Kinetics of the oral antiarrhythmic lidocaine congener, tocainide.

Tocainide, a primary amine analogue of lidocaine, is effective against some experimental and clinical arrhythmias. Its pharmacokinetic behavior was studied in 6 healthy male subjects. Peak blood levels (CB max) and area under the blood concentration-time curve (AUC) were linearly related to dose with slopes of 0.0067 mcg/ml and 6 min mcg/ml per milligram of dose, respectively. Renal clearance of tocainide averaged 59 ml/min when urinary pH was uncontrolled or acidified, while it was reduced to 13 ml/min during intense sodium bicarbonate loading. Blood levels following intravenous infusion were well described by a 2-compartment open model with a volume of the central compartment of 0.92 L/kg. The t 1/2 beta was 11 hr and total body clearance was 166 ml/min. Loo-Riegelman analysis of the absorption rate did not allow unequivocal assignment of an "order" to the absorption process. Bioavailability approached 100%. Administration of drug 5 min after a test meal suppressed CB max 40% but minimally affected AUC. Approximately 50% of the drug was found to be plasma protein bound at clinically effective concentrations.

Localization of NCAM on NCAM-B-expressing cells with inhibited migration in collagen.

The extracellular matrix is a key element in neuronal development and tumour invasion, providing a substratum which sustains the adhesion and migration of cells. In order to study interactions between the neural cell adhesion molecule (NCAM) and collagen, we transfected mouse L cells with cDNA encoding the human transmembrane NCAM isoform of 140 kDa (NCAM-B). An L-cell/collagen type I system was used to study the influence of NCAM expression on in vitro invasion. We here report that migration of NCAM-expressing cells in collagen was inhibited compared to that of NCAM-negative cells transfected with the empty vector. Immunofluorescence confocal laser scanning microscopy (CLSM) and immunogold electron microscopy using anti-human NCAM antibodies demonstrated a heterogeneous distribution of NCAM on the plasma membrane of transfected L cells grown on collagen. NCAM was preferentially located at the surface of broad cytoplasmic protrusions and slender extensions, some of which were facing the collagen. This was in contrast to the homogeneous surface distribution of NCAM on cells grown on plastic. These data suggest that NCAM and collagen type I interact, and that this might lead to the migration inhibition of NCAM-expressing cells.

Birth weight-specific rates as a bias in the effects of smoking and other perinatal hazards.

Perinatal mortality was examined in the Ontario Perinatal Mortality Study (1960 to 1961) subset of 31,788 births and perinatal deaths among English-speaking Canadian-born women. Overall perinatal mortality rose from 22.0 to 28.2 per 1000 if the mother smoked, a 27% increase. When perinatal mortality was computed in birth weight-specific groups (less than 2500 g and 2500 g or more), the rates for smokers were lower than those for nonsmokers in both subgroups. These results occurred because maternal smoking had an even stronger effect on birth weight than on perinatal mortality, increasing the proportion of births of infants weighing less than 2500 g by 106%. These data confirm the hazard of maternal smoking for the unborn, and pinpoint how some studies that have seemingly inconsistent results have erred in analysis.

Absorption kinetics of procainamide in humans.

Plasma procainamide concentrations following the administration of 500 mg of procainamide hydrochloride via intravenous infusion, conventional capsules, and sustained-release tablets were compared in 11 healthy male volunteers. Two-compartment open modeling of the plasma levels from the intravenous infusion experiments yielded mean Kel, k12, and k21 values of 0.0162, 0.0542, and 0.0233 min-1, respectively. The bioavailability of the oral preparations (versus intravenous) averaged 83% for the capsule and 79% for the sustained-release tablet. Calculations using a previously reported method suggested that absorption was a first-order process with mean ka's of 0.0336 and 0.0039 min-1 for the capsule and sustained-release tablet, respectively. The sustained-release formulation exhibited delayed release and adequate bioavailability.

Assay of tocainide in blood by high-pressure liquid chromatography.

A sensitive, specific, high-pressure liquid chromatographic assay for the determination of tocainide in whole blood is described. The residue from a methylene chloride extract of alkalinized blood was resolvated in a mobile phase of methanol--water (47:53) containing 1% acetic acid and 6.16 mM 1-octanesulfonic acid, adjusted to pH 4.0. Chromatography was performed on a reversed-phase column with detection at 254 or 225 nm. The limits of accurate measurement were 2 microgram/ml for a 1-ml blood sample monitored at 254 nm and 0.2 microgram/ml for a 2-ml sample monitored at 225 nm. The assay was tested on samples from emergency protocol patients and was also found suitable for single-dose pharmacokinetic studies.

Tocainide conjugation in humans: novel biotransformation pathway for a primary amine.

The metabolism of tocainide, an experimental antiarrhythmic drug, was studied in humans. Urinary excretion of unchanged drug was 28-55% in 24 hr after oral dosing. Urine hydrolysis with hydrochloric acid or beta-glucuronidase increased tocainide recovery to 55-79%. Saccharo-1,4-lactone inhibited the beta-glucuronidase-mediated tocainide recovery increase. Adjustment of urine to pH 13 produced a compound identified as 3-(2,6-xylyl)-5-methylhydantoin. Evidence suggests that it was derived from the same metabolite that formed the additional tocainide after acid or beta-glucuronidase treatment. Tocainide carbamoyl O-beta-D-glucuronide is the structure proposed for the metabolite. The suggested pathway for its formation involves the addition of carbon dioxide to the amino nitrogen of tocainide followed by uridine diphosphate-glucuronic acid conjugation.

Development of a sample equilibration system for the TEOM continuous PM monitor.

In recent years, scientific discussion has included the influence of thermodynamic conditions (e.g., temperature, relative humidity, and filter face velocity) on PM retention efficiency of filter-based samplers and monitors. Method-associated thermodynamic conditions can, in some instances, dramatically influence the presence of particle-bound water and other light-molecular-weight chemical components such as particulate nitrates and certain organic compounds. The measurement of fine particle mass presents a new challenge for all PM measurement methods, since a relatively greater fraction of the mass is semi-volatile. The tapered element oscillating microbalance (TEOM) continuous PM monitor is a U.S. Environmental Protection Agency (EPA) PM10 equivalent method (EQPM-1090079). Several hundred of these monitors are deployed throughout the United States. The TEOM monitor has the unique characteristic of providing direct PM mass measurement without the calibration uncertainty inherent in mass surrogate methods. In addition, it provides high-precision, near-real-time continuous data automatically. Much attention has been given to semi-volatile species retention of the TEOM method.

The effects of maternal smoking in pregnancy.

PIP: A review of the extensive literature on the effects of smoking in pregnancy reveals that smoking causes significant reductions in birthweight, increases in premature births, increases in fetal and neonatal loss, and possible long-term disabilities in height, reading ability, and social adjustment. The association for the physical effects is dose-related. The effect of maternal smoking on perinatal mortality is positive and proportional to the level of smoking but varies according to other characteristics of the pregnancy. Studies indicate that this increased perinatal mortality is not due to aspects of the fetus but to smoking-related pregnancy complications. The immediate cause of most smoking-related fetal deaths is probably anoxia; the cause of neonatal mortality results from the increased risk of early delivery to smokers. It is recommended that the risks associated with smoking in pregnancy be widely publicized. Patients, especially those with high risk factors, should be advised against continued smoking during pregnancy.^ieng

How does maternal smoking affect birth weight and maternal weight gain? Evidence from the Ontario Perinatal Mortality Study.

A large data set was used to examine the possibility that maternal smoking during pregnancy causes low birth weights by reducing maternal appetite, eating, and weight gain. As always, birth weight distributions shifted downward as maternal smoking level increased. Maternal weight gain distributions, on the other hand, were the same for smokers and nonsmokers. Within each level of maternal weight gain, from less than five pounds to over 40 pounds, the more the mothers smoked the greater was the percentage of neonates weighing less than 2,500 grams. This evidence supports a direct effect of maternal smoking on birth weight, possibly due to the hypoxic effects of carbon monoxide, rather than one mediated through eating. Efforts to prevent or reduce smoking should have greater benefits for mother and child than would efforts to increase food intake among pregnant women who smoke.

Maternal smoking, pregnancy complications, and perinatal mortality.

Analysis of data from the Ontario Perinatal Mortality Study has shown that perinatal mortality increases directly with the level of maternal smoking during pregnancy. Increases in smoking level are associated with increases in the frequency of early fetal deaths and of neonatal deaths due to premature delivery. These deaths in turn are associated with smoking-related increases in the incidence of bleeding during pregnancy, abruptio placentae, placenta previa, and premature and prolonged rupture of the membranes.

Long-term effects of prenatal x-ray of human females. I. Reproductive experience.

A cohort of singleton black human females exposed to diagnostic x-ray in utero and controls matched by parity, hospital of birth and birthdate have have been followed to ages 25-30 years in Baltimore, Maryland. The search for possible effects of prenatal irradiation has focused on health, growth, development and reproductive experience of exposed and control women. This paper reports findings related to reproductive experience. From an original data set of 1458 matched exposed-control pairs of women, questionnaire responses were received from 1109 exposed and 1124 control women including 852 each from pairs in which both the exposed and control woman responded. After careful search for alternative explanations of the findings, the authors concluded that females exposed in utero to low doses of x-ray (probably 1-5 rads) had significant increases in their rates of early onset of menses, births at age 15 years or less, numbers of living children, stillbirths, and sterilizing operations by their mid-twenties. These findings are compatible with animal studies in which prenatal irradiation kills many oocytes, but accelerates the development of remaining cells to stages more closely correlated with fertility. Although these animals subsequently became sterile, this cannot be tested in the current study because significantly more of the irradiated women have had surgical sterilizations.

Long-term effects of prenatal x-ray of human females. II. Growth and development.

Experimental studies and studies of survivors of in-utero exposure to atomic bomb blasts have shown significant stunting of growth and mental retardation following these exposures. Central nervous system damage following very low doses of x-ray at around the time of birth has also been observed in experimental animals. This long term follow-up studies of 1458 human females exposed in utero to diagnostic x-rays and of 1458 matched unexposed controls studied in Baltimore, Maryland, included measurements of height, weight and school achievement. Women who had been exposed to x-rays in utero were significantly shorter in their mid-twenties than were their matched, unexposed controls, even after adjustment for other social and economic factors. However, additional follow-up revealed that mothers of exposed women were also shorter than the control mothers. Short stature appeared to be a selective factor for x-ray during pregnancy (mostly pelvimetry, 1947-1952). Mothers' and daughters' heights were similarly correctly among exposed and control mother-daughter pairs, suggesting that the height differences between exposed daughters and their controls were due to these selective factor rather than to any direct effect of radiation on growth. Exposed women reported poorer school achievement than control women. However, except for a higher proportion of exposed women leaving school because of pregnancy, these measurements were no longer significantly different when rates were simultaneously adjusted for socioeconomic differences between exposed and control women.

Long-term effects of prenatal x-ray of human females. III. Mortality and morbidity.

Experimental studies and long-term studies of humans exposed to ionizing radiation in utero and after birth show that these exposures increase the risk of cancer in childhood and in later life. A possible life-shortening effect has also been reported. This study followed to their mid-twenties 1458 women exposed in utero to diagnostic x-rays and 1458 matched, unexposed controls in Baltimore, Maryland, and obtained responses from over 1100 women in each group. Information about general health and specific diseases was obtained from questionnaires. Deaths were ascertained through family members and death certificates. Mortality rates were slightly higher among exposed than control women, and did not differ by gestational age at the time of exposure. Exposed women reported poor general health significantly more often than controls. Specific diseases occurred similarly in the two groups, although exposed women reported more epilepsy or fits, more ovarian tumors, and more high blood pressure. The strong correlation between weight and high blood pressure and the heavier weights of exposed women seemed to account for this difference. In summary, these matched exposed and control women, followed to their mid-twenties, experienced similar rates of morbidity and mortality. Radiation-induced cancers and life-shortening effects, if any, might not become evident until older ages.

The interrelationship of maternal smoking and increased perinatal mortality with other risk factors. Further analysis of the Ontario Perinatal Mortality Study, 1960-1961.

Increased perinatal mortality among smokers' babies has been observed in many but not in all studies, with a statistically significant difference in some. This paper explores the hypothesis that maternal smoking may interact with other risk factors, so that a dose-related increase in perinatal mortality may be enhance or masked depending upon the presence or absence of these factors. Data are from the Ontario Perinatal Mortality Study of all single b irths in 10 teaching hospitals in Ontario in 1960-1961 a total of 51,490 births, including 701 fetal deaths and 655 early neonatal deaths. Perinatal mortality increased significantly with smoking, and was also affected by such factors as maternal age, parity, hospital status, previous pregnancy history, hemoglobin level, and others. Smoking frequencies also varied by many of these characteristics. Perinatal mortality was therefore analyzed by the amount smoked during pregnancy within subgroups of these antecedent risk factors. When smoking and other risk factors were cross-tabulated among 52 data subgroups, only the light smokers (less than 1 pack per day) under age 20 had lower perinatal mortality rates than their nonsmoking counterparts. In almost all subgroups the mortality increase with smoking was dose-related, but not in a simple, linear way. The increased risk of perinatal mortality associated with light smoking among young, low-parity, non-anemic mothers was less than 10 percent. At the other extreme, mothers of high parity, public hospital status, with previous low birthweight births, or with hemoglobin less than 11 gm had increased perinatal mortality risks of 70-100 percent when they were heavy smokers. The failure of some studies to find a significant increase in perinatal mortality with maternal smoking may be due to selection of study populations from the end of the spectrum where light smoking is associated with only a slight increase in perinatal risk. Other studies may select higher risk populations, where the influence of smoking on mortality is stronger. Depending on the magnitude of the difference, the amount smoked, and the size of the study, results might or might not be statistically significant.

Perinatal events associated with maternal smoking during pregnancy.

To identify components of smoking-related increased perinatal mortality, detailed analyses of data from the Ontario Perinatal Mortality Study (50,000 births, 1,300 deaths, 1960-1961) measured the relationship of maternal smoking to birth weight, gestation, placental complications, and perinatal mortality. Cross-tabulations with other factors and multiple adjustment showed increases with amount smoked of birth weights less than 2500 gm, gestations less than 38 weeks, placenta previa, abruptio placentae, and perinatal mortality. These significant, smoking-related increases were independent of mother's height, weight, hospital status, age-parity group, birthplace, previous pregnancy history, weight gain, time of registration, and sex of child. Maternal smoking had the strongest effect on birthweight in the 8 factor regression, and birth less than 2500 gm increased directly with smoking level from 20% to 340% in 37 data subgroups. Births less than 38 weeks increased 20% and 50% and perinatal mortality increased 20% and 35% for less than 1 pack and 1 + pack smokers, respectively, adjusted for 7 other factors. Placental complications increased consistently with smoking level in all of 37 subgroups except for primiparous less than 1 pack smokers. Adjusted rates increased 25% and 92% for placenta previa, 23% and 86% for abruptions among smokers of less than 1 pack and 1 + packs, respectively. These complications carry high perinatal mortality risk, and account for one-third to one-half of the perinatal deaths attributable to maternal smoking.

PIP: To identify components of smoking-related increased perinatal mortality, detailed analyses of data from the Ontario Perinatal Mortality Study (50,000 births, 1300 deaths, 1960-1961) measured the relationship of maternal smoking to birth weight, gestation, placental complications, and perinatal mortality. Cross-tabulations with other factors and multiple adjustment showed increases with amount smoked of birth weights 2500 gm, gestations 38 weeks, placenta previa, abruptio placentae, and perinatal mortality. These significant, smoking-related increases were independent of mother's height, weight, hospital status, age-parity group, birthplace, previous pregnancy history, weight gain, time of registration, and sex of child. Maternal smoking had the strongest effect on birthweight in the 8 factor regression, and birth 2500 gm increased directly with smoking level from 20 to 340% in 37 data subgroups. Births 38 weeks increased 20 and 50% and perinatal mortality increased 20 and 35% for 1 pack and 1 + pack smokers, respectively, adjusted for 7 other factors. Placental complications increased consistently with smoking level in all of 37 subgroups except for primiparous 1 pack smokers. Adjusted rates increased 25 and 92% for placenta previa, 23 and 86% for abruptions among smokers of 1 pack and 1 + packs, respectively. These complications carry high perinatal mortality risk, and account for 1/3 to 1/2 of the perinatal deaths attributable to maternal smoking.

Respiratory effects on household exposures to tobacco smoke and gas cooking.

The records of 1,724 residents of Washington County, Maryland, who had participated in 2 studies of respiratory symptoms and ventilatory function were analyzed to evaluate the effects of exposures at home to tobacco smoke generated by other members of their households and to fumes from the use of gas as a cooking fuel. Currently smoking subjects showed the highest frequency of respiratory symptoms and impaired ventilatory function; former smokers showed a lower frequency of these findings; and persons who had never smoked had the lowest prevalence of abnormal respiratory findings. The presence of a smoker in the household other than the subject was not associated with the frequency of respiratory symptoms, and only suggestively associated with evidence of impaired ventilatory function. The use of gas for cooking was related to an increased frequency of respiratory symptoms and impaired ventilatory function among men, being most marked among men who had never smoked. There was not evidence that cooking with gas was harmful to women.

Hypothesis: the role of the lung in stomach carcinogenesis.

It is proposed that pulmonary defense mechanisms play an important role in stomach carcinogenesis. Inhaled carcinogens reach the stomach by normal pulmonary clearance and account for the association of stomach cancer with dusty occupations. We postulate that although familial and other factors determine the susceptibility to endothelial cancer (both stomach and lung), those persons whose pulmonary clearance mechanisms are more susceptible to impairment by cigarette smoke retain carcinogens and other particulate matter in the lungs and are at increased risk for lung cancer. Those whose clearance mechanisms are not impaired continue to clear these particles from their lungs, unconsciously swallow the cleared particles, receive more of these substances in the stomach, and are at increased risk for stomach cancer. This accounts for: first, the very striking dose-response relationship between the amount of smoking and lung cancer mortality and the relatively weak relationship between smoking and stomach cancer, and second, for observed reciprocal relationships in time trends of mortality between stomach cancer and lung cancer.