Biomedical Engineering Reference
In-Depth Information
4
Conclusions
Many TA are well characterized with respect to their binding properties towards
diverse receptors including MR, 5-HT
3
R, a 1-AR and a7-nAChR. Most frequently
TA were identified as competitive acetylcholine antagonists on MR thus exhibit-
ing therapeutic benefit to induce mydriasis, spasmolysis of the respiratory system,
GIT and overactive bladder, anaesthesia and analgesia (atropine, benztropine,
N
-butyl-scopolamine, cimetropium, homatropine, ipratropium, methyl scopol-
amine, scopolamine,
S
-hyoscyamine, tiotropium, and trospium). In contrast, cer-
tain TA such as satropane show contrary effects such as smooth muscle contraction
thus being considered for glaucoma treatment. TA that exhibit strong binding to
5-HT
3
R allow their use as antiemetic (bemesetron, granisetron, scopolamine, tro-
pisetron). In addition, affinity of some TA towards a1-AR provides activity to
treat circulatory disorders and septic shock by improvement of blood flow (aniso-
damine, anisodine).
Whereas most TA discussed in this chapter are well-established drugs either
worldwide or in specific countries, a huge number of synthetic derivatives might
be designed to improve efficacy, selectivity and reduce potential adverse side
effects.
Such novel APIs are to be characterized with respect to, e.g. biotransformation,
distribution, PK behaviour and other pharmacological properties. Elaboration of
these data will require sensitive, selective and robust analytical methods most pre-
sumably based on LC-MS techniques. With respect to optimized economic feasibil-
ity procedures should be preferred that allow both (a) reduced consumption of
organic solvents for sample preparation and chromatographic separation and (b)
short run-time analysis.
These requirements may be best fulfilled when using automated approaches for
sample preparation or implementing in-line sample processing that minimize the
extent of manual working steps. Chromatography could be optimized by the use of
sub-2 mm particles for improved resolution and solvent reduction. Comparable
results might be expected when applying fused core particles (2.7 mm overall diam-
eter) providing a solid, non-porous core (1.7 mm diameter) that is coated with a thin
porous shell (0.5 mm thickness). The shell contains the functionalized chromato-
graphic phase, e.g. C18, interacting with the analytes. Therefore, only the thin layer
is accessible for diffusion thus improving mass transfer kinetics, reducing axial dis-
persion of solute and minimizing peak width.
With respect to MS equipment significant performance improvements are prom-
ised by the use of most modern mass analysers (e.g. Orbitrap, FT-ICR, TOF-TOF)
that provide highest resolution and mass accuracy important for, e.g. in-depth eluci-
dation of biotransformation.
Nevertheless, despite the use of high-end LC and MS systems validation of any
method should be carried out carefully to characterize validity and reliability.
Special attention should be paid to matrix effects occurring during ionization of
analytes that might deteriorate analytical performance.
