A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.
Long posterior fusion constructs in the lumbar spine cause substantial posteriorly directed loading of the supporting pedicle screws, particularly during patient bending activities. Although there are numerous documented accounts of clinical failure at the pedicle screw-bone interface [1,2], the in situ pull-out strength of pedicle screws in long surgical constructs has not been characterized. Previous biomechanical studies have quantified pedicle screw pull-out force in cadaveric models through destructive testing or in nondestructive cases, through the use of custom-machined pedicle screws instrumented with strain gages [3–6]. However, these techniques involve altering screw geometry and may fail to properly simulate in vivo mechanical loading conditions. The goal of this study was to develop and validate a sensor system for measuring pedicle screw pull-out forces in long posterior constructs in situ during multi-segmental cadaveric testing.
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