Journal of pharmaceutical sciences
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Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). ⋯ In the case of EM, the Emax model with an "effect compartment" could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation) induced by coadministration of DP and EM in rats.
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The signal flow diagram is a graphic method used to represent complex data that is found in the field of biology and hence the field of medicine. The signal flow diagram is analyzed against a table of data and a flow chart of data and evaluated on the clarity and simplicity of imparting this information. The data modeled is from previous clinical studies and nontraditional medicine from Africa, China, and South America. This report is a development from previous presentations of the signal flow diagram.1-4
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An aqueous formulations of propofol 1 can be prepared by solubilizing it in the presence of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD). This is potentially useful for parenteral administration of the drug. The aqueous solubility of 1 linearly increased as a function of HP-beta-CD concentration and showed features of an AL type diagram. ⋯ These studies revealed that the whole aromatic ring, as well as part of the isopropyl groups of the guest molecule, is located inside the HP-beta-CD cavity, while the hydroxy group is located at the rim of the wider cavity end. The geometrical features of the inclusion complex 1-HP-beta-CD are confirmed by 1D NOE difference spectra and molecular modeling experiments. The anesthetic activity in rat was investigated, and it was found that there are significant differences in induction time and sleeping time between 1 solubilized in the presence of HP-beta-CD and the formulation currently used (Diprivan), which is a 1% w/v oil/water emulsion.
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Propofol is a unique highly lipid-soluble anesthetic that is formulated in a fat emulsion (Diprivan) for intravenous (i.v.) use. It has the desirable properties of rapid onset and offset of effect following rapid i.v. administration and minimal accumulation on long-term administration. Based on physicochemical properties and preliminary brain solubility data, propofol should have an extended effect-site turnover and a resulting prolonged effect. ⋯ Like other general anesthetics, the concentration-EEG effect relationship of propofol is biphasic. At a propofol concentration of 0.6 (+/- 35%) microg/mL, the number of EEG waves/s was maximal at 175% of baseline awake state. Further increases in the concentration of propofol depressed EEG activity until complete suppression occurred at 7 (+/- 22%) microg/mL.