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Current Pharmaceutical
Analysis
ISSN: 1573-4129
Current Pharmaceutical
Analysis
Volume 2, Number 3, August 2006
Contents
Therapeutic Drug Monitoring: A Tool to Individualize
Highly Active Antiretroviral Therapy in HIV Infected Patients
Pp. 205-217
Peter Langmann, Michael Zilly, Ralf Winzer and Hartwig Klinker
[Abstract]
Molecular Imprinted Polymers: Useful Tools for
Pharmaceutical Analysis Pp. 219-247
Claudio Baggiani, Laura Anfossi and Cristina Giovannoli
[Abstract]
Quality Control of Recombinant Pollen Allergens
Pp. 249-257
Roland Suck and Oliver Cromwell
[Abstract]
Drug Acyl Glucuronides: Reactivity and Analytical
Implication Pp. 259-277
Xiao-Xia Yang, Ze-Ping Hu, Urs Alex Boelsterli and Shu-Feng
Zhou
[Abstract]
Ion-Pair Reversed-Phase Denaturing HPLC-Based Biotechnology
as a Tool for Genetic Analysis Pp.
279-287
Maria Visalli, Isabella Venza, Mario Venza, Teresa Catalano
and Diana Teti
[Abstract]
Advances of Liquid Chromatographic Determination
of Fumonisins; Potential Mycotoxins for Humans Pp.
289-297
Masayo Kushiro, Kenji Tanaka, Shigeru Miyazaki and Tadahiro
Nagata
[Abstract]
Electrospray Ionisation - Mass Spectrometry (ESI-MS)
and Liquid Chromatography -Electrospray Ionisation - Mass
Spectrometry (LC-ESI-MS) of Selected Pharmaceuticals
Pp. 299-311
W.F. Smyth
[Abstract]
Degradation Behavior of Selected Pharmaceuticals
and Their Main Metabolites in Model Systems for Slow Sand
Filtration Pp. 313-322
Mahmoud Bataineh, Jürgen Nolte, Birgit Kuhlmann,
Ninette Zullei Seibert,Markus Borges, and Manfred Grote
[Abstract]
Abstracts
[Back to top]
Therapeutic Drug Monitoring: A Tool to Individualize
Highly Active Antiretroviral Therapy in HIV Infected Patients
Peter Langmann, Michael Zilly, Ralf Winzer and Hartwig Klinker
In HIV-infection, therapeutic drug monitoring (TDM) has been
proposed to optimize highly active antiretroviral therapy
(HAART) response. Pharmacokinetics of protease inhibitors
(PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI)
efavirenz and nevirapine have been proved suitable for monitoring
their plasma drug levels. In contrast, nucleoside reverse
transcriptase inhibitors (NRTI) contain lack of a certain
correlation between plasma levels and drug efficacy. Currently,
TDM under HAART is limited by some uncertainty which pharmacokinetic
predictor to prefer and on which drug concentration or range
to rely on. In a therapy naive patient trial (ATHENA) on indinavir
or nelfinavir based drug regimens, the study arm with use
of TDM resulted in prevention of virological failure or treatment
discontinuation due to drug toxicity. Current data ascribed
increasing importance to TDM in ritonavir boosted PI combinations
especially for lopinavir, atazanavir and fosamprenavir. Besides,
further applications are proposed in selected patients groups
(i.e. children, pregnancy, renal or hepatic dysfunction, weight
loss) to confirm adequate drug concentrations and manage drug-drug-
interactions. PI double-boosting in salvage regimens in patients
with multiple NRTI associated mutations should also require
TDM for handling dose adjustments, moreover, treatment experienced
patients might benefit from TDM in combination with viral
resistance testing. Limitations to the application of TDM
are considered as non standardized procedures or techniques
permitted to correlate pharmacological and virological data
therefore, an approach towards standardization is needed.
So far the inhibitory quotient (IQ) (necessitating phenotypical
resistance testing) or the genotypic inhibitory quotient (GIQ)
(referring to the number of viral mutations using a genotypic
resistance test), could become increasingly important in this
context. In assessing adherence, TDM allows to confirm the
correct medication intake, but only the last few doses taken
by a patient will be reflected. Without TDM, numerous interactions
by co-administered drugs (antibiotics, antacid drugs, hypnotics,
herbals, life-style drugs) turn out to possibly lead to obscure
interpretations and individual medical care remains elusive.
Currently, the interpretation of PI and NNRTI drug levels
is based on increasing experience using TDM. Even though TDM
in HAART is not the gold standard of care, yet, it provides
security in guiding patients on an individual therapy and
might be linked with pharmacogenomics in resource-rich countries.
[Back to top]
Molecular Imprinted Polymers: Useful Tools for
Pharmaceutical Analysis
Claudio Baggiani, Laura Anfossi and Cristina Giovannoli
Molecular imprinted polymers are man-made materials with predetermined
selectivity towards one or more analytes. They have been used
as selective stationary phases in several analytical separative
techniques. This review discusses the possible uses of imprinted
polymers, with a particular emphasis on their use as high
pressure and electrochromatographic stationary phases for
resolution of optical enantiomers, materials for fast screening
of libraries and selective solid-phase extraction for sample
clean-up and preconcentration.
[Back to top]
Quality Control of Recombinant Pollen Allergens
Roland Suck and Oliver Cromwell
Allergen-specific immunotherapy (SIT) is an effective
form of treatment for IgE-mediated type I allergy and represents
the only curative approach. Presently SIT is performed with
complex natural extracts that contain allergens (representing
active pharmaceuticals ingredients, APIs) together with non-allergenic
proteins and other macromolecules. These extracts are difficult
to standardize and it is not possible to define each component
quantitatively. In order to overcome such difficulties in
standardization and batch-to-batch consistency, highly purified
recombinant allergens (r-allergens) and hypoallergenic variants
may be considered as novel candidates for the production of
high quality therapeutic preparations offering safer and more
effective SIT.
The availability of detailed information on the characteristics
of r-allergens makes it possible to apply a variety of methods
in order to ensure purity, identity, quantity, safety and
potency compared to allergen extracts. Besides determination
of potential process-related contaminants such as endotoxin
and residual host-cell-protein a central consideration focuses
on the investigation of the folding status, as pathologic
IgE-binding is highly dependent on the conformation of the
molecules. The primary structure on the other hand determines
the therapeutic potential through the specific T cell epitopes
and the ability to induce a curative reorientation of the
T-cell response. Suitable methods for evaluation of the relevant
properties include immunologic methods such as ELISA and Western
blots together with robust chromatographic and electrophoretic
techniques. Promising results from early clinical studies
suggest that the use of r-allergens for SIT will become a
reality and therefore it is appropriate to consider how all
aspects of the quality of these proteins might be evaluated.
[Back to top]
Drug Acyl Glucuronides: Reactivity and Analytical
Implication
Xiao-Xia Yang, Ze-Ping Hu, Urs Alex Boelsterli and Shu-Feng
Zhou
There is increasing in vitro and in vivo
evidence indicating that acyl glucuronides of various drugs
are chemically reactive and potentially cause organ toxicity.
Such conjugates are chemically unstable, undergoing hydrolysis
and pH-dependent intramolecular migration to generate isomers
and covalent binding with various tissue proteins to result
in drug-protein adducts. This review highlights the reactivity
of drug acyl glucuronides and commonly used analytical techniques
for these metabolites and resultant drug-protein adducts used
in preclinical and clinical studies. The stability of acyl
glucuronides is dependent on many factors including pH, temperature,
nature of the aglycon, and the presence of plasma or albumin.
Drug acyl glucuronides may cause toxicity either through changes
in the functional properties of the modified proteins, through
initiation of antigen-mediated immune responses, or unknown
mechanisms. The conjugates and sometimes the drug-protein
adducts can achieve appreciable blood concentrations following
drug administration. With careful sample handling procedures
(e.g. quick cooling and acidification) during preclinical
and clinical studies, drug acyl glucuronides in biological
matrixes can be reliably identified and quantitated using
appropriate analytical methods such as HPLC, LC-MS and NMR
techniques. The drug-protein adducts can also be identified
and determined using these highly sensitive chromatographic
techniques after proper sample processing. In addition, their
protein adducts with plasma or cellular proteins can be determined
after electrophoretic separation, followed by blotting. ELISA
techniques have been used to assess the presence of antibodies
against acyl glucuronide-protein adducts in vivo.
Further studies are needed to explore the clinical and toxicological
implications of acyl glucuronides of various drugs and to
establish the relationships between the toxicity of drugs
and their acyl glucuronide levels by close monitoring using
above analytical techniques.
[Back to top]
Ion-Pair Reversed-Phase Denaturing
HPLC-Based Biotechnology as a Tool for Genetic
Analysis
Maria Visalli, Isabella Venza, Mario Venza, Teresa Catalano
and Diana Teti
DHPLC (denaturing high-performance liquid chromatography)
has established itself as one of the most powerful tools for
DNA variation screening and allele discrimination for the
characteristics of sensitivity, accuracy and efficiency that
allow a rapid detection of SNPs, insertions and deletions.
Moreover, it has the advantages of full-automation and cost
effectiveness.
Aside from its well-known application in identifying mutations
in human diseases, it has been also implemented in the quantitative
measurement of gene expression and the analysis of single
nucleotide extension products.
In this paper, we aimed at summarizing the general properties
and the main applications of DHPLC in the biomedical field
as well as comparing this newly developed biotechnology with
other conventional pre-screening methods for mutation scanning,
such as single strand conformational polymorphisms (SSCP),
conformation sensitive gel electrophoresis (CSGE) and two
dimensional gene scanning (TDGS).
[Back to top]
Advances of Liquid Chromatographic Determination
of Fumonisins; Potential Mycotoxins for Humans
Masayo Kushiro, Kenji Tanaka, Shigeru Miyazaki and Tadahiro
Nagata
Fumonisins, first identified in 1988, are naturally-occurring
mycotoxins mainly produced by Fusarium verticillioides
and F. proliferatum, food-borne fungi widely distributed
in crops, and occur as one of the most common contaminants
of corn and corn-based foods and feeds.
The most abundant fumonisin, fumonisin B1 (FB1),
is associated with a range of toxicological effects in animals
including equine leukoencephalomalacia, porcine pulmonary
edema, and rodent carcinogenicity. In humans, FB1
has been associated with high rates of esophageal cancer and
the International Agency for Research on Cancer evaluated
the FB1 derived from F. verticililoides
as Group 2B, i.e. a possible human carcinogen. Furthermore,
FB1 has been found to be a potential cause of human
neural tube defects. Fumonisins bear a remarkable structural
similarity to sphingosine and their mode of toxic action is
in part elucidated in that they may inhibit ceramide synthase,
causing accumulation of bioactive intermediates of sphingolipid
metabolism.
In spite of the need for efficient analysis, the quantification
of fumonisins is a difficult task, since they do not bear
suitable chromophores nor fluorophores for detection. Practical
fluorometric-based high-performance liquid chromatography
analysis methods for derivatized fumonisins have been developed
since 1990 and a method using o-phthalaldehyde as
a fluorescent reagent has been validated. Recently, mass spectrometry
analysis has been used to identify fumonisins as liquid chromatography-mass
spectrometry interfaces became more widely available. This
appears to be the superior method to perform quantitative
and qualitative analysis without the need of derivatization
procedures. Very recently, the application of tandem mass
spectrometry for confirmation and quantification of mycotoxins
including fumonisins has been reported. This paper reviews
those liquid chromatographic methods developed for this group
of mycotoxins.
[Back to top]
Electrospray Ionisation - Mass Spectrometry (ESI-MS)
and Liquid Chromatography -Electrospray Ionisation - Mass
Spectrometry (LC-ESI-MS) of Selected Pharmaceuticals
W.F. Smyth
This review surveys recent publications on the Electrospray
Ionisation - Mass Spectrometry (ESI-MS) of drugs of small
molecular mass taken from selected drug classes using the
Web of Knowledge database. The structural classes are antibiotics/antibacterials,
steroids, cannabinols, antidiabetics, immunosuppressants,
antitumour drugs, antiretroviral drugs, nonsteroidal antiinflammatories,
mucolytic drugs, anticoagulants, cyclooxygenase inhibitors,
stimulants, noradrenergic agents, anti-TB drugs and erectile
dysfunction agents. Fragmentation information that these drugs
exhibit in-source and in ion-trap, triple quadrupole and time-of
flight mass spectrometers is also provided. An appraisal of
applications for the period 2004-2005, again taken from the
Web of Knowledge database, of the technique liquid chromatography
- electrospray ionization - mass spectrometry (LC-ESI-MS)
to the detection and determination of these drugs, primarily
in biomatrices, is then made. Information on such aspects
as sample concentration, LC separation conditions, recoveries
from biological media and limits of detection (LODs) are provided.
[Back to top]
Degradation Behavior of Selected Pharmaceuticals
and Their Main Metabolites in Model Systems for Slow Sand
Filtration
Mahmoud Bataineh, Jürgen Nolte, Birgit Kuhlmann,
Ninette Zullei Seibert,Markus Borges, and Manfred Grote
The scope of this study was to investigate the fate and behavior
of selected pharmaceuticals and main metabolites under defined
conditions in model systems simulating slow sand filtration.
For this purpose, analytical procedures were developed for
the simultaneous identification and quantification of carbamazepine
(CBZ), diclofenac (DCF), ibuprofen (IBU) and
sulfamethoxazole (SFM). The following main metabolites
were synthesized for method development: N-1-glucuronide-sulfamethoxazole
(Glucu-SFM), N-4-acetyl-sulfamethoxazole (Ac-SFM) and
2-hydroxyibuprofen (OH-IBU). The procedures
comprised solid phase extraction (SPE) for enrichment using
polymeric material (Oasis HLB) and determination of the analytes
with both GC/MS and LC/ESI-MS. For GC/MS, an additional derivatization
step was necessary. Best results were obtained with the application
of diazomethane as derivatizing agent. As a consequence, the
determination of DCF, IBU and OH-IBU was preferably carried
out by GC/MS, whereas SFM, Ac-SFM and Glucu-SFM were determined
by LC/ESI-MS. CBZ could be sufficiently analyzed by both techniques,
however, GC/MS is preferred because of much lower interferences
by sample matrix. LC/ESI-MS allowed the measurement of the
active drugs and their metabolites with quantification limits
down to 10 ng/L in the MS/MS mode while GC/MS permitted the
quantification in the same range or lower for some analytes,
except SFM and its metabolites. The developed method was applied
to real surface water samples from the river Ruhr, Germany.
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