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AAPS PharmSci (2)
Bodor, Nicholas (1)
Browne, Clinton E. (1)
Buchwald, Peter (1)
Derendorf, Hartmut (1)
Farag, Hassan H. (1)
Huang, Fenglei (1)
Ji, Fubao (1)
Krishnaswami, Sriram (1)
Wu, Wnei-Mei (1)
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Receptor binding studies of soft anticholinergic agents
Browne, Clinton E.
Farag, Hassan H.
Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using 4 cloned human muscarinic receptor subtypes. The measured pKi values of the soft anticholinergic agents ranged from 6.5 to 9.5, with the majority being in the range of 7.5 to 8.5. Strong correlation was observed between the pKis determined here and the pA2 values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (r2) were 0.80, 0.73, 0.81, and 0.78 for pKi(m1), pKi(m2), pKi(m3), and pKi(m4), respectively. Quantitative structure-activity relationship (QSAR) studies were also performed, and good characterization could be obtained for the soft anticholinergics containing at least 1 tropine moiety in their structure. For these compounds, the potency as measured by the pKi values was found to be related to geometric, electronic, and lipophilicity descriptors. A linear regression equation using ovality (Oe), dipole moment (D), and a calculated log octanol-water partition coefficient (QLogP) gave reasonably good descriptions (r=0.88) for the pKi(m3) values.
drug design; soft drugs; receptor binding; metabolism; drug evaluation; muscarinic antagonists
An interactive algorithm for the assessment of cumulative cortisol suppression during inhaled corticosteroid therapy
The objective of the study was to develop an algorithm based on a pharmacokinetic-pharmacodynamic (PK/PD) modeling approach to quantify and predict cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. Two Excel spreadsheets, one for single dose and another for steady-state multiple doses of inhaled steroids, were developed for predicting CCS. Four of the commonly used inhaled steroids were chosen for the purposes of simulation: fluticasone propionate (EP), budesonide (BUD), flunisolide (FLU), and triamcinolone acetonide (TAA). Drug-specific PK and PD parameters were obtained from previous single- and multiple-dose studies. In cases in which multiple-dose data were not available, the single-dose data were extrapolated. The algorithm was designed to calculate CCS based on 5 input parameters: name of drug, dose, dosing interval, time(s) of dosing, and type of inhaler device. In addition, a generalized algorithm was set up to calculate CCS based on clearance, volume of distribution, absorption rate, protein binding, pulmonary deposition, oral bioavailability, and unbound EC50 of the corticosteroid of interest. The spreadsheet allowed predictions of CCS for single doses as well as steady-state conditions. A simple method has been developed that facilitates comparisons between various drugs and dosing regimens and has the potential to significantly reduce the number of comparative clinical trials to be performed for evaluating the short-term systemic activity of inhaled corticosteroids).
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