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Current
Drug Therapy
ISSN: 1574-8855
Current Drug Therapy
Volume 4, Number 1, January 2009
Contents
Editorial Pp. 1
Anti Oxidant Property of New Cephalosporin-Aminoglycoside
Fixed Dose Combination Pp. 2-6
Manu Chaudhary, Arvind Soni, Vivek Kumar
Dwivedi and Rajesh Sehgal
[Abstract] [Full
text article]
Paliperidone: A Clinical Review Pp.
7-11
Ben Green
[Abstract] [Full
text article]
Sinus Node If Channel
Inhibition – A New Therapeutic Approach to Heart Rate
Lowering Pp. 12-18
Anne E. Scott, Kirsten Kruszewski and
Stephen J. Leslie
[Abstract] [Full
text article]
Unlocking the Molecular Mechanisms of DNA Repair and
Platinum Drug Resistance in Cancer Chemotherapy Pp.
19-28
Jing Jie Yu
[Abstract] [Full
text article]
A Role of DEAD-Box RNA Helicase rck/p54 in Cancer
Cells Pp. 29-37
Yukihiro Akao
[Abstract] [Full
text article]
Natural and Synthetic Furanocoumarins as Treatment
for Vitiligo and Psoriasis Pp. 38-58
Filomena Conforti, Mariangela Marrelli,
Federica Menichini, Marco Bonesi, Giancarlo Statti, Eugenio
Provenzano and Francesco Menichini
[Abstract] [Full
text article]
Trimetazidine: Does it Actually Reduce QT Dispersion
After First Acute Myocardial Infarction? Pp.
59-64
Khaled El-Meniawy, Hanan Hafez, Hala Bamatraf
and Wail Nammas
[Abstract] [Full
text article]
Pharmacological Overview and Future Perspectives of
Cholinergic Therapy in Alzheimer’s Disease Pp.
65-72
Hiroo Ogura
[Abstract] [Full
text article]
In Vitro Microbial Efficacy of Sulbactomax:
A Novel Fixed Dose Combination of Ceftriaxone Sulbactam and
Ceftriaxone Alone Pp. 73-77
Sanjay Mohan Shrivastava, Sandeep Saurabh,
Dharmendra Rai, Vivek Kumar Dwivedi and Manu Chaudhary
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial:
On starting a new year, one usually reflects upon
the recent past. Perhaps in more than many other years, changes,
some good and some not so good, appeared to be the hallmark
of 2008. One of the good changes, often overlooked, is the
accrual of knowledge. In few areas, this is more important
than the medical sciences. Although there is much to do and
the number of questions seems to be growing rather than becoming
smaller, much has been learned, and there has been a lot of
progress. Current Drug Therapy is pleased to participate
in the dissemination of information about this progress. In
keeping with the tradition of providing readers an array of
informative review articles and reports of original research,
this issue contains papers on a variety of topics, briefly
summarized here in the order in which they appear.
All drugs have unwanted effects. Strategies to minimize these
side effects are being developed, as exemplified by the paper
describing the antioxidant properties of cephalospirins used
in conjunction with aminoglycosides.
In the area of neuropsychopharmacology, we have a review of
paliperidone, which is the active metabolite of respiridone.
Although not a truly new drug, patients respond differently,
and having more treatment options are of value.
Advances in understanding of ion channels have led to safer
and more effective therapies for patients with cornonary artery
disease. Ivabradine, an If
channel blocker, lowers heart rate by selective action at
the sinoatrial node.
In the area of oncology, we have a comprehensive review of
mechanisms of platinum resistance. Understanding of how cancer
cells resist chemotherapeutic agents, allows the development
of new treatment strategies.
Understanding of biochemical processes involved in carcinogenesis
will likely to lead to the development of new treatments.
In this regard, work on the role of mRNA translation in tumor
cells provides insight into how inhibition of these processes
may lead to the control of tumor growth.
Phototherapy, use of drugs in conjunction with light has been
hampered by increased risk of skin malignancies. Development
of drugs which do not cross link DNA may reduce this risk.
Patients suffering with myocardial infarctions may develop
arrhythmias, which may themselves be fatal. QT dispersion
has been reported to be predictive of ventricular arrhythmias.
Trimetazidin is reported to reduce QT dispersion and the frequency
of ventricular arrhythmias.
One of the cardinal features of Alzheimer’s disease
is death of cholinergic neurons, leading to decreased acetylcholine
mediated neural transmission. Inhibitors of cholinesterases,
which metabolize this neurotransmitter have been used in the
symptomatic treatment of dementias, but may also modify the
pathologic processes involved.
Widespread use of antibiotics has led to the evolution of
resistant strains of bacteria. Production of beta lactamase
has allowed several strains of bacteria to evade beta lactam
antibiotics. Co-administration of the beta lactamase inhibitor
Sulbactam has been shown to increase the potency of Ceftriaxone.
JOACHIM F. WERNICKE, PhD, MD
(Editor-in-Chief)
Associate Director
Neuroscience, Global Product Safety
Eli Lilly and Company, Lilly Research Laboratorie
Indianapolis, IN 46285
USA
E-mail: jfwernicke@lilly.com
[Back to top]
Anti Oxidant Property of New Cephalosporin-Aminoglycoside
Fixed Dose Combination
Manu Chaudhary, Arvind Soni, Vivek Kumar
Dwivedi and Rajesh Sehgal
[Full
text article]
Aminoglycosides are known to cause oxidative stress related
toxicities and tissue injuries. Present study was planned
to evaluate the effect of aminoglycosides on blood oxidative
stress parameters in mice and free radical scavenging potential
of cephalosporins, when combined as a single injection with
aminoglycosides using chemical vector mediated technology.
Mus musculus mice were divided into five groups:
Control group animals (treated with normal saline), amikacin
treated group, tobramycin treated group, cefepime + amikacin
treated group and ceftazidime + tobramycin treated group.
A significant improvement in superoxide dismutase (SOD), catalase
activities, along with malonaldialdehyde (MDA) levels and
creatinine levels were observed in fixed dose combination
of cephalosporins and aminoglycosides treated groups as compared
to aminoglycosides alone (amikacin and tobramycin) treated
groups. These findings indicate that on combining cephalosporins
with aminoglycosides using chemical vector mediated technology
prevents oxidative stress related tissues injury induced by
aminoglycosides.
[Back to top]
Paliperidone: A Clinical Review
Ben Green
[Full
text article]
Paliperidone is an antipsychotic recently made available
in the US and UK in a special oral extended release form.
Paliperidone is a modified form of risperidone namely 9-hydroxyrisperidone,
(itself the active metabolite of risperidone). Since risperidone
has been available for many years some argue that paliperidone
is not a novel antipsychotic but a newly marketed variant.
An injectable form, paliperidone palmitate is being trialled.
Paliperidone is mainly excreted renally and there is only
limited hepatic metabolism. Paliperidone works by partially
blocking D2 dopamine receptors and fully blocking serotonin.
The normal dosing range for paliperidone is 3-12 mg daily.
Efficacy studies with paliperidone indicate that it is effective
against schizophrenia and also has a similar side effect profile
compared to other antipsychotics. There is an absence of effects
on glucose and lipids in comparison with olanzapine. Symptom
reduction in schizophrenia occurs as soon as day four of treatment
with paliperidone. Clinical experience with risperidone over
many years suggests that paliperidone would have a valuable
role as an antipsychotic. The entity is not truly novel, but
rather than being a variant existing purely for marketing
purposes, should be regarded as an upgrade.
[Back to top]
Sinus Node If Channel
Inhibition – A New Therapeutic Approach to Heart Rate
Lowering
Anne E. Scott, Kirsten Kruszewski and
Stephen J. Leslie
[Full
text article]
Heart rate lowering has an important role in the treatment
of coronary artery disease. Lower heart rates extend diastolic
filling, facilitating improved myocardial perfusion and reduced
myocardial oxygen demand. This has traditionally been achieved
with beta-blockers or calcium-channel blockers. Unfortunately
both these classes of drugs have side-effects in a significant
minority of patients.
The recent development of ivabradine, which acts specifically
on the sinoatrial node, offers promise in achieving heart
rate reduction without major side effects. Ivabradine selectively
and specifically inhibits the If channel which is integral
to the generation of the pacemaker current in the sinoatrial
node. Initial studies utilising ivabradine show improvements
in exercise tolerance and time to developing ischaemia during
exercise in patients with chronic stable angina. Ivabradine
has no negative inotropic effects and does not appear to have
any major side-effects. It has been shown to have similar
anti-anginal and anti-ischaemic effects to atenolol and amlodipine.
Animal studies have suggested that ivabradine may have beneficial
effects in chronic heart failure leading to improvements in
left ventricular function. In humans with stable coronary
artery disease, left ventricular dysfunction and heart rates
of 70bpm or more, ivabradine appears to reduce rates of revascularisation
and hospitalisation for myocardial infarction.
[Back to top]
Unlocking the Molecular Mechanisms of DNA Repair and
Platinum Drug Resistance in Cancer Chemotherapy
Jing Jie Yu
[Full
text article]
This review article is devoted exclusively to DNA repair
and acquired resistance to platinum compounds, with an emphasis
on research needs and clinical application. It focuses on
the role of genetic variants (gene mutations and SNPs) and
epigenetic alterations (methylation and acetylation). Four
major DNA repair pathways and one enzyme-correction mechanism
are presented: Base Excision Repair, Nucleotide Excision Repair,
DNA Double-Strand Break Repair, Mismatch Repair and Direct
Damage Reversal. It is suggested that one cause of platinum
resistance is more accurately described as alterations
of DNA repair system rather than activation
of DNA repair mechanism, as this cause of resistance
is brought about by changes in genetic and epigenetic regulation.
Given what is known, research on DNA repair and platinum resistance
might best be directed at 1) transcriptional cis-elements
(activators/repressors) within promoters of essential DNA
repair genes, 2) effects of epigenetic alterations, and 3)
connections between gene expression and DNA methylation or
protein acetylation. Special attention should be directed
at three interrelationships: between the different DNA repair
pathways; between DNA methylation and protein acetylation;
and between DNA repair pathways and DNA methylation or protein
acetylation. Improved clinical outcomes may be achieved by
restoring wild type p53 with small molecule drugs, the use
of gene demethylation strategies, individual-targeted treatment
of BRCA mutation carrier, and combining platinum compounds
with molecularly-targeted drugs such as EGFR inhibitors.
[Back to top]
A Role of DEAD-Box RNA Helicase rck/p54 in Cancer
Cells
Yukihiro Akao
[Full
text article]
Promising targets for cancer drugs are translation initiation
factors. mRNA translation is regulated in many cancers via
a combination of protein overexpression and defects in the
pathways that signal the translation machinery. Previously,
we reported evidence that human RNA structure-modifying helicase
rck/p54, a member of DEAD-box family, was highly expressed
in most of the malignant cell lines tested and that this expression
was linked to the maintenance of growth in cancer cells. In
cell growth and differentiation induced by external stimuli,
the level of rck/p54 expression was up-regulated during cell
proliferation and down-regulated during differentiation. The
knockdown of rck/p54 by using siRNA of RCK induced
cell growth inhibition through cell cycle arrest at the S
phase in HeLa cells. Immunoprecipitation using anti-rck/p54
antibody in HeLa cells demonstrated the co-precipitation of
rck/p54 with eIF4E, which is well known to bind to the 5’cap-structure
and to be a rate-limiting factor in the initiation of translation.
On the other hand, by use of cell and cell free systems we
found that rck/p54 acts as a translation repressor of mRNAs
such those of as c-myc and hepatitis C virus,
which have an internal ribosomal entry site structure. The
results of our recent study indicated that rck/p54 contributes
to the suppression of the expression of let-7 which targets
RAS. These data altogether suggest that rck/p54 positively
affects cell growth probably by playing a role in the selection
and quantity control of mRNAs at the translational level,
leading to the fidelity of desirable gene expression for cell
proliferation in cancer cells, which is a newly defined mechanism
leading to carcinogenesis.
[Back to top]
Natural and Synthetic Furanocoumarins as Treatment
for Vitiligo and Psoriasis
Filomena Conforti, Mariangela Marrelli,
Federica Menichini, Marco Bonesi, Giancarlo Statti, Eugenio
Provenzano and Francesco Menichini
[Full
text article]
Phototherapy has been used for centuries to treat various
skin disorders. Numerous inflammatory skin diseases, such
as atopic dermatitis and pigment disorders like vitiligo and
psoriasis, benefit from ultraviolet light treatment.
Psoralen-containing plants have been used for centuries in
popular medicine to treat vitiligo, a skin disease characterized
by lack of pigmentation. Further advancement in treatments
using different psoralen molecules should strive to decrease
the possibility of long-term side effects such as cutaneous
malignancies. One of the directions for continued refinement
of photochemotherapy in the future, as well as one of the
new paradigms associated with photochemotherapy itself, is
devel-opment of other psoralen molecules that do not form
bifunctional adducts, which provide a basis for the DNA cross-linking.
One such class of furanocoumarins is the methylangelicins
(angular furanocoumarins) which only forms mono-functional
adducts. There is clearly a theoretical basis that monofunctional
adducts would less likely promote cutaneous malignancies as
compared to bifunctional adducts.
In this review we wish to present recent pharmacological approaches
of furanocoumarins, particularly angular furanocoumarins,
and a detailed investigation on the photocytotoxicity exerted
by these compounds. Furthermore the edible vegetables and
fruits which contain these compounds are showed.
[Back to top]
Trimetazidine: Does it Actually Reduce QT Dispersion
After First Acute Myocardial Infarction?
Khaled El-Meniawy, Hanan Hafez, Hala Bamatraf
and Wail Nammas
[Full
text article]
We sought to explore whether trimetazidine addition reduces
QT dispersion early after acute myocardial infarction. Prospectively,
we randomized 60 consecutive patients with first acute ST
elevation myocardial infarction to receive either trimetazidine
20 mg tid (trimetazidine group =30 patients), or placebo (placebo
group =30 patients). QT dispersion and corrected QT dispersion
were measured on day 3 and day 7 of admission. Patients were
followed during hospitalization for the occurrence of ventricular
arrhythmias (sustained ventricular tachycardia or ventricular
fibrillation). QT dispersion and corrected QT dispersion were
significantly lower in trimetazidine group in both days, compared
to control group: day 3, 58±5 msec versus 78±6
msec, and 69±11
msec versus 91±10
msec, respectively, p<0.001
for both; day 7, 41±7 msec versus 60±8 msec,
and 47±9 msec versus 69±6
msec, respectively, p<0.0001
for both. This finding was consistent in all prespecified
subgroups. During hospital stay, 3 patients (10%) of the placebo
group developed sustained ventricular tachycardia and 2 (6.6%)
died of ventricular fibrillation, but no one in the trimetazidine
group had such arrhythmias. Conclusion: In patients with first
acute myocardial infarction, the addition of trimetazidine
significantly reduced both QT dispersion and corrected QT
dispersion and reduced the occurrence of ventricular arrhythmias
throughout hospitalization.
[Back to top]
Pharmacological Overview and Future Perspectives of
Cholinergic Therapy in Alzheimer’s Disease
Hiroo Ogura
[Full
text article]
Since damage to cholinergic neurons was found widely
and severely in the brain of Alzheimer’s disease (AD)
patients in 1970s, many clinical trials of several kinds of
cholinomimetics have been actively undertaken to stimulate
the central cholinergic system which might be involved in
cognitive function. Although there are various drug targets
to activate the cholinergic system, only cholinesterase inhibitors
prevailed in the clinical trials with regard to AD. At present,
three cholinesterase inhibitors donepezil, galantamine, and
rivastigmine are prescribed as a symptomatic treatment for
AD. This class of drugs inhibits cholinesterase which breaks
down acetylcholine), thus raising the level of acetylcholine
in the synaptic clefts, activating central cholinergic function
and finally leading to improvement of cognitive function,
as well as other symptoms associated with AD. Clinical studies
revealed that cholinesterase inhibitors reliably improved
clinical rating scales of the two co-primary endpoints, typical
cognition measured by ADAS-cog (Alzheimer’s Disease
Assessment Scale cognitive subscale) and global function assessed
by CIBIC-plus (Clinician's Interview-Based Impression of Change),
in mild-to-moderate AD patients. Furthermore, clinical evidence
has accumulated to show efficacy in other states of dementia
as well, namely dementia with Lewy bodies and severe AD. In
addition to their symptomatic effects in AD, recent pharmacological
studies showed that some cholinesterase inhibitors displayed
certain disease modifying characteristics, namely interaction
with the amyloid processing pathway, neuroprotection and enhancement
of adult brain neurogenesis.
[Back to top]
In Vitro Microbial Efficacy of Sulbactomax:
A Novel Fixed Dose Combination of Ceftriaxone Sulbactam and
Ceftriaxone Alone
Sanjay Mohan Shrivastava, Sandeep Saurabh,
Dharmendra Rai, Vivek Kumar Dwivedi and Manu Chaudhary
[Full
text article]
Microorganism susceptible to beta lactam antibiotics
are fastly becoming resistant because of production of beta
lactamase by microorganisms. This study is aimed at evaluating
microbial efficacy of Sulbactomax drug, a novel fixed dose
combination of beta lactam antibiotic Ceftriaxone and beta
lactamase inhibitor Sulbactam drugs. Efficacy was evaluated
on the basis of Minimum Inhibitory Concentration (MIC) and
time kill curve analysis in Escherichia coli, Pseudomonas
aeruginosa, Staphylococcus aureus, Bacillus subtilis and Klebsiella
pneumoniae. The MIC for Sulbactomax in E. coli
was 0.0625 mg/l whereas Ceftriaxone alone showed MIC of 0.25
mg/l. In case of S. aureus and P. aeruginosa
MIC were found to be 1 mg/l for Sulbactomax and 2 mg/l for
Ceftriaxone. There was significant reduction of MIC values
to 8 mg/l of Sulbactomax from 32mg/l of Ceftriaxone in
B. subtilis and 2mg/l of Sulbactomax from 16mg/l of Ceftriaxone.
In all organisms under study, time-kill curve analysis demonstrated
bacterial maximum killing at 6 hours. Sulbactomax demonstrated
better bactericidal activity than Ceftriaxone alone.
In conclusion, Sulbactomax was found to have more bacterial
inhibiting properties than Ceftriaxone alone in in vitro
analysis.
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