Pharmacokinetics of moricizine in young patients.

Moricizine is a novel phenothiazine antiarrhythmic agent that depresses the activity of ectopic foci, has a low incidence of adverse effects relative to other agents, and is useful in treating pediatric atrial ectopic tachycardia. A study was conducted to determine the pharmacokinetics of moricizine in children after oral administration. Moricizine was isolated from frozen serum obtained from four male patients (ages 7, 8, 9, and 18 years) receiving the drug for supraventricular tachycardia and analyzed by high-performance liquid chromatography with ultraviolet detection according to an established protocol. Peak serum levels were between 400 and 2000 ng/mL. Elimination of moricizine did not follow simple single-compartment pharmacokinetics. In three patients we observed an increase or slower decline in blood level occurring after 4 hours. Because of the paroxysmal nature of the tachycardias, decreases in patient heart rate could not be correlated with moricizine blood level. These results suggest that the pediatric pharmacokinetics of moricizine excretion are complex and may differ from those seen in adults.

The effects of vitamin C and urate on the oxidation kinetics of human low-density lipoprotein.

Oxidative modification of human low-density lipoprotein (LDL) is believed to play an important role in atherogenesis. Vitamin C (ascorbate) and urate are major water-soluble plasma antioxidants in humans. Urate levels (300-395 microM) in human serum are considerably higher than ascorbate levels (30-50 microM). In this study, we compared the ability of urate to protect human LDL from in vitro oxidation with that of ascorbate. LDL was subjected to in vitro oxidation at 30 degrees C with an O2 saturated solution (0.15 M NaCl/0.25 mM EDTA) and 15 mM of a thermally labile water soluble azo-initiator (ABAP or azobis-2-amidinopropane HCl). In parallel experiments, 50 microM ascorbate or 50 microM urate were present in the oxidation buffer. The consumption of alpha-tocopherol, gamma-tocopherol, urate or ascorbate and the formation of lipid hydroperoxides were measured as a function of time in the in vitro oxidation system. The rate of lipid hydroperoxide formation was found to be significantly increased after the LDL tocopherols (alpha-plus gamma-tocopherol) were totally consumed, i.e., after the lag phase. Urate (50 microM) was more effective than ascorbate (50 microM) in extending the lag phase. Moreover, urate was consumed more slowly than ascorbate under identical oxidation conditions. Urate was not, however, as effective as ascorbate in preventing the formation of lipid hydroperoxides before the lag phase. An empirical mathematical model was also developed to describe the oxidation kinetics of LDL alpha- and gamma-tocopherol in the presence or absence of urate or ascorbate.

Abnormal protein translocation as the elusive cause of cystic fibrosis: an hypothesis.

Despite the recent rapid advances in isolation of the abnormal gene responsible for cystic fibrosis, there remains the need to explain the mechanism by which a single gene mutation causes the widespread clinical effects seen in this disease. Careful review of the otherwise unexplained abnormalities of cystic fibrosis from the perspective of cell biology reveals the following common features: (1) all these abnormalities involve proteins which are either (A) inserted into cell membranes in the RER and arrested after partial translocation or (B) inserted into RER membranes and fully translocated to be compartmentalized away from the cytosol in secretory vacuoles, lysosomes or peroxisomes; (2) all the involved proteins have minor abnormalities in their physicochemical properties or activity functions; (3) none of the involved proteins are missing or totally deficient in function; (4) final compartmentalization of the involved proteins is unaffected. These observations have directed our attention to the process by which most proteins are inserted into and translocated across lipid bilayer membranes, namely the signal peptide mechanism. This mechanism, not previously examined in cystic fibrosis, is reviewed in detail. Of the major proteins controlling signal peptide translocation, deficiencies in the function of signal peptidase activity appear most capable of causing the effects seen in cystic fibrosis.