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Current
Clinical Pharmacology
ISSN: 1574-8847
Current Clinical
Pharmacology
Volume 4, Number 3, September 2009
Contents
Methods of Fitting Straight Lines where Both Variables are
Subject to Measurement Error Pp. 164-171
Jonathan Gillard and Terence Iles
[Abstract] [Full
Text Article] [PMID:
19500068 PubMed - indexed for MEDLINE]
Vascular and Cellular Calcium in Normal and Hypertensive Pregnancy
Pp. 172-190
Zuzana Adamova, Sifa Ozkan and Raouf
A. Khalil
[Abstract] [Full Text Article] [PMID:
19500073 PubMed - indexed for MEDLINE]
Molecular Determinants of Fluoroquinolone Antibacterial
Agents Pharmacokinetics Pp. 191-197
Dominique Levêque and François
Jehl
[Abstract] [Full
Text Article] [PMID:
19500069 PubMed - indexed for MEDLINE]
Evidence-Based Efficacy of Adaptogens in Fatigue, and Molecular
Mechanisms Related to their Stress-Protective Activity
Pp. 198-219
Alexander Panossian and Georg Wikman
[Abstract] [Full
Text Article] [PMID:
19500070 PubMed - indexed for MEDLINE]
Is There a Place for Drug Combination Strategies Using Clinical
Pharmacology Attributes? – Review of Current Trends
in Research Pp. 220-228
Nuggehally R. Srinivas
[Abstract] [Full
Text Article] [PMID:
19500074 PubMed - indexed for MEDLINE]
Gender Differences in Aminoglycoside Induced Nephrotoxicity:
A Prospective, Hospital - Based Study Pp. 229-232
Waleed M. Sweileh
[Abstract] [Full
Text Article] [PMID:
19500072 PubMed - indexed for MEDLINE]
Identifying the Metabolic Syndrome in Obese Children and Adolescents:
Do Age and Definition Matter? Pp.
233-238
Mariska van Vliet, Inès A. von Rosenstiell, Roger K.
Schindhelm, Desiderius P.M. Brandjes, Jos H. Beijnen and
Michaela Diamant
[Abstract] [Full
Text Article] [PMID:
19500071 PubMed - indexed for MEDLINE]
Erratum Pp. 239
[Full
Text Article]
Abstracts
[Back to top] [Full
Text Article] [PMID:
19500068 PubMed - indexed for MEDLINE]
Methods of Fitting Straight Lines where Both Variables are
Subject to Measurement Error
Jonathan Gillard and Terence
Iles
In this paper errors in variables methods for fitting
straight lines to data are reviewed. In these methods the
x and y variables are both assumed to be subject to measurement
error and not, as in simple least squares linear regression,
just one of them. The methods are described in a unified context
using the statistical principle of the method of moments.
Guidance is given on the choice of an appropriate method of
estimating the slope and intercept of the fitted line. Formulas
for the approximate standard errors of the estimators are
provided in a technical appendix. A numerical example from
biochemical studies is included to illustrate the methodology.
[Back to top]
[Full
Text Article] [PMID:
19500073 PubMed - indexed for MEDLINE]
Vascular and Cellular Calcium in Normal and Hypertensive Pregnancy
Zuzana Adamova, Sifa Ozkan and Raouf
A. Khalil
Normal pregnancy is associated with significant hemodynamic
changes in the cardiovascular system in order to meet the
metabolic demands of mother and fetus. These changes include
increased cardiac output, decreased vascular resistance, and
vascular remodeling in the uterine and systemic circulation.
Preeclampsia (PE) is a major complication of pregnancy characterized
by proteinuria and hypertension. Several risk factors have
been implicated in the pathogenesis of PE including genetic
and dietary factors. Ca2+
is an essential dietary element and an important regulator
of many cellular processes including vascular function. The
importance of adequate dietary Ca2+
intake during pregnancy is supported by many studies. Pregnancy-associated
changes in Ca2+ metabolism
and plasma Ca2+ have been
observed. During pregnancy, changes in intracellular free
Ca2+ concentration ([Ca2+]i)
have been described in red blood cells, platelets and immune
cells. Also, during pregnancy, an increase in [Ca2+]i
in endothelial cells (EC) stimulates the production of vasodilator
substances such as nitric oxide and prostacyclin. Normal pregnancy
is also associated with decreased vascular smooth muscle (VSM)
[Ca2+]i
and possibly the Ca2+-sensitization
pathways of VSM contraction including protein kinase C, Rho-kinase,
and mitogen-activated protein kinase. Ca2+-dependent
matrix metalloproteinases could also promote extracellular
matrix degradation and vascular remodeling during pregnancy.
Disruption in the balance between dietary, plasma and vascular
cell Ca2+ may be responsible
for some of the manifestations of PE including procoagulation,
decreased vasodilation, and increased vasoconstriction and
vascular resistance. The potential benefits of Ca2+
supplements during pregnancy, and the use of modulators of
vascular Ca2+ to reduce the
manifestations of PE in susceptible women remain an important
area for experimental and clinical research.
[Back to top] [Full
Text Article] [PMID:
19500069 PubMed - indexed for MEDLINE]
Molecular Determinants of Fluoroquinolone Antibacterial Agents
Pharmacokinetics
Dominique Levêque and
François Jehl
This review presents the published data regarding the
molecular determinants (enzymes, transporters, orphan nuclear
receptors) of fluoroquinolones pharmacokinetics in humans.
The clinical impact of these determinants (drug disposition,
drug-drug interactions) is also discussed.
[Back to top] [Full
Text Article] [PMID:
19500070 PubMed - indexed for MEDLINE]
Evidence-Based Efficacy of Adaptogens in Fatigue, and Molecular
Mechanisms Related to their Stress-Protective Activity
Alexander Panossian and Georg Wikman
The aim of this review article is to assess the level
of scientific evidence presented by clinical trials of adaptogens
in fatigue, and to provide a rationale at the molecular level
for verified effects. Strong scientific evidence is available
for Rhodiola rosea SHR-5 extract, which improved
attention, cognitive function and mental performance in fatigue
and in chronic fatigue syndrome. Good scientific evidence
has been documented in trails in which Schisandra chinensis
and Eleutherococcus senticosus increased endurance
and mental performance in patients with mild fatigue and weakness.
Based on their efficacy in clinical studies, adaptogens can
be defined as a pharmacological pharmacotherapeutic instead
of pharmacological group of herbal preparations that increase
tolerance to mental exhaustion and enhance attention and mental
endurance in situations of decreased performance. The beneficial
stress-protective effect of adaptogens is related to regulation
of homeostasis via several mechanisms of action associated
with the hypothalamic-pituitary-adrenal axis and the control
of key mediators of stress response such as molecular chaperons
(e.g. Hsp70), stress-activated c-Jun N-terminal protein kinase
(JNK1), Forkhead Box O transcription factor DAF-16, cortisol
and nitric oxide (NO). The key point of action of phytoadaptogens
appears to be their up-regulating and stress-mimetic effects
on the "stress-sensor" protein Hsp70, which plays
an important role in cell survival and apoptosis. Hsp70 inhibits
the expression of NO synthase II gene and interacts with glucocorticoid
receptors directly and via the JNK pathway, thus
affecting the levels of circulating cortisol and NO. Prevention
of stress-induced increase in NO, and the associated decrease
in ATP production, results in increased performance and endurance.
Adaptogen-induced up-regulation of Hsp70 triggers stress-induced
JNK-1 and DAF-16-mediated pathways regulating the resistance
to stress and resulting in enhanced mental and physical performance
and, possibly, increased longevity.
[Back to top] [Full
Text Article] [PMID:
19500074 PubMed - indexed for MEDLINE]
Is There a Place for Drug Combination Strategies Using Clinical
Pharmacology Attributes? – Review of Current Trends
in Research
Nuggehally R. Srinivas
Drug discovery is the main flag ship of the pharmaceutical
industry in order to ensure that innovations constantly occur
in the identification and development of novel therapeutic
options for the management of diseases. Recently, research
trends that take advantage of the safety and efficacy of marketed
products by combining such products with other agents to influence
certain clinical pharmacology attribute(s) have emerged. The
focus of the review is to evaluate ongoing research trends
that have considered leveraging on certain clinical pharmacology
attributes in the areas of viral infection (HIV and influenza)
and oncology. Case studies discussed in this review include:
a) the use of probenecid to block the organic anion renal
transport of oseltamivir carboxylate (a key active metabolite
of oseltamivir phosphate) to reduce the oral dose of oseltamivir
phosphate; b) the use of rifampicin to induce the CYP2C19
enzyme and thereby, promote the formation of a potent active
metabolite M8 (nelfinavir hydroxyl-t-butylamide) and achieve
sustained blood levels to combat HIV infection along with
ritonavir; c) the use of CYP3A4 inhibitors such as ketoconazole,
cyclosporin A, ritonavir etc to overcome the extensive presystemic
metabolism of docetaxel and enhance the oral bioavailability
of docetaxel. Along with the case studies, several hurdles
for drug development such as dose selection, frequency of
dosing, and duration of the clinical studies, picking the
right surrogate(s) for efficacy, evaluation of drug-drug interaction
potential with other co-substrates have been discussed in
line with the current day requirements for a sound clinical
and regulatory strategy. In summary, based on the collated
information, a pragmatic approach would render feasibility
for a balanced therapy management using combined clinical
pharmacology attributes of drugs.
[Back to top] [Full
Text Article] [PMID:
19500072 PubMed - indexed for MEDLINE]
Gender Differences in Aminoglycoside Induced Nephrotoxicity:
A Prospective, Hospital - Based Study
Waleed M. Sweileh
Aim: Impact of gender on aminoglycoside induced nephrotoxicity
is still controversial and inconclusive. The objective of
this study was to investigate the nephrotoxic potential of
amikacin (AK) and gentamicin (GM) in male and female hospitalized
patients.
Methodology: A one-year, non-interventional prospective
study of patients administered either GM or AK. The study
was carried out at the internal medicine department of Al-Watani
governmental hospital. Nephrotoxicity was defined as a blood
creatinine (Cr) increase of ≥
0.5 mg/ dL from the basal (normal) Cr level. Data
were entered and analyzed using SPSS 16.
Results: A total of 94 patients were identified (GM,
n = 45 and AK, n = 49). Male and female patients on GM had
comparable characteristics except that males had significantly
higher number of co-existing chronic diseases. No gender differences
were observed in gentamicin induced nephrotoxicity (37% in
males versus 33.3% in females, P = 0.8). Male and
female patients on AK were also comparable in demographic
and clinical characteristics. However, significant differences
in gender susceptibility were observed with AK induced nephrotoxicity
(31.6% in females versus 6.7% in males, P = 0.043).
Pattern of serum creatinine changes in patients on GM were
comparable between males and females. However, in females
on AK, s.cr levels were rising sharply after the fourth day
compared with that in male patients on AK.
Conclusion: Gender differences in aminoglycoside
induced nephrotoxicty were seen with AK where females were
more vulnerable to nephrotoxicity. Such gender differences
did not exist with GM.
[Back to top] [Full
Text Article] [PMID:
19500071 PubMed - indexed for MEDLINE]
Identifying the Metabolic Syndrome in Obese Children and Adolescents:
Do Age and Definition Matter?
Mariska van Vliet, Inès A. von Rosenstiell, Roger K.
Schindhelm, Desiderius P.M. Brandjes, Jos H. Beijnen and
Michaela Diamant
Objectives: To assess the prevalence of the metabolic
syndrome (MetS) in overweight/obese children and adolescents
of an out-patient clinic, and to compare two definitions of
MetS in adolescents.
Methods: In total, 528 overweight/obese children
(3-16 years), of multi-ethnic origin, underwent an oral glucose
tolerance test, blood collections and anthropometric measurements.
In children <
10 years, MetS was assessed according to child-specific
cut-off values (MetS-child). In adolescents, MetS-child and
MetS-adolescent (the recommendation of the International Diabetes
Federation for adolescents) were compared.
Results: The prevalence of MetS-child within the
cohort (median age 11.3, range 3.1-16.4 years) was 18.6% (children
<10
years vs. adolescents: 14.1% vs. 20.7%,
P=0.073). Insulin resistance was present in 47.7%
(children <10
years vs. adoles-cents: 21.8% vs. 60.1%,
P<0.001).
MetS-child was highly prevalent, and not statistically significant
between age groups. In adolescents, the prevalence of MetS-adolescent
was higher than MetS-child (33.2% vs. 20.7%, P<0.001).
The agreement between the MetS definitions was moderate (κ=0.51),
with the agreement for the MetS-criteria for abnormal lipid
levels being substantial to very good (κ=0.71
to 0.80).
Conclusions: MetS-child was highly prevalent in overweight/obese
children and adolescents. A higher prevalence of MetS according
to adolescent- as compared to child-specific criteria was
found.
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