Accuracy and consistency of respiratory inductive plethysmography for overnight tidal volume measurement.

To validate the accuracy and consistency of respiratory inductive plethysmography (RIP) in measuring tidal volume after an overnight sleep, tidal volumes of 18 patients with suspected sleep-disordered breathing and 8 normal volunteers were measured simultaneously with RIP (VTRIP) and with an ultrasonic airflow meter (VTUFM) before and after an unstrained overnight sleep on supine and lateral decubitus. The bias of the VTRIP was expressed as (VTRIP-VTUFM)/ VTUFM.100%, limits of agreement between VTRIP and VTUFM was measured by averaged bias +/- 2 s. Results showed that in normal subjects, the bias of RIP before and after overnight sleep was precise and consistent in both supine (0.7% and -1.6%) and lateral decubitus (3.7% and -0.56%). In these patients, the bias of RIP before and after sleep in supine also remained small (1.9% and 1.7%), but it became larger in lateral decubitus (24.5% and 20.4%) and 11.5% exceeded the limits of agreement observed in the evening. The patients' body mass indices (BMI) were higher than those of normal subjects (median 34.2 vs. 27.8 kg/m2). Pooled data showed that the bias of VTRIP in the morning on lateral decubitus but not on supine was correlated to BMI (Spearman R = 0.32, n = 52, P = 0.02). Thus, we were led to conclude that the accuracy of VTRIP overnight was precise and consistent in normal subjects, but the deviation of VTRIP measured on lateral decubitus in patients especially in those with excessive obesity was greater, thus, the method should not be used for quantitative determination.

The Dose--Plasma Concentration Relationship of Tranexamic Acid during Surgery.

Plasma specimens from 59 patients undergoing cardiac operations utilizing extracorporeal circulation underwent determination of tranexamic acid concentration to explore the effect of dose administered to plasma concentration. Each patient received one of five doses of tranexamic acid in double-blinded, randomized fashion, ranging from 2.5 to 40 mg kg(minus sign1) for the loading dose and from 0.25 to 4.0 mg kg(minus sign1) h(minus sign1) for a subsequent infusion. Plasma collections occurred after completion of the loading dose, during extracorporeal circulation, before protamine infusion, after protamine infusion, and following arrival in the intensive care unit. The samples were analyzed using high-performance liquid chromatography. The logarithm of plasma concentration varied linearly with the logarithm of dose administered at each sampling time (r(2) values 0.82, 0.95, 0.89, 0.74 and 0.93 for the respective collection times). Plasma concentrations did not decrease during extracorporeal circulation despite absence of tranexamic acid in the pump prime. However, concentrations varied inexplicably following protamine administration and decreased in the intensive care unit.

Determination of cocaine usage in pregnant women by a urinary EMIT drug screen and GC-MS analyses.

In mothers who had no prenatal care and in their newborns, the presence of cocaine and benzoylecgonine (BE) was determined in urine, hair, and meconium. Samples of urine and hair were obtained from pregnant women who entered the hospital for delivery. Cocaine usage was assessed by a urinary enzyme-multiplied immunoassay technique (EMIT) and by gas chromatography-mass spectrometry (GC-MS). GC-MS was used to detect the presence of cocaine and BE in maternal urine and hair and in meconium and hair obtained from their newborns. In this study of 40 women, the EMIT assay for urinary BE identified 17 (42.5%) of the women as having used cocaine. Of these 17 women, all of their newborns were exposed to cocaine during gestation, based on the analysis of neonatal hair and meconium for cocaine or BE. From the maternal samples that were assayed for cocaine and BE by GC-MS, it appears that hair analysis identified the most cocaine users (70%) of the 40 women who participated in the study. When GC-MS was used to analyze the various samples from mothers and their newborns, 80% of the neonates showed exposure to cocaine. This study shows that women with no prenatal care who have a positive urinary drug screen by EMIT for BE have exposed their newborns to cocaine. The data from pregnant women with a negative drug screen for BE show that 52.2% of their newborns had prior fetal exposure to cocaine.

The presence of cocaine and benzoylecgonine in rat cerebrospinal fluid after the intravenous administration of cocaine.

Cocaine hydrochloride, in doses of 0.5, 1.0, 2.0 and 4.0 mg/kg, iv, was administered to male Sprague-Dawley rats. Cerebrospinal fluid (CSF) was collected from the cisterna magna over a 20 min period and blood samples were obtained at 20 min after cocaine administration. In addition, blood samples for the 1 mg/kg dose of cocaine were collected at 2, 10, 20 and 30 min following drug injection. Gas chromatography/mass spectrometry was used for the analysis of cocaine and its metabolites in plasma and CSF. The disappearance of cocaine (1 mg/kg) from the plasma exhibited first order kinetics with a half-life of 18.11 +/- 3.22 min. Cocaine and benzoylecgonine were found in CSF and the concentrations of cocaine and benzoylecgonine increased in CSF as the doses of cocaine were increased. CSF flow rates were not altered by the iv administration of cocaine or benzoylecgonine. The CSF-to-plasma ratios for cocaine were quite similar to each other over the dosage range of cocaine that was administered; however, the CSF-to-plasma ratios for benzoylecgonine decreased as the concentrations of benzoylecgonine increased in plasma and CSF. When benzoylecgonine (2 mg/kg, iv) was given, the compound was detected in CSF indicating that benzoylecgonine can enter into the central nervous system from the peripheral blood. This investigation shows that cocaine and benzoylecgonine can be assayed in CSF and that the plasma levels of these compounds correlate with their concentrations in CSF.

The accumulation and disappearance of cocaine and benzoylecgonine in rat hair following prolonged administration of cocaine.

Hair samples were obtained at various time periods from male Sprague-Dawley rats following the injection of cocaine hydrochloride in doses of 5, 10, and 20 mg/kg, ip, for 28 days. Hair samples were also taken continually after the dosing was stopped until the presence of cocaine and benzoylecgonine were no longer detected in hair. Cocaine and benzoylecgonine in hair and plasma were analyzed by gas chromatography/mass spectrometry. Both cocaine and benzoylecgonine were found in hair samples 4 days after the initiation of cocaine administration. When cocaine dosing was stopped after 28 days, approximately 25 to 30 days were required for cocaine and benzoylecgonine to disappear from rat hair in the group of animals that received the highest dose of cocaine. The disappearance of cocaine and benzoylecgonine followed first-order kinetics. The mean rate constant and mean half-life for cocaine disappearance from hair were 0.212 +/- 0.005 day-1 and 3.31 +/- 0.09 days, respectively, and the mean rate constant and mean half-life for benzoylecgonine disappearance from hair were 0.098 +/- 0.006 day-1 and 6.90 +/- 0.28 days, respectively. The mean plasma concentrations of cocaine on Day 25 for the 5, 10, and 20 mg/kg doses of cocaine were 508 +/- 42, 852 +/- 95, and 2027 +/- 75 ng/mL, respectively, and the mean plasma benzoylecgonine levels for the 5, 10, and 20 mg/kg doses of cocaine were 49.9 +/- 7.0, 103.3 +/- 9.3, and 191.0 +/- 16.0 ng/mL, respectively. There was a positive correlation between the doses of cocaine hydrochloride administered and the plasma levels of both cocaine and benzoylecgonine. This study showed that cocaine and benzoylecgonine can be measured in rat hair following the administration of cocaine and that it was possible to correlate the concentrations of cocaine and benzoylecgonine found in hair with the doses of cocaine that were administered.

Effect of heterocyclic amines and beef extract on chromosome aberrations and sister chromatid exchanges in cultured human lymphocytes.

Two of the major bacterial mutagens formed in heated meat products, 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline or the basic fraction of beef extract induced a low frequency of sister chromatid exchanges in human lymphocyte cultures in the presence of metabolic activation. Structural chromosome aberrations were not induced at comparable high concentrations in human lymphocytes with intact repair system, suggesting that repair or induction of point mutations are involved in the DNA-damaging effect of heterocyclic amines rather than structural chromosome aberrations. Accordingly it may be concluded that mammalian cells with both intact repair and enzyme systems are more relevant than bacterial systems for evaluating the carcinogenic potential of heterocyclic amines.

The effect of acute hepatic injury on the disposition of vitamin A in the rat.

The distribution of vitamin A was measured in various body fluids and tissues in rats with carbon tetrachloride induced acute liver injury compared to vehicle treated controls. All rats received 25,000u of retinol palmitate intraperitoneally 24 hr prior to study and 50,000u on the day of the study. Rats with liver injury had significant elevations of unesterified retinol in plasma and saliva, and significant elevations of retinol palmitate in plasma, urine, and kidney. Also, liver disease caused a significant decrease in the liver concentration of retinol palmitate, and a significant decrease in the bile and kidney levels of unesterified retinol. These results suggest that redistribution of vitamin A from liver to other areas occurs after acute liver injury in rats. Also, increased levels of vitamin A in urine, saliva or plasma may be a noninvasive marker for liver injury in man after vitamin A challenge.

The effect of delta-9-tetrahydrocannabinol on rat cerebrospinal fluid.

The effect of delta-9-tetrahydrocannabinol (THC) on cerebrospinal fluid (CSF) flow in rats was studied. The ventricular system of rats anesthetized with ketamine sulfate was cannulated via cisternal puncture, and CSF production was recorded. When administered in doses of 25 mg/kg to 45 mg/kg intraperitoneally, THC caused inhibition of CSF flow; in larger doses a smaller response was noted. In response to THC, CSF flow showed an initial drop, a return toward baseline, and a secondary decrease. It is postulated that this biphasic effect is due to a combination of THC's sympathomimetic effects on the CNS plus the local action that this drug has on choroidal synaptosomal neurotransmitters.

Instant and brewed coffees in the in vitro human lymphocyte mutagenicity test.

Incubation of instant and 'home brew' coffees (caffeinated and decaffeinated) and of coffee aroma with cultured human lymphocytes in the presence and absence of S-9 increased the number of total aberrations. However, the increase was smaller in the presence of S-9 than in its absence. Pure caffeine tested with or without S-9 at doses equivalent to levels in caffeine-containing coffee did not give statistically significant increases of any type of aberration when compared with controls. In all in vitro test systems used to date, coffee and coffee aroma or their reactive compounds were metabolically deactivated in the presence of S-9. This could explain the negative results obtained in mutagenicity assays in vivo.

Investigation of coffee in sister chromatid exchange and micronucleus tests in vivo.

Administration of a single oral dose of instant coffee to Chinese hamsters at levels up to 2.5 g/kg body weight did not increase the frequency of sister chromatid exchanges. Furthermore, five consecutive daily oral doses of instant coffee given to Swiss OF-1 mice up to 3 g/kg/day did not induce increases in micronuclei above spontaneous levels. Similarly, no effect was observed in the micronucleus test after mice received two oral doses of coffee aroma of up to 50 ml/kg.

5-Fluorouracil concentrations in rat plasma, parotid saliva, and bile and protein binding in rat plasma.

The pharmacokinetics of 5-fluorouracil were studied over a 60-min period in rats that received 12.5, 25.0, and 50.0 mg/kg iv. The plasma concentration-time relationship and the detectability in bile and parotid saliva (a route of elimination heretofore given little or no attention) were examined. Protein binding of 5-fluorouracil at concentrations chosen to approximate those found in plasma was determined by equilibrium dialysis. Bile-plasma and parotid saliva-plasma concentration ratios were calculated. 5-Fluorouracil concentrations were quantitated by high-performance liquid chromatography. Plasma concentrations at all doses studied appeared to rapidly decline. The half-life, however, at the 50.0-mg/kg dose (27 min) was significantly longer (p less than 0.025) than the corresponding half-life at the 25.0-mg/kg dose (22 min). This may be attributed to an easily saturable hepatic degradation. Although an observed decline in bile-plasma and parotid saliva-plasma concentration ratios at higher doses may represent saturation of these excretary routes, the small amounts of 5-fluorouracil detected in bile and parotid saliva probably contribute negligibly to the elimination of the total drug equivalents administered. Parotid saliva-plasma concentration ratios were not useful in predicting plasma protein binding as determined by equilibrium dialysis. Excretion of intravenously administered 5-fluorouracil in saliva, however, exposes the upper GI tract to this agent and may play a part in causing stomatitis in patients receiving the drug by this route.

Doxorubicin and 5-fluorouracil plasma concentrations and detectability in parotid saliva.

Doxorubicin and 5-fluorouracil pharmacokinetics were studied in 19 volunteers with various advanced neoplastic diseases who received 50-90 mg doxorubicin or 600-1000 mg 5-fluorouracil intravenously, followed by plasma and parotid saliva collection over a 75 min period. The extent to which these chemotherapeutic agents are bound to plasma proteins, at concentrations chosen to approximate plasma concentrations, was measured by equilibrium dialysis. Both agents were quantitated by high-performance liquid chromatography. As reported previously, a wide range of plasma levels were found among patients receiving similar doses of either doxorubicin or 5-fluorouracil. It appears that in addition to being quickly cleared from the plasma both chemotherapeutic agents are excreted in detectable amounts in parotid saliva, a route of elimination heretofore given little or no attention. Excretion in the saliva exposes the mucosa of the upper gastrointestinal tract to 5-fluorouracil after intravenous administration and may play a part in causing stomatitis in patients receiving it by this route. Since there are huge interindividual and pronounced intraindividual differences in S/P ratios mostly not systematically related to the drugs' concentration in plasma, the concentration in parotid saliva was not useful in predicting the level of free doxorubicin or 5-fluorouracil in plasma.

Investigation of digoxin, quinidine, and disopyramide interactions in rats utilizing parotid saliva, blood, and other tissues.

Blood, parotid saliva, heart, liver, and kidney concentrations of digoxin and quinidine were determined in rats chronically treated with digoxin and in nontreated (control) rats after the administration of quinidine (20 mg/kg ip) and disopyramide (10 mg/kg ip). The results indicated that digoxin concentrations increased significantly and proportionally in parotid saliva and plasma after quinidine, but did not increase after disopyramide. With the exception of the liver, which showed an increase in digoxin concentrations, tissue concentrations of digoxin did not differ from control animals. In rats pretreated chronically with digoxin, quinidine concentrations in plasma, parotid saliva, or heart tissue did not differ significantly from control animals, but were significantly lower than controls in liver and kidney tissues. The results presented here lend additional support to the hypothesis that the increase in digoxin plasma concentration following quinidine administration is primarily due to interference with renal excretion and displacement of digoxin by quinidine binding sites. Furthermore, its was demonstrated that disopyramide has little or no effect on plasma digoxin levels in rats.

Nonmutagenicity in vivo of the food flavonol quercetin.

Mice given quercetin per os at concentrations that were about 10(3) times greater than the estimated average human intake of total flavonols were tested for mutagenicity with 2 complementary in vivo mutagenicity/carcinogenicity screening tests--the micronucleus test and the host-mediated assay employing the Ames Salmonella tester strain TA 98 as indicator organism. No mutagenic effect was detected with either test.

Human whole blood and parotid saliva concentrations of oral and intramuscular promethazine.

Ten healthy male subjects received 25 mg of promethazine intramuscularly, followed within 3 weeks by oral administration of 25 mg. Whole blood and parotid saliva were collected over a 12-hr period after drug administration. Promethazine was quantitated by high-performance liquid chromatography. After intramuscular administration, the promethazine concentrations were 3.0-22.4 ng/ml in blood and 0.9-2.8 ng/ml in parotid saliva. After oral administration, the promethazine concentrations were 1.4-5.5 ng/ml in blood and 0.2-0.8 ng/ml in parotid saliva. The peak blood promethazine concentration after the intramuscular dose was four times higher than that following the oral dose, which indicates that promethazine possesses an extensive first-pass effect. The mean parotid saliva to whole blood ratio (S/B) was calculated to be 0.24 after the intramuscular route an 0.20 after the oral route over the 12-hr period. The calculated percentage of free drug in the blood was 20-24% of the whole blood concentration determined from the S/B ratio.