Metabolism of doxylamine succinate in Fischer 344 rats. Part II: Nonconjugated urinary and fecal metabolites

Elimination and metabolic profiles of doxylamine and its nonconjugated metabolites were determined after the oral administration of [14C]-doxylamine succinate (13.3 mg/kg and 133 mg/kg doses) to male and female Fischer 344 rats. Total urine and fecal recovery of the administered dose was greater than 90% regardless of sex or dose. The cumulative urinary and fecal elimination of these nonconjugated doxylamine metabolites at the 13.3 mg dose was 44.4 +/- 4.4% and 36.0 +/- 5.8% of the total recovered dose for male and female rats, respectively. The cumulative urinary and fecal elimination of the doxylamine nonconjugated metabolites at the 133 mg/kg dose was 38.7 +/- 2.7% and 41.4 +/- 1.0% of the total recovered dose for male and female rats, respectively. In order to determine the contribution of mammalian and bacterial enzymes in the overall metabolism and excretion patterns for doxylamine, two in vitro techniques were investigated. Incubation of [14C]-doxylamine succinate with human and rat intestinal microflora indicated that anaerobic bacteria were not capable of effecting the degradation of [14C]-doxylamine succinate. However, the incubation of [14C]-doxylamine succinate with isolated rat hepatocytes generated several metabolites similar to those observed in vivo. The nonconjugated doxylamine metabolites isolated and identified include: doxylamine N-oxide, desmethyldoxylamine, didesmethyldoxylamine and ring-hydroxylated products of doxylamine and desmethyldoxylamine. The studies demonstrate the role of hepatic metabolism in the elimination of doxylamine succinate in the rat.     

Diazepam-induced amnesia: a neuropharmacological model of an "organic amnestic syndrome"

Diazepam has well-known amnestic properties. These effects, however, are selective for certain psychobiologically distinct memory functions. In this study, incremental doses of diazepam administered to 10 normal volunteers selectively impaired anterograde episodic memory and attention while totally sparing access to information in long-term memory (semantic or knowledge memory). This pattern of disruption mimics that seen in patients with organic amnesias and is in sharp contrast to the pattern seen in patients with dementia. These findings provide a framework for defining specific psychobiological determinants of cognitive failure.     

Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line.

We selected two drug resistant variants of the MCF7 human breast cancer cell line by chronic in vitro exposure to doxorubicin (MCF7/D40 cell line) and mitoxantrone (MCF7/Mitox cell line), respectively. The cell lines are similar in growth characteristics including doubling time, DNA synthetic phase and cell size. Resistance to mitoxantrone conferred only partial resistance to doxorubicin; whereas resistance selected for doxorubicin appeared to confer complete resistance to mitoxantrone. Both agents selected for cross resistance to the Vinca alkaloids. MCF7/D40 cells display a classic-multi-drug resistance phenotype with expression of P-glycoprotein, decreased drug accumulation relative to the parental line and reversal of drug accumulation and drug resistance by verapamil. MCF7/Mitox cells likewise display resistance to multiple drugs, but in contrast to MCF7/D40 cells do not express P-glycoprotein by immunoblot or RNA blot analysis. Net drug accumulation in MCF7/Mitox cells was decreased relative to the parental cells but there was no selective modulation of drug accumulation or in vitro drug resistance by the addition of verapamil. Efflux of mitoxantrone was enhanced in both the MCF7/D40 and MCF7/Mitox cell lines relative to the MCF7/S cell line. We conclude that the two drug resistant cell lines have different mechanisms of decreased drug accumulation.     

Does magnesium sulfate alter the maternal cardiovascular response to vasopressor agents in gravid ewes?

Magnesium sulfate (MgSO4) attenuates the maternal compensatory response to hemorrhage in gravid ewes, perhaps by decreasing the response to endogenous vasopressors. The purpose of this study was to determine whether MgSO4 alters the cardiovascular response of gravid ewes to vasopressor agents. Sixteen gravid ewes underwent a series of experiments consisting of administration of two exogenous and two endogenous vasopressors, each with and without a concurrent MgSO4 infusion. Dose-response curves were constructed for phenylephrine (an alpha 1-adrenergic agonist), ST-91 (an alpha 2-adrenergic agonist), angiotensin II, and arginine vasopressin (AVP). MgSO4 significantly attenuated the increase in maternal mean arterial pressure and systemic vascular resistance and the decrease in cardiac output during ST-91 infusion but not during phenylephrine, angiotensin II, or AVP infusions. MgSO4 significantly attenuated the increase in uterine vascular resistance during phenylephrine, ST-91, and angiotensin II infusions and the decrease in uterine blood flow during phenylephrine and angiotensin II infusions. MgSO4 also appeared to attenuate the decrease in uterine blood flow during ST-91 infusion (P = 0.067). The present study suggests that MgSO4 antagonizes the effects of alpha 1-adrenergic agonists, alpha 2-adrenergic agonists, and angiotensin II on the uterine vasculature, thus providing a level of protection for the fetus in situations of maternal stress.     

Deep-freezing versus 4 degrees preservation of avascular osteocartilaginous shell allografts in rats

Osteocartilaginous allografts (distal femurs of rats) were stored at 4 degrees for six, 12, 24, and 48 hours and at -80 degrees for five days and then evaluated for viability of the bone and cartilage. Storage at 4 degrees for 12 or 24 hours had little effect on cartilage viability but decreased bone viability to 40% and 10% of controls, respectively. Storage at -80 degrees for five days resulted in nonviable bone in all cases but showed an either/or response of cartilage, with high viability in two cases and nonviability in the other eight cases. In a second set of experiments, femurs from rats were stored in situ at 4 degrees for 12 or 24 hours or were harvested and stored at -80 degrees for five days, after which they were transplanted into rats of a different strain. The antibody response to each set of femurs was measured at two, six, and 12 weeks after operation. The 4 degrees storage resulted in a moderately decreased immunogenicity, whereas the storage at -80 degrees resulted in significantly reduced immunogenicity.     

Measurement of oxygen uptake in the non-steady-state

The purpose of these experiments was to develop and validate an open-circuit technique for measurement of gas exchange during the transition from rest to constant load steady-state exercise. The design of the open-circuit system employed to measure gas exchange in these experiments used a mixing chamber to collect the subject's expired ventilation where fractions of O2 and CO2 were determined via electronic gas analyzers. A gasometer was used to measure inspired ventilation and the analog signals from the two gas analyzers and the gasometer were sent to a microcomputer for computation of VO2. In calculating VO2, the mixed expired gas concentrations were matched with ventilatory volume using a previously determined time delay. To determine the validity of the open-circuit system, four subjects performed a series of 16 rest-to-work transitions on a cycle ergometer. In eight of the experiments, serial measurements of VO2 were obtained every 20 s for 3 min using the open-circuit mixing chamber system while the additional eight experiments used the Douglas bag technique. No significant difference (p greater than 0.05) existed between VO2 values calculated by the two techniques. Mean differences in VO2 between the two techniques during the first three 20-s measurement periods were 6, 53, and 63 ml, respectively. Using the Douglas bag technique as the standard, this represents a relative measurement error of 0.1%, 4.5%, and 3.6%, respectively, at the above time intervals. These data demonstrate that an open-circuit system employing a mixing chamber and the appropriate time delay to match expired gas fractions and ventilation is a sensitive means of measurement of VO2 in the non-steady-state.