that stimulate
growth hormone (GH) release, via a separate pathway
distinct from GH releasing hormone (GHRH)/somatostatin. Ghrelin
displays strong GH-releasing activity through the activation
of the GHS-R 1a. Apart from stimulating GH secretion, ghrelin
and many synthetic GHSs: 1) stimulate prolactin and ACTH secretion;
2) negatively influence the pituitary-gonadal axis; 3) stimulate
appetite and positive energy balance; 4) modulate pancreatic
endocrine function and affect glucose levels; 5) have cardiovascular
actions. The control of ghrelin secretion is not well established
at present, although nutrition is an important regulator.
Investigators have exploited the ability of GHSs and ghrelin
to release GH by mechanisms different from GHRH as a diagnostic
tool, which is the present main clinical use of some GHSs.
As an alternative to GH, GH deficient conditions could be
treated with any substance which would release endogenous
GH, such as synthetic GHSs. It is likely that GHSs, acting
as either agonists or antagonists on different pathophysiological
processes, might have some other clinical impact and therapeutic
potential. At least theoretically ghrelin receptor antagonists
could be anti-obesity drugs, as blockers of the orexigenic
signal from the gastrointestinal tract to the brain. Inverse
agonists of the ghrelin receptor, by blocking the constitutive
receptor activity, might lower the set-point for hunger between
meals.
[Back to top] [PMID:
19275541 PubMed - indexed for MEDLINE]
Development of Multifunctional Nanoparticles for Targeted
Drug Delivery and Noninvasive Imaging of Therapeutic Effect
Hari Krishna Sajja, Michael P. EastHui Mao,
Y. Andrew Wang, Shuming Nie and Lily Yang
[Full
Text Article]
Nanotechnology is a multidisciplinary scientific field undergoing
explosive development. Nanometer-sized particles offer novel
structural, optical and electronic properties that are not
attainable with individual molecules or bulk solids. Advances
in nanomedicine can be made by engineering biodegradable nanoparticles
such as magnetic iron oxide nanoparticles, polymers, dendrimers
and liposomes that are capable of targeted delivery of both
imaging agents and anticancer drugs. This leads toward the
concept and possibility of personalized medicine for the potential
of early detection of cancer lesions, determination of molecular
signatures of the tumor by noninvasive imaging and, most importantly,
molecular targeted cancer therapy. Increasing evidence suggests
that the nanoparticles, whose surface contains a targeting
molecule that binds to receptors highly expressed in tumor
cells, can serve as cancer image contrast agents to increase
sensitivity and specificity in tumor detection. In comparison
with other small molecule contrast agents, the advantage of
using nanoparticles is their large surface area and the possibility
of surface modifications for further conjugation or encapsulation
of large amounts of therapeutic agents. Targeted nanoparticles
ferry large doses of therapeutic agents into malignant cells
while sparing the normal healthy cells. Such multifunctional
nanodevices hold the promise of significant improvement of
current clinical management of cancer patients. This review
explores the development of nanoparticles for enabling and
improving the targeted delivery of therapeutic agents, the
potential of nanomedicine, and the development of novel and
more effective diagnostic and screening techniques to extend
the limits of molecular diagnostics providing point-of-care
diagnosis and more personalized medicine.
[Back to top] [PMID:
19275542 PubMed - indexed for MEDLINE]
Sculpted Amphiphilic Liposomal Particles for Modifiable
Medicinal Applications
Dipak K. Sarker
[Full
Text Article]
The surface coverage and leaflet anchoring of polymeric surfactants
and other amphiphiles can be used to provide a particle with
extensive modifiable 'stealth' properties. This is not a new
conceptual tool but one which has significant strategic advantage
and recent proven clinical application in a "drug-delivery-package".
This has been established and widely reported as a fundamental
basis for optimal utility with long-circulation drug nanoparticles.
The indirect "disguising" of the medicinal payload
presents itself as a form of "pro-drug" system that
can be used to extend circulation lifetime and that is key
to a number of essential current and future risk-bearing therapies.
Appropriate particle sizing and leaflet chemical structuring,
in terms of number of strata, complexity, extent and curvature
can also be used as the means to “drug anchoring"
for the incorporation of "hydrophobic" drugs. Actives
that are chemo- or solvent labile can also be housed, often
routinely, within the inner-protected chamber of such capsular
systems. This has frequently formed the basis of a number
of recently developed commercial preparations that are used
ubiquitously in now standard chemotherapy. Additionally, the
use of complementary and non-complementary phospholipid or
other vesicle ingredient mixtures below, at or above the lipid
"gel transition" temperature or within a "glassy"
crystalline packing configuration can provide a particle of
varied physical and mechanical composition that provides a
possible route to the production of fusogenic nano-drugs or
control over the drug release profile. Successive layering
of the nanoparticle can in principle provide the means to
a step-wise or timed release of the particle contents and
one that can be adapted to the site of intended use.
[Back to top] [PMID:
19275543 PubMed - indexed for MEDLINE]
The Role of the RhoA/rho-kinase Pathway in Pulmonary
Hypertension
Bobby D. Nossaman and Philip J. Kadowitz
[Full
Text Article]
The small GTP-binding protein, RhoA, and its downstream effector
protein, rho-kinase, have been implicated in the pathogenesis
of a number of cardiovascular diseases. The activation of
rho-kinase is involved in the development of increased vascular
tone, endothelial dysfunction, inflammation, and restenosis;
and that the inhibition of rho-kinase has been shown to have
a beneficial effect in a variety of cardiovascular disorders.
It is our hypothesis that rho-kinase inhibitors promote vasodilation
independent of the mechanism that increases vasoconstrictor
tone and moreover, the RhoA/rho-kinase pathway has a role
in the regulation of smooth muscle tone under physiological
conditions. The objective of this review is to improve our
current understanding of the role of RhoA/rho-kinase pathway
in the regulation of vasoconstrictor tone and the use of rho-kinase
inhibitors in the treatment of cardiovascular disorders with
an emphasis on pulmonary hypertension.
[Back to top] [PMID:
19275544 PubMed - indexed for MEDLINE]
Using Pharmacologic Data to Plan Clinical Treatments
for Patients with Peritoneal Surface Malignancy
Kurt Van der Speeten, Oswald Anthony Stuart and
Paul H. Sugarbaker
[Full
Text Article]
The surfaces of the abdomen and pelvis are an important anatomic
site for the dissemination of gastrointestinal and gynecologic
malignancy. This transcoelomic spread of cancer cells gives
rise to peritoneal carcinomatosis which, without special treatments,
is a fatal manifestation of these diseases. In order to control
peritoneal carcinomatosis cytoreductive surgery to remove
gross disease is combined with perioperative intraperitoneal
and perioperative intravenous chemotherapy to eradicate microscopic
residual disease. Chemotherapy agents are selected to be administered
by the intraperitoneal or intravenous route based on their
pharmacologic properties. A peritonealplasma barrier which
retards the clearance of high molecular weight chemotherapy
from the peritoneal cavity results in a large exposure of
small cancer nodules on abdominal and pelvic surfaces. Tissue
penetration is facilitated by moderate hyperthermia (41-42°C)
of the intraperitoneal chemotherapy solution. A constant dose
of chemotherapy agent and volume of carrier solution based
on body surface area allows prediction of systemic drug exposure
and systemic toxicity. Timing of the chemotherapy as a planned
part of the surgical procedure to maximize exposure of all
peritoneal surfaces is crucial to success.
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