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Current
Clinical Pharmacology
ISSN: 1574-8847
Current Clinical Pharmacology
Volume 6, Number 1, Feburary 2011
Contents
A Comprehensive Literature Search: Drugs as Possible Triggers
of
Takotsubo Cardiomyopathy Pp. 1-11
Pedro Amariles
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The Pharmacological Management of Intrahepatic Cholestasis
of Pregnancy Pp. 12-17
Francesco Azzaroli, Laura Turco, Andrea Lisotti, Claudio
Calvanese and Giuseppe Mazzella
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Article]
Tigecycline Treatment of Critically Ill Patients:
The Latinuser Experience Pp. 18-25
Daniel Curcio, Sandra Whittle Vargas, Sebastián
Ugarte Ubiergo, Fabio Varón, José Rojas Suarez,
Carlos Paz Chávez, Ariel Curiale, on behalf of the
Latin American Tigecycline Initial Use Registry (LatinUser)
[Abstract] [Purchase
Article]
Comparative Bioavailability Study of a New Formulation
of Injection of 75 mg Diclofenac Sodium in 1 mL with the Conventional
Injection of 75 mg Diclofenac Sodium Given in 3 mL Volume Pp. 26-29
Dhaneshwar Shep, Ashwini Ojha, Sweta Patel, Manish
Nivsarkar, Vijaya Jaiswal and Harish Padh
[Abstract] [Purchase
Article]
Pharmacodynamic Biomarkers in Model-Based Drug Development
in Oncology Pp. 30-40
Ron J. Keizer, Jan H.M. Schellens, Jos H. Beijnen
and Alwin D.R. Huitema
[Abstract] [Purchase
Article]
Proton Pump Inhibitors in Pediatrics: Evaluation of
Efficacy in GERD Therapy Pp. 41-47
Claudio Romano, Andrea Chiaro, Donatella Comito,
Italia Loddo and Valeria Ferrau´
[Abstract] [Purchase
Article]
Bronchodilator Combination Therapy for the Treatment
of Chronic Obstructive Pulmonary Disease Pp. 48-61
Sanjay Sethi and Claudia Cote
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Article]
Drug Utilization 75% (DU75%) in 17 European Hospitals
(2000 - 2005): Results from the ESAC-2 Hospital Care Sub Project
Pp. 62-70
Peter Zarb, Faranak Ansari, Arno Muller, Venessa Vankerckhoven,
Peter G. Davey and Herman Goossens
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Article]
Abstracts
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A Comprehensive Literature Search: Drugs as Possible
Triggers of
Takotsubo Cardiomyopathy
Pedro Amariles
Background: Takotsubo cardiomyopathy (TCM) is
a syndrome of transient cardiac dysfunction precipitated by
intense emotional or physical stress. Excessive sympathetic
stimulation is believed to be central to the pathogenesis
of this condition, thus drugs with sympathetic effect could
precipitate TCM. The aim of this study was to conduct a comprehensive
literature search to identify drugs that could precipitate
TCM.
Methods: Published case reports of TCM associated
with drug-used were identified by a comprehensive literature
search using the Medline/PubMed database, from January 1990
to November 2010. Search terms included Takotsubo cardiomyopathy,
Tako-tsubo cardiomyopathy, stress cardiomyopathy, transient-left-ventricular
ballooning syndrome, ampulla cardiomyopathy, apical ballooning
syndrome, OR broken heart syndrome; together with “iatrogenic”,
“drug-induced”, OR “induced by”. Only
publications in English or Spanish, in Humans, and with links
to full text were retrieved. Then, articles that recognized
any drug as a possible drug-induced TCM were selected. Additionally,
citation lists from identified articles were subsequently
reviewed to identify additional relevant articles.
Results: Overall, 401 different references were retrieved
and 42 selected. Additionally, 5 articles were identified
from citation list of selected articles. Thus, 47 articles
with one report of more drugs as a possible trigger of 58
cases of SCM were reviewed, in which 20 different drugs were
recognized as possible drug-induced TCM.
Conclusion: There are some reports that linked the
drug-used, mainly associated to sympathetic overstimulation,
with the development of TCM. Consequently, drug-induced TCM
would be considered in patients with TCM, particularly those
in which no clear emotional or stress trigger could be identified.
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The Pharmacological Management of Intrahepatic Cholestasis
of Pregnancy
Francesco Azzaroli, Laura Turco, Andrea Lisotti, Claudio
Calvanese and Giuseppe Mazzella
Intrahepatic cholestasis of pregnancy is the most common
liver disease occurring in the second half of pregnancy, characterized
by pruritus and elevated serum bile acids often coupled to
abnormal liver tests. Maternal prognosis is favourable with
a complete symptom resolution after delivery, while preterm
deliveries, fetal respiratory distress and stillbirths may
occur. The goal of the pharmacological treatment of the disease
is to improve maternal symptoms and biochemical alterations
and, most importantly, to reduce fetal adverse events. The
present manuscript will review the current knowledge on the
pharmacological treatment of intrahepatic cholestasis of pregnancy.
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Tigecycline Treatment of Critically Ill Patients:
The Latinuser Experience
Daniel Curcio, Sandra Whittle Vargas, Sebastián
Ugarte Ubiergo, Fabio Varón, José Rojas Suarez,
Carlos Paz Chávez, Ariel Curiale, on behalf of the
Latin American Tigecycline Initial Use Registry (LatinUser)
Tigecycline is the first of a new class of antibiotics
named glycylcyclines and it was approved for the treatment
of complicated intra-abdominal infections and skin and skin
structure infections and community-acquired bacterial pneumonia.
Notwithstanding this, the tigecycline’s pharmacological
and microbiological profile encourage physicians’ use
of the drug in other infections. The aim of this study was
to characterize the indications type, pathogens, and outcomes
of patients who were treated with tigecycline.
We analyzed the tigecycline prescriptions in 209 patients
in 23 Latin American centres using an electronic form included
in the website LatinUser™ (http://www.clinicalrec.com.ar).
Sixty-six patients (31.5%) received tigecycline for approved
indications, and 143 (68.5%) for “off label” indications
(47% with scientific support and 21.5% with limited or without
any scientific support). The most frequent “off label”
use was ventilator-associated pneumonia (VAP) (76 patients).
The etiology of infections was established in 88 patients
(42%). Acinetobacter spp. (54.5%, in 65% of cases carbapenemsresistant),
methicillin-resistant Staphylococcus aureus (12%),
and extended spectrum β-lactamases-producing
Enterobacteriaceae (10%) were the most common microorganisms
isolated.
Overall, attending physicians reported clinical success in
144 of the 209 patients (69%). Global mortality proportion
was 35.5% (74/209 patients).
Our study shows that the off label use of tigecycline is frequent,
especially in VAP due to multidrug-resistant pathogens, where
the therapeutic options are limited (e.g.: carbapenems-resistant
Acinetobacter spp.). Physicians must evaluate the
benefits/risks to use this antibiotic for indications that
lack rigorous scientific support.
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Comparative Bioavailability Study of a New Formulation
of Injection of 75 mg Diclofenac Sodium in 1 mL with the Conventional
Injection of 75 mg Diclofenac Sodium Given in 3 mL Volume
Dhaneshwar Shep, Ashwini Ojha, Sweta Patel, Manish
Nivsarkar, Vijaya Jaiswal and Harish Padh
Objectives: Diclofenac a non-steroidal anti-inflammatory
drug (NSAID) is widely used for the management of various
musculoskeletal conditions. An injectable test formulation
of diclofenac sodium (75 mg/mL) was prepared to facilitate
reduction in injection volume as compared to already marketed
formulations of diclofenac sodium (75 mg/3mL). The objective
of this study was to compare the bioavailability of test formulation
with the reference formulation given intramuscularly in healthy
volunteers.
Methods: This two way randomized crossover study
was performed in 14 healthy, adult, Indian, male human subjects
to compare bioavailability. The formulations were administered
intramuscularly (intragluteal) to the volunteers in a two
way randomized fashion with a wash out period of 6 days. Blood
samples were collected till 6.0 h following drug administration.
The samples were analyzed using pre-validated HPLC method.
Results: The mean Cmax
and Tmax for the test and
reference formulations were 2.14 μg/mL,
1.91 μg/mL
and 0.49 h, 0.50 h respectively. The mean AUC0-t
for test and reference formulations were 3.79 μg.h/mL,
and 3.43 μg.h/mL
respectively. The mean AUC0-∞
for test and reference formulation were 4.03 μg.h/mL
and 3.65 μg.h/mL
respectively. The mean (90% CI) Cmax,
AUC0-t and AUC0-∞
ratio (Test:Reference) were 1.15 (100.25–132.99), 1.10
(100.34–119.96) and 1.09 (100.78– 118.88), respectively.
Conclusion: The test formulation shows a comparable
AUC0-t and AUC0-∞
but a higher Cmax in comparison to the reference when given
intra-gluteally. The lower volume of the test formulation
offers advantage of injection at other sites, like deltoid
region. Absence of propylene glycol in the test formulation
could be advantageous in terms of improved tolerability. Hence,
such formulations of previously well established molecules
provide a new direction towards developing better and convenient
dosing alternatives.
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Pharmacodynamic Biomarkers in Model-Based Drug Development
in Oncology
Ron J. Keizer, Jan H.M. Schellens, Jos H. Beijnen
and Alwin D.R. Huitema
Introduction: Model-based drug development (MBDD) is
recognized as an initiative able to improve success rates
in the development of new anti-cancer agents. The use of pharmacodynamic
(PD) biomarkers may be valuable in this context. The implementation
of biomarkers in MBDD in oncology is the subject of this review.
Methods: Literature was searched for articles and
relevant conference abstracts concerning application of biomarkers
in MBDD in oncology. First, papers are discussed concerning
the use of biomarkers in modeling and simulation analyses
in preclinical and early clinical phases of drug development.
Subsequently, articles concerning late-stage clinical drug
development are discussed.
Results: Only a limited set of articles and conference
presentations were identified. As expected, the majority of
publications are concerned with targeted anti-cancer drugs.
In the early development of novel anti-cancer agents, most
publications concerned to the evaluation of dosing regimens
for further clinical evaluation, or the identification of
the required levels of target modulation. In general, combined
analysis of clinical and preclinical data provide the most
informative analyses. The use of biomarkers in late-stage
drug development has mainly been confined to the prediction
of phase III outcome on the basis of tumor growth data obtained
from phase II trials, with tumor growth as biomarker for outcome.
Conclusion: The use of suitable biomarkers in MBDD,
has shown its merits in oncology, especially in early clinical
development. Considering the low number of reports in literature,
we would propose a more active use of presented techniques
during all developmental phases of new anticancer agents.
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Proton Pump Inhibitors in Pediatrics: Evaluation of
Efficacy in GERD Therapy
Claudio Romano, Andrea Chiaro, Donatella Comito,
Italia Loddo and Valeria Ferrau´
Gastroesophageal reflux (GER) is defined as the passage
of gastric contents into the esophagus. It occurs in healthy
infants and can be considered physiological process. Uncomplicated
GER can present with recurrent vomiting or regurgitation without
any other symptoms and is usually managed by educating, reassuring,
and guiding the parent without other intervention. GER disease
(GERD) refers to the appearance of troublesome symptoms or
complications (erosive esophagitis, ulceration, Barrett’s
esophagus) and may warrant acid suppression. Proton Pump Inhibitors
(PPIs) are the most effective pharmacologic agents available
for the treatment of children with GERD. In the pediatric
practice only omeprazole, lansoprazole and esomeprazole are
available over the first year of life. The empiric use in
infants with nonspecific symptoms (excessive crying, regurgitation,
feeding refusal, chronic cough) is frequent without randomized
controlled study. Our paper will focus on the correct indications,
dosages, duration of treatment and safety of PPI use in pediatric
population.
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Bronchodilator Combination Therapy for the Treatment
of Chronic Obstructive Pulmonary Disease
Sanjay Sethi and Claudia Cote
Chronic obstructive pulmonary disease (COPD) is a major
cause of morbidity and mortality, and its prevalence is rising
worldwide. Bronchodilators remain the cornerstone of COPD
treatment, especially inhaled β2-adrenergic
receptor agonists and inhaled anticholinergics. Long-acting
bronchodilators are considered more effective and convenient
than short-acting bronchodilators for maintenance treatment
in patients with moderate to very severe COPD. There are currently
3 long-acting inhaled bronchodilators available in the United
States: the β2-adrenergic
receptor agonists formoterol and salmeterol, and the anticholinergic,
tiotropium. All 3 long-acting bronchodilators have been shown
to be effective and well tolerated for the management of patients
with stable COPD in clinical studies. The combination of β2-adrenergic
receptor agonists and anticholinergics has been shown to provide
superior bronchodilatory effect than either agent alone, possibly
because of the different mechanisms of action of these agents.
The current treatment guidelines recommend the use of one
or more long-acting bronchodilators for patients with moderate
to severe stable COPD who remain symptomatic with single-agent
bronchodilator therapy. The objective of this article is to
review clinical data on combined bronchodilator therapy with
β2-adrenergic
receptor agonists and anticholinergics in patients with COPD.
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Drug Utilization 75% (DU75%) in 17 European Hospitals
(2000 - 2005): Results from the ESAC-2 Hospital Care Sub Project
Peter Zarb, Faranak Ansari, Arno Muller, Venessa Vankerckhoven,
Peter G. Davey and Herman Goossens
The study aimed to assess 75% of drug utilization (DU75%)
in participating hospitals and identify quality indicators
which should be used to monitor performance within the hospitals.
In the European Surveillance of Antimicrobial Consumption
(ESAC; http://www.esac.ua.ac.be) project anatomic therapeutic
chemical (ATC), defined daily dose (DDD) and route of administration
(RoA) were used for drug categorization. Data were collected
for: antibacterials for systemic use; intestinal antibiotics;
rifampicin; and nitroimidazole derivatives. Each hospital’s
annual data were analyzed separately (hospital-year) adding
up to a total of 97 hospital-year data-sets. The drug most
persistently present within DU75% was ciprofloxacin (84/97
hospital-years). Co-amoxiclav was the drug which most frequently
ranked first (28 times). The number of drugs constituting
the DU75% by substance ranged from 7-15 (median 12) and 8-
19 (median 15) by RoA which identified oral amoxicillin most
frequently ranking first (17 times). In many hospitals the
oral route accounted for most of the DU75%. Therefore, the
extent of oral use was identified as a quality indicator which
could be monitored using DU75% methodology. Since substantial
variation both in extent and distribution of antibiotic use
was observed, DU75% methodology is best adapted for intra-hospital
consumption trend analyses or for hospitals with comparable
characteristics and formularies. The number of drugs within
DU75% was identified as another quality indicator. Thus, aspiring
to decrease the consumption of overused drug classes should
be set by the hospitals as a quality indicator on prescribing
patterns.
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