| Current
Clinical Pharmacology
ISSN: 1574-8847
Current Clinical
Pharmacology
Volume 4, Number 1, January 2009
Contents
Rosuvastatin Induced Rhabdomyolysis in a Low Risk Patient:
A Case Report and Review of the Literature Pp.
1-3
Fahmi Yousef Khan and Wael Ibrahim
[Abstract] [Full
Text Article] [PMID:
19149497 PubMed - indexed for MEDLINE]
State of the Art Clinical Efficacy and
Safety Evaluation of N-Acetylcarnosine Dipeptide Ophthalmic
Prodrug. Principles for the Delivery, Self-Bioactivation,
Molecular Targets and Interaction with a Highly Evolved Histidyl-Hydrazide
Structure in the Treatment and Therapeutic Management of a
Group of Sight-Threatening Eye Diseases Pp.
4-37
Mark A. Babizhayev and Anne Kasus-Jacobi
[Abstract] [Full
Text Article] [PMID:
19149498 PubMed - indexed for MEDLINE]
Evaluation of Human Plasma Protein Binding of Trabectedin
(Yondelis™,
ET-743) Pp. 38-42
Jan Hendrik Beumer, L. Lopez-Lazaro, Jan
H.M. Schellens, Jos H. Beijnen and Olaf van Tellingen
[Abstract] [Full
Text Article] [PMID:
19149499 PubMed - indexed for MEDLINE]
Anti-Cancer Properties of Nigella spp. Essential
Oils and their Major Constituents, Thymoquinone and β-Elemene
Pp. 43-46
Amr E. Edris
[Abstract] [Full
Text Article] [PMID:
19149500 PubMed - indexed for MEDLINE]
Novel Options for the Pharmacological Treatment of Chronic
Anal Fissure – Role of Botulin Toxin Pp.
47-52
Mariusz Madalinski and Leszek Kalinowski
[Abstract] [Full
Text Article] [PMID:
19149501 PubMed - indexed for MEDLINE]
Recent Advances in Obesity Pharmacotherapy Pp. 53-61
Marcos A. Mayer, Christian Höcht, Ana
Puyó and Carlos A. Taira
[Abstract]
[Full Text Article] [PMID:
19149502 PubMed - indexed for MEDLINE]
Evaluation of Efficacy and Safety of Fixed Dose Combination
of Ceftazidime-Tobramycin in Comparison with Ceftazidime in
Lower Respiratory Tract Infections Pp. 62-66
Manu Chaudhary, Sanjay Mohan Shrivastava
and Rajesh Sehgal
[Abstract]
[Full Text Article] [PMID:
19149503 PubMed - indexed for MEDLINE]
Structurally Modified ‘Dietary Flavonoids’: Are
these Viable Drug Candidates for Chemoprevention? Pp.
67-70
Nuggehally R. Srinivas
[Abstract] [Full
Text Article]
[PMID:
19149504 PubMed - indexed for MEDLINE]
Intensive Insulin Therapy in Critical Care
Settings Pp. 71-77
Darla Klug Eastman, Michelle M. Bottenberg,
Karly A. Hegge, Heather Ourth and Udaya Kabadi
[Abstract] [Full
Text Article] [PMID:
19149505 PubMed - indexed for MEDLINE]
Pharmacological Profile of SSRIs and SNRIs in the Treatment
of Eating Disorders Pp. 78-83
Anna Capasso, Claudio Petrella and
Walter Milano
[Abstract] [Full
Text Article]
[PMID:
19149506 PubMed - indexed for MEDLINE]
Abstracts
[Back to top] [PMID:
19149497 PubMed - indexed for MEDLINE]
Rosuvastatin Induced Rhabdomyolysis in a Low Risk Patient:
A Case Report and Review of the Literature
Fahmi Yousef Khan and Wael Ibrahim
[Full
Text Article]
We report a case of rosuvastatin induced rhabdomyolysis in
a low risk patient, who presented with five-day history of
generalized muscle pain, weakness and easy fatigability associated
with passing dark urine. Initial investigations showed creatinine
140μmol/L,
creatine kinase (CK) 4566 U/L and serum myoglobin 2694 ng/ml
with a significant increase in urine myoglobin. Although there
were no obvious risk factors, the patient was diagnosed with
rosuvastatin induced rhabdomyolysis. The drug was stopped
on the first day of admission and the patient was initiated
on intravenous fluid with cautious monitoring of serum electrolytes.
On the following days the level of creatine kinase and serum
myoglobin returned toward normal and consequently he was discharged
without statins but on dietary therapy. On follow-up evaluation,
the patient was symptom free his serum creatinine was 106μmol/L,
whereas his LDL cholesterol was 2.1mmol/L. The rosuvastatin
induced rhabdomyolysis is discussed and the danger of its
use in low risk patients is emphasized.
[Back to top]
[PMID:
19149498 PubMed - indexed for MEDLINE]
State of the Art Clinical Efficacy and Safety Evaluation of
N-Acetylcarnosine Dipeptide Ophthalmic Prodrug. Principles
for the Delivery, Self-Bioactivation, Molecular Targets and
Interaction with a Highly Evolved Histidyl-Hydrazide Structure
in the Treatment and Therapeutic Management of a Group of
Sight-Threatening Eye Diseases
Mark A. Babizhayev and Anne Kasus-Jacobi
[Full
Text Article]
Objective: The exact biological functions of
the aminoacyl-histidine dipeptides in ophthalmology are still
unknown but they are the subject of intensive research activities
at Innovative Vision Products, Inc. (IVP). Numerous studies
have demonstrated, both at the tissue and organelle levels,
that naturally occuring imidazole containing peptidomimetics
possess strong and specific antioxidant properties, by preventing
and reducing the accumulation of oxidised products derived
from the lipid peroxidation (LPO) of biological membranes.
Carnosine has been shown to act as a competitive inhibitor
of the non-enzymatic glycosylation of proteins.Thus, carnosine
may prevent and reverse (de-link) the formation of the advanced
glycation end-products (AGEs), whose accumulation in the ocular
tissues has been proposed to play a direct role in the etiology
and pathogenesis of cataract and diabetic ocular complications
(DOC). Besides, histidine-containing dipeptides are believed
to act as cytosolic buffering agents.
Aims: To compare the efficacy of L-carnosine
and derivatives in inhibiting/reversing oxidative stress-induced
reactions relevant for cataract pathogenesis. To assess the
transglycation activity of carnosine versus representatives
of a new group of synthetic carnosine histidyl-hydrazide analogs.
To test the clinical efficacy of N-acetylcarnosine prodrug
eye drops, developed by IVP’s scientists, in decreasing
the symptoms of age-related cataract.
Main Methods: Antioxidant activity
of L-carnosine and N-acetylcarnosine was studied in liposomes,
a model of lipid membranes. Iron/ascorbate was used for induction
of LPO and peroxidation products were measured. Second-generation
carnosine analogs were synthesized and tested vs.
L-carnosine for their ability to reverse the glycation process,
ultimately resulting in the formation of the AGEs. Visual
acuity and glare sensitivity was measured before and after
9-month of topical administration of N-acetylcarnosine eye
drops in a randomized placebo-controlled cohort of patients
presenting age-related uncomplicated cataract and non-cataract
subjects of the same age range.
Key Findings: L-carnosine operates
as aldehyde and reactive oxygen species (ROS) scavenger in
aqueous and lipid environments, preventing ROS-induced damage
to biomolecules. L-carnosine and histidyl-hydrazide analogs
present transglycation properties which could be used to decrease
the occurrence of long term complications of AGE formation
in DOC and age-related cataracts. In the patented ophthalmic
formulations, the designed leucyl-histidylhydrazide (not hydrolizable
by carnosinase substrate) is endowed with a highly evolved
structure optimized for the bioactivation of a N-acetylcarnosine
dipeptide prodrug, targeting therapeutics of the main DOC:
cataract, diabetic retinopathy, central retinal vein occlusion,
central retinal artery occlusion and neovascular glaucoma.
Besides, the data support the clinical application of N-acetylcarnosine
lubricant eye drops to compensate corneal acidosis. Nine-month
treatment with N-acetylcarnosine resulted in improved visual
acuity in subjects with cataract. Glare sensitivity was improved
in subjects with cataract and in non-cataract older subjects.
The results from the matched studies indicate that the N-acetylcarnosine–laden
therapeutic contact lenses increasing the intraocular and
systemic absorption of the active dipeptide carnosine ingredient,
are an effective and well-tolerated bandage lens for anterior
segment disease and for post-operative management of LASEK
patients.This allows practitioners to prescribe extended wear
of therapeutic contact lenses loaded with N-acetylcarnosine
during medical treatment of cataracts, ocular complications
of diabetes, primary open-angle glaucoma and potentially creates
a healthier eye and body environment during healing. A number
of clinically developed with alliance groups famous International
brands of patented by IVP N-acetylcarnosine lubricant eye
drops (Can-C ™,
IVP C ™
and D-Smile ™)
are described with a quick reference guide for completing
a vendor official registration in EC countries, U.A.E., Indonesia,
Japan for human and veterinary use. In a separate development
series of data Carcinine (beta-alanylhistamine) significantly
protected photoreceptors against light-induced apoptosis,
suggesting that this compound is sufficiently resistant to
degradation with enzymatic hydrolysis and can be used in
vivo representing new strategies in the anti-apoptotic
ophthalmic therapy.
[Back to top]
[PMID:
19149499 PubMed - indexed for MEDLINE]
Evaluation of Human Plasma Protein Binding of Trabectedin
(Yondelis™,
ET-743)
Jan Hendrik Beumer, L. Lopez-Lazaro, Jan
H.M. Schellens, Jos H. Beijnen and Olaf van Tellingen
[Full
Text Article]
Trabectedin (ET-743, Yondelis™)
is a novel anticancer drug with impressive activity in soft
tissue sarcoma with a manageable, non-cumulative toxicity
profile. Protein binding can be a major determinant of unbound
concentration, volume of distribution, renal and hepatic clearance,
and the half-life of a drug. Human plasma protein binding
of trabectedin has not previously been reported. Using ultrafiltration
techniques, we determined the human plasma protein binding
of trabectedin at a clinically relevant concentration. Experiments
with a panel of co-medications representing all known protein-binding
sites showed that the concentration of unbound trabectedin
could be increased by high concentrations of phenytoin. The
other tested co-medications, at concentrations covering their
respective therapeutic ranges, did not displace trabectedin
from its plasma protein binding. This suggests that trabectedin
binds to albumin site I (total protein binding of 94.2 ±0.6
%) displaying an association constant of 2.6 ±0.2
104 M-1.
Because trabectedin is an intermediate-to-high hepatic extraction
drug, changes in unbound fraction will not have a major impact
on elimination processes. The high protein binding may have
implications for the interpretation of in vitro data,
which are usually performed in the presence of low protein
levels. We can conclude that the studied co-medications are
unlikely to have clinically relevant effects on trabectedin
binding to plasma proteins at therapeutic concentrations.
[Back to top]
[PMID:
19149500 PubMed - indexed for MEDLINE]
Anti-Cancer Properties of Nigella spp. Essential
Oils and their Major Constituents, Thymoquinone and β-Elemene
Amr E. Edris
[Full
Text Article]
Essential oils are the volatile fraction of aromatic and medicinal
plants after extraction by steam or water distillation. They
have been used for their pharmaceutical potential since early
times, and even now are still subject to a great deal of attention,
as is clear from the increasing number of publications each
year on this subject. This review presents both fundamental
and recent studies concerned with the role of Nigella
species essential oils and their major constituents, thymoquinone
and β-elemene,
as potential chemotherapeutic and chemopreventive anti-cancer
agents. The mechanism of action and the factors which determine
the concentrations of these major constituents in the essential
oil are also reviewed.
[Back to top]
[PMID:
19149501 PubMed - indexed for MEDLINE]
Novel Options for the Pharmacological Treatment of Chronic
Anal Fissure – Role of Botulin Toxin
Mariusz Madalinski and Leszek Kalinowski
[Full
Text Article]
A chronic anal fissure (CAF) is commonly referred to as an
ischemic ulcer. For many years it was thought that sphincteroctomy
produces anal sphincter relaxation, enhances microcirculation
and promotes CAF healing. The latest studies have shown that
fissure healing does not appear to be dependent on reduction
in mean resting anal pressure. Our description of the process
of CAF healing is based on understanding the balance between
nitric oxide (NO) concentration and a level of oxidative and
nitroxidative stress in wounds, which is responsible for contraction
of smooth muscles (also anal sphincters), endothelial/skeletal
muscle cell remodelling and proliferation. Pharmacological
sphincterotomy with botulinum toxin (BTX) has an effect on
motor endplate but it also has an influence on nitric oxide
synthase (NOS) and other agents. Hypoxia in contracted anal
sphincters induces vasoconstriction, in part, by decreasing
endothelial NOS expression. Clostridium botulinum
C3 exoenzyme - Rho-kinase inhibitor reverses this vasoconstriction.
CAF is a site where the haemostatic mechanisms are activated.
Rho inactivator C3-transferase from Clostridium botulinum
abolished thrombin - stimulated endothelial cell contraction.
Attenuated biotransformation of Glyceryl trinitrate (GTN)
by mitochondrial aldehyde dehydrogenase and suppression of
cGMP-dependent protein kinase expression may play a key role
in understanding the problem of synergistic action of BTX
and GTN. BTX and GTN are different forms of pharmacological
sphincterectomies. This mechanism could explain the potentiate
effect of BTX action after NO donors application for CAF.
The application of BTX releases the blockage in GTN bioactivation
in smooth muscle cells and suppresses basal continuous sympathetic
activity, causing modulation of anal sphincters. It is responsible
for CAF healing.
[Back to top]
[PMID:
19149502 PubMed - indexed for MEDLINE]
Recent Advances in Obesity Pharmacotherapy
Marcos A. Mayer, Christian Höcht, Ana
Puyó and Carlos A. Taira
[Full
Text Article]
Obesity is considered a worldwide epidemic. Weight reduction
by means of lifestyle changes is difficult to achieve, and
pharmacotherapy is frequently needed. Although all currently
approved anti-obesity agents have proven to be effective to
achieve some degree of weight reduction and improve cardiometabolic
risk factors, different compounds differ in their mechanism
of action and safety profile. However, it is still difficult
to achieve and maintain therapeutic objectives along time.
The aim of the present article is to summarize the main characteristics
of available anti-obesity agents and to explore novel agents
that may provide significant clinical benefits in the future.
[Back to top]
[PMID:
19149503 PubMed - indexed for MEDLINE]
Evaluation of Efficacy and Safety of Fixed Dose Combination
of Ceftazidime-Tobramycin in Comparison with Ceftazidime in
Lower Respiratory Tract Infections
Manu Chaudhary, Sanjay Mohan Shrivastava
and Rajesh Sehgal
[Full
Text Article]
Lower respiratory tract infections are major cause of morbidity
and mortality. Objectives were to evaluate efficacy and safety
of fixed dose combination (FDC) of Ceftazidime and Tobramycin
in comparison with Ceftazidime alone in patients with lower
respiratory tract infections. Patients (n=240) were randomly
distributed in two arms: one arm was treated with Ceftazidime(1g)-Tobramycin(120mg)
and other arm was treated with Ceftazidime (1g) alone. Patients
were clinically, radiologically and bacteriologically evaluated.
Clinically successful outcome was seen in 88.4% of the patients
in Ceftazidime-Tobramycin treated group as compared to 61.2%
in Ceftazidime alone treated group. In Ceftazidime-Tobramycin
treated group, majority of pathogen isolated were H.inflenzae
(35%), P. aeruginosa (24.16%), K. pneumo-niae (16.66%) and
M. catarrhalis (24.16%), whereas in Ceftazidime alone
treated group majority of pathogen isolated were H.inflenzae
(33.33%), P. aeruginosa (20%), K. pneumoniae (18.33%) and
M. catarrhalis (28.33%). In Ceftazidime-Tobramycin treated
group (98%), a significantly higher bacterial eradication
was observed than Ceftazidime alone treated group (79%). Radiological
improvement was also superior in Ceftazidime-Tobramycin treated
group. No major adverse events were observed. Results showed
that fixed dose combination of Ceftazidime Tobramycin is superior
than Ceftazidime alone in the treatment of lower respiratory
tract infections.
[Back to top]
[PMID:
19149504 PubMed - indexed for MEDLINE]
Structurally Modified ‘Dietary Flavonoids’: Are
these Viable Drug Candidates for Chemoprevention?
Nuggehally R. Srinivas
[Full
Text Article]
The field of chemoprevention continues to be a heavily researched
area since a few decades now. Whereas, the dietary intake
of flavonoids occur via daily intakes of fruits,
vegetables, herbal preparations, beverages etc, it appears
that the active ingredients(s) contained in these dietary
sources may not reach the required plasma and/or tissue concentrations
in vivo to produce the desired pharmacological response
expected of these agents. Akin to the common problems of druggability
encountered often times in drug discovery/development scenario,
low bioavailability of flavonoids have been attributed to:
lack of stability, excessive metabolism, permeability problems,
lack of site specificity in distribution, rapid elimination
etc. The scope of the review is to assess and put into perspectives
salient features of some of the recently reported work on
dietary flavonoids including the methylated compounds that
showed improved drug-like properties in context with the required
features for the lead optimization program rendering a clinical
candidate. In addition, it aims to provide some perspectives
into the present day considerations for early drug development
such as healthy subjects versus cancer patients, single agent
versus combination potential with other cancer therapeutics,
selection of a cancer indication, potential for drug-drug
interaction etc. Although there has been an unabated use of
‘dietary flavonoids’ with tall order claims for
chemoprevention, it may be extremely challenging to confirm
it in a clinical setting. Overall, it appears prudent to develop
a comprehensive prospective strategy for clinical development
and regulatory approval.
[Back to top]
[PMID:
19149505 PubMed - indexed for MEDLINE]
Intensive Insulin Therapy in Critical Care Settings
Darla Klug Eastman, Michelle M. Bottenberg,
Karly A. Hegge, Heather Ourth and Udaya Kabadi
[Full
Text Article]
Hyperglycemia in hospitalized patients has been shown to increase
both morbidity and mortality, regardless of the presence of
preexisting diabetes. In order to achieve recommended glycemic
goals, many patients require the use of intravenous insulin
therapy in the critical care setting. Following the publication
of a landmark trial evaluating the benefits of intensive insulin
therapy in critically ill patients, a worldwide increased
effort to achieve strict glycemic control has ensued. Maintaining
blood glucose levels between 80 and 110 mg/dL has been shown
to improve outcomes such as mortality and infectious complications
in critically ill patients, while also decreasing length of
hospital stay and healthcare expenditures. However, achieving
strict glycemic control has proven to be a challenge for many
institutions, partly due to the prevalence of hypoglycemia.
As demonstrated by studies which have been terminated prematurely
due to increased risk for hypoglycemic episodes, the benefits
versus risks of intensive insulin therapy must be weighed
carefully. Patients receiving continuous infusions of insulin
require close monitoring, which may increase workload for
intensive care unit staff. In an effort to balance the risks
and benefits of intensive insulin therapy, many hospitals
are incorporating standardized protocols and using an interdisciplinary
approach toward patient care.
[Back to top]
[PMID:
19149506 PubMed - indexed for MEDLINE]
Pharmacological Profile of SSRIs and SNRIs in the Treatment
of Eating Disorders
Anna Capasso, Claudio Petrella and
Walter Milano
[Full
Text Article]
Bulimia Nervosa (BN) and Binge Eating Disorder (BED) are some
of the most common eating disorders (ED) in industrialized
societies, characterized by uncontrolled binge eating and
self-induced purging or other compensatory behaviours aiming
to prevent body weight gain. It has been suggested that reduced
serotonergic and noradrenergig tone triggers some of the cognitive
and mood disturbances associated with ED. In fact in the active
phase of ED the concentration of serotonin and noradrenaline
in cerebral fluid is reduced. For these reasons, the pharmacologic
treatment of ED consists mainly of selective serotonin reuptake
inhibitors (SSRIs) or selective noradrenaline reuptake inhibitors
(SNRIs) . At present, the physiologic basis of this disorder
are not yet completely understood. In this review we evaluate
several randomized controlled trials to compare the efficacy
of several SSRIs and SNRIs in patients with a diagnosis of
ED as defined by the fourth edition of the Diagnostic
and Statistical Manual of Mental Disorders [DSM IV])
These findings indicate that both SSRIs and SNRIs are well
tolerated and reduce effectively the bulimic crisis and purging
episodes in patients with ED.
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