Warfarin use in hemodialysis patients: what is the risk?

BACKGROUND: There is a paucity of data concerning the risks associated with warfarin in hemodialysis (HD) patients. We compared major bleeding episodes in this group with HD patients not receiving warfarin and with a cohort of non-HD patients receiving warfarin. METHODS: A retrospective review of 141 HD patients on warfarin (HDW), 704 HD patients not on warfarin (HDNW) and 3,266 non-dialysis warfarin patients (NDW) was performed. Hospital admissions for hemorrhagic events and ischemic strokes were examined as was hospital length of stay and blood product use. INR variability was also assessed. RESULTS: The incidence rates for major hemorrhage per 100 patient years was 10.8 in the HDW group as compared to 8.0 in the HDNW (p = 0.593) and 2.1 in the NDW (p < 0.001) groups. Mean units of red blood cell transfusions required was higher in patients on dialysis with no significant difference between HDW and HDNW groups. The risk of ischemic stroke per 100 patient years was 1.7 in the HDW group as compared to 0.7 in the HDNW groups (p = 0.636) and 0.4 in the NDW (p = 0.003). The HDW group had higher inter-measurement INR variability compared to the NDW group (p = 0.034). In patients with atrial fibrillation, HDW group had a higher incidence of ischemic stroke than the NDW group (2.2 versus 0.4 events per 100 patient years; p = 0.024). CONCLUSIONS: This study confirms the higher bleeding risk associated with HD/ESRD but suggests that warfarin use in these patients may not add significantly to this risk. We also demonstrated high rates of ischemic stroke in HD patients despite warfarin use. SUMMARY: Our study compares the frequency of major hemorrhage and secondarily, ischemic stroke in HD patients receiving or not receiving warfarin, with non-HD patients receiving warfarin. The major finding was that frequency of hemorrhage was higher in HD patients receiving warfarin than in non-HD patients receiving warfarin, but not different in HD patients with or without warfarin. A secondary finding was that INR variability was significantly higher in HD patients than non-HD patients on warfarin.

Increased serotonin receptor density and platelet GPIIb/IIIa activation among smokers.

This study sought to determine whether depressive symptoms and/or platelet serotonin receptor (5HT2A) density are associated with increased platelet activation (PA) found among smokers. Flow cytometric detection of PA was used to study 36 smokers and 16 nonsmokers, aged 18 to 48 years. Subjects were tested at baseline and after either smoking 2 cigarettes (smokers) or a similar resting interval (nonsmokers). Assessment of PA included both platelet secretion and fibrinogen receptor (GPIIb/IIIa) binding. Platelet 5HT2A receptor binding and saturation were tested using [3H]LSD, and depressive symptoms were measured using the Beck Depression Inventory. Platelet 5HT2A receptor density was increased among smokers versus nonsmokers (82.7+/-67.7 versus 40.0+/-20.2 fmol/mg protein; P<0.005), and there was a dose-dependent relationship between receptor density and packs/d among smokers. Baseline wound-induced GPIIb/IIIa binding at 1 minute and GPIIb/IIIa binding in response to collagen stimulation in vitro was increased among smokers (P<0.05); there were no changes in PA among smokers after smoking, and platelet secretion was not elevated among smokers. Depressive symptoms were associated with 5HT2A receptor density among nonsmokers (P<0.005), but no such relationship was evident among smokers; PA was unrelated to 5HT2A receptor density in either group. The findings indicate that smoking is associated with increased platelet serotonin receptor density and with increased GPIIb/IIIa receptor binding, although these 2 factors are not related to each other or to depressive symptoms among smokers. Serotonergic dysfunction may be an important factor in the development of cardiovascular disease among smokers.

Effects of stress on circulating nicotine and cotinine levels and in vitro nicotine metabolism in the rat.

The effects of physical and psychological stress on circulating nicotine levels and conversion of nicotine to cotinine were examined in the rat. Animals received one of three dosages of nicotine (0, 6, and 12 mg/kg) via miniosmotic pumps. On day 14 of drug infusion, animals from each drug condition were randomly assigned to one of three stress conditions (noise, rubber ligature, or no stress). After 2.5 h of stress exposure, animals were killed and plasma nicotine and cotinine were measured in vivo and hepatic conversion of nicotine to cotinine was determined in vitro. Stress lowered blood nicotine levels. However, this difference was statistically significant only among animals receiving 12 mg/kg per day nicotine. In contrast, stress had no consistent effect on either measure of conversion of nicotine to cotinine in rats. Taken together, these results suggest that stress lowers circulating nicotine levels. However, the mechanism by which this occurs remains unclear.

Ten-year trends in cigarette smoking among young adults, 1986-1996: the CARDIA study. Coronary Artery Risk Development In Young Adults.

PURPOSE: To calculate ten-year smoking trends in a longitudinal cohort of young adults, and to characterize trends by race, sex, education, and birth cohort. METHODS: Data on cigarette smoking have been collected for ten years (1986-1996) from 5115 black and white men and women, aged 18-30 years, participating in the Coronary Artery Risk Development In Young Adults (CARDIA) study. Regression analysis adjusting for intra-person correlation over time and weighting for factors affecting follow-up was used to estimate change in smoking rates. RESULTS: Overall, smoking rates declined in white women (-0.50%/year, p < 0.001) and white men (-0.24%/year, p = 0.03). Rates remained stable in black women and increased in black men (0.37%/year, p = 0.01). Declining rates were generally observed in white women of all educational levels and birth cohorts and in several subgroups of white men. Increasing rates among black men could be attributed primarily to increasing rates in the youngest birth cohort. Among black men and women, prevalence of smoking in 1986 was considerably lower in the youngest birth cohort compared to the oldest; however, the increasing rates of change in smoking rates observed among the youngest birth cohorts (and decreasing rates in the oldest) lessened the disparity in prevalence rates across birth cohorts by 1996. Smoking initiation rates were highest among black men; cessation rates were highest among white women. CONCLUSIONS: These findings confirm that declines in smoking prevalence are not occurring across all groups, and reveal populations in special need of targeted interventions, particularly young black men.

Acute administration of phenylpropanolamine fails to affect resting energy expenditure in men of normal weight.

Studies have consistently found that dieters using over-the-counter weight control products containing phenylpropanolamine (PPA) are more successful at losing weight than those who do not. To explore the possibility that drug-induced metabolic changes contribute to weight loss associated with this compound, this study investigated the effects of PPA on resting metabolic rate in 20 healthy men of normal weight between the ages of 18 and 29. After the arrival of the subjects to the laboratory, blood pressure was taken and resting energy expenditure (REE) and respiratory quotient (RQ) were assessed for 20 minutes (Baseline) via indirect calorimetry. Half of the subjects were then given 75 mg of immediate-release PPA (administered orally via a gelatin capsule), while the other half received placebo. Immediately after drug administration, metabolic rate was measured for an additional 95 minutes (During Drug). After this assessment, blood pressure was again measured. Although significant increases in both systolic and diastolic blood pressure were observed after PPA administration, the drug had no effect on REE or RQ. These results, consistent with that previously reported in mildly overweight women, further establish that it is unlikely that drug-induced metabolic changes contribute to PPA-induced weight loss in humans.

Are weight concerns predictive of smoking cessation? A prospective analysis.

Participants in an 8-session, community based smoking cessation intervention rated whether they would stay quit if they experienced weight gain. The majority reported that they would not relapse to smoking, even after a 20-lb, (9.07-kg) weight gain. Those who were weight concerned were more likely to be female, to weight less and be normal or underweight, and to report chronic dieting. This group was also significantly less likely to be abstinent posttreatment, and at the 1-, 6- and 12-month follow-ups. Individuals presenting for formal smoking cessation interventions may be less weight concerned than the general population of smokers. However, weight-concerned smokers who do present for treatment are less likely to quit smoking. Implications for recruitment and intervention are discussed.

How much weight gain occurs following smoking cessation? A comparison of weight gain using both continuous and point prevalence abstinence.

Estimates of postcessation weight gain vary widely. This study determined the magnitude of weight gain in a cohort using both point prevalence and continuous abstinence criteria for cessation. Participants were 196 volunteers who participated in a smoking cessation program and who either continuously smoked (n = 118), were continuously abstinent (n = 51), or who were point prevalent abstinent (n = 27) (i.e., quit at the 1-year follow-up visit but not at others). Continuously abstinent participants gained over 13 lbs. (5.90 kg) at 1 year, significantly more than continuously smoking (M = 2.4 lb.) and point prevalent abstinent participants (M = 6.7 lbs., or 3.04 kg). Individual growth curve analysis confirmed that weight gain and the rate of weight gain (pounds per month) were greater among continuously smoking participants and that these effects were independent of gender, baseline weight, smoking and dieting history, age, and education. Results suggest that studies using point prevalence abstinence to estimate postcessation weight gain may be underestimating postcessation weight gain.

Smoking, nicotine dependence, and depressive symptoms in the CARDIA Study. Effects of educational status.

The present study was designed to determine whether depressive symptoms are independently associated with smoking and nicotine dependence among cigarette smokers, using 1990-1991 data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. A total of 3,933 participants (788 black men, 1,090 black women, 974 white men, and 1,081 white women) aged 23-35 years were included. Analyses were stratified by race and sex. Depressive symptoms were measured by means of the Center for Epidemiologic Studies Depression (CES-D) Scale. Nicotine dependence was defined as smoking one's first cigarette of the day within 30 minutes of awakening. Analysis of covariance was used to control for potential covariates (age, body mass index, alcohol consumption, and education). In unadjusted comparisons, smokers had more depressive symptoms than never smokers in all groups except white men; this relation showed little change after adjustment for age, body mass index, and alcohol consumption. However, after adjustment for education in addition to the above variables, these differences became attenuated and were significant only among white women (adjusted CES-D score difference = 1.9, p < 0.02). When analyses were further stratified by nicotine dependence, dependent smokers had higher CES-D scores than never smokers in all groups. The differences again became attenuated when education was added to the model, and were significant only among black women (adjusted CES-D score difference = 2.3, p < 0.01). These results indicate that although smoking in general and nicotine-dependent smoking in particular are related to symptoms of depression, controlling for educational level attenuates these relations.

Changes in food consumption and body weight associated with smoking cessation across menstrual cycle phase.

Forty women smokers were randomly assigned to smoking cessation for a 10-day period of time, either during the follicular or the luteal phase of their menstrual cycle. Measurements of dietary intake and body weight were collected during the same phase the previous (smoking as usual) month and during the cessation phase. Physical activity was controlled across the 2 months. Comparisons between the smoking and cessation months indicated that both groups increased their dietary intake during the cessation month, but no interaction occurred between phase and month. That is, women in both groups increased dietary intake to the same degree. All energy nutrients tested (fat, complex carbohydrates, and sugar) increased significantly from baseline to cessation. Conversely, body weight increased by 1.8 kg (4 lb) in the Luteal group, while weight remained stable (0.1 kg change) in the Follicular group.

The relationship between a history of depression and adherence to a multicomponent smoking-cessation program.

The purpose of this study was to determine whether a history of depression in female smokers (age 18-65) who did not self-report any current depression was associated with adherence to a multisession, multicomponent smoking-cessation program. Participants in a 13-week cognitive-behavioral group program plus random assignment to nicotine gum, appetite suppressant gum, or placebo chewing gum were grouped by depressive-history and compared on attendance, average expired carbon monoxide after planned cessation, and number of pieces of gum chewed. No significant differences between the depressive history (yes/no) subgroups were found on any of the three measures of adherence. The power to detect a significant difference (alpha = 0.05) was calculated to be 0.89. Group cognitive-behavioral treatment appears to be the basis of an effective smoking-cessation program for women with a history of depression who are not currently depressed.

Effects of chronic phenylpropanolamine infusion and termination on body weight, food consumption and water consumption in rats.

The present study determined the effect of chronic PPA infusion and withdrawal on weight regulation. Male Sprague-Dawley rats received PPA (0, 90 or 180 mg/kg) via miniosmotic pumps for 2 weeks. Body weight and food and water consumption were measured daily before, during, and for 2 weeks after PPA infusion. Additionally, body weight was measured once 6 weeks after the last day of drug administration. PPA infusion produced dose-dependent reductions in body weight and food consumption throughout drug administration. During the first week of PPA termination, food consumption returned to control levels; however, body weights of drug-treated animals remained below those of controls throughout the 6-week post-drug period. PPA depressed water intake during the first week of drug administration, but tolerance to this effect developed by the second week of administration. These results suggest chronic PPA infusion produces persistent appetite suppression and weight loss and that discontinuation of PPA does not result in hyperphagia or rapid weight gain. These findings may have clinical significance for the many individuals who wish to lose weight but have difficulty reducing intake without pharmacologic assistance.

Effects of nicotine cycling on weight loss and regain in male rats.

Over successive periods of weight loss and regain caused by deprivation and refeeding, weight loss becomes slower during deprivation and weight is regained quicker during refeeding. One period of nicotine administration and termination results in changes in intake and weight gain comparable to that caused by one period of food deprivation and refeeding. However, no study has examined the effect of multiple periods of nicotine administration and cessation on weight loss and regain. The present study examined the effect of repeated cycles of nicotine administration and cessation on growth rate. Thirty-two male Sprague-Dawley rats underwent three nicotine administration cycles. Cycles consisted of 2 weeks of nicotine or saline followed by 2 weeks of no drug. Nicotine administration decreased growth and food consumption, and cessation resulted in a resumption of normal growth and intake. However, changes in food consumption and body weight were similar across cycles. Thus, although nicotine administration and cessation produced reliable changes in food consumption and body weight similar to those caused by diet cycling, there were no comparable cumulative effects of nicotine cycling on growth rate.

Effects of phenylpropanolamine on regulatory and nonregulatory ingestion in adult rats.

This experiment examined the effects of phenylpropanolamine (0.0, 5.0, 10.0, 20.0 mg/kg PPA) on regulatory (RG) and nonregulatory (NRG) eating and drinking in rats using a within-subjects design. Administration of PPA produced dose-dependent reductions in eating in animals deprived to 80-85% of baseline weight, and reduced drinking after 23.5-h of water deprivation. Nonregulatory eating, elicited by tail pinch in nondeprived animals, was similarly inhibited. Nonregulatory drinking was elicited in the schedule-induced polydipsia (SIP) paradigm. Water consumption, locomotion, licking, lick efficiency (licks/ml water), and entries into the food magazine were simultaneously measured. At the lowest dose, only locomotion was significantly reduced. At 10.0 mg/kg, lick efficiency and entries into the food magazine were also significantly reduced, while all measured behaviors, including licking and water consumption, were decreased by the highest dose of PPA. The reduction in lick efficiency suggested a PPA-induced motor impairment in the capacity for licking. Considered together, these results indicated that the observed decreases in regulatory and nonregulatory eating and drinking could be at least partially accounted for by the drug's effects on behaviors contributing to ingestion, as well as apparent motor impairments in ingestive behavior at higher doses.

Effects of phenylpropanolamine infusion and withdrawal on body weight and dietary composition in male and female rats.

Male and female rats with ad lib access to separate sources of carbohydrate, fat, and protein were implanted with minipumps providing one of three dosages (0.0, 40.0, or 80.0 mg/kg/day) of phenylpropanolamine (PPA) for 2 weeks. Body weight, macronutrient intake, and water consumption were measured daily before, during, and after PPA treatment. Phenylpropanolamine lowered body weight and caloric intake in males and females, and water consumption in females, but did not alter dietary composition in either sex. After PPA termination, caloric intake returned to control levels in both males and females. However, body weight returned to control levels in males only, while PPA-treated females continued to weigh less than controls. Phenylpropanolamine termination was associated with significant increases in water consumption and the percentage of total calories consumed from protein and reductions in the percentage of calories from carbohydrate in males. In contrast, water and macronutrient consumption was similar comparing PPA-treated females to controls after drug termination. These results suggest there are sex differences in the effects of PPA termination on water and macronutrient consumption that result in differential weight gain in males and females.

Use of phenylpropanolamine to reduce nicotine cessation induced weight gain in rats.

The present study was conducted to determine if phenylpropanolamine (PPA) administered during the first week of nicotine termination could reduce or eliminate the body weight rebound which accompanies nicotine cessation. Sprague-Dawley rats were administered nicotine for 2 weeks after which they received either PPA or saline for 1 week. Control animals received saline during both drug periods. Body weight, food consumption, and water consumption were measured daily before drug, during nicotine and PPA administration, and for 14 days after PPA administration. In contrast to animals receiving saline upon termination of nicotine, animals receiving PPA did not gain weight at an accelerated rate. Termination of PPA did not result in a body weight rebound. To the extent that these results generalize to humans, they suggest that PPA could be used to reduce or eliminate postcessation weight gain in smokers who stop smoking.

Gender differences in tobacco use.

Gender differences in overall tobacco use clearly exist. In general, men are more likely to use tobacco products than are women. However, this simple generalization, ignoring type of tobacco products, time, and culture, masks many more interesting gender differences in tobacco use. There are pronounced gender differences in tobacco use of specific tobacco products within some cultures but not others. Yet these differences have changed across time, including narrowing and widening of this gender gap, depending on culture and tobacco product. This article addresses these issues and presents possible psychosocial, biological, and psychobiological explanations for these phenomena. In addition, the implications of these differences and ways to learn more about these important differences are discussed.

Effects of nicotine on body weight, food consumption and body composition in male rats.

The present study examined the effects of nicotine administration and cessation on body weight, food consumption, and body composition in rats. Administration of nicotine was associated with attenuated body weight gains and cessation was associated with accelerated body weight gains. Changes in fat composition paralleled changes in body weight, whereas changes in body water and protein did not. These results suggest that nicotine administration decreases body weight through its effects on fat stores in the body. After cessation of nicotine, body fat rapidly approached levels of control animals.

Effects of chronic nicotine administration on insulin, glucose, epinephrine, and norepinephrine.

There is an inverse relationship between nicotine administration and body weight. Previous research indicates that this relationship results partially from effects of nicotine on energy intake. The present research includes two animal studies designed to investigate the effects of chronic nicotine administration on biochemical responses that affect energy utilization. The results indicate that chronic nicotine administration is accompanied by significant decreases in circulating insulin levels. Nicotine increases levels of catecholamines, but this effect is short-lived. The effects of nicotine on insulin are consistent with the conclusion that nicotine administration increases energy utilization.

Effects of nicotine on body weight in rats with access to "junk" foods.

The present experiment examined effects of nicotine on body weight of male and female rats when Oreo cookies, potato chips, laboratory chow, and water were available. Body weight and eating behavior were measured for 17-day periods before, during, and after nicotine or saline administration. There was an inverse relationship between nicotine and body weight. These effects were paralleled by changes in consumption of sweet foods. There were no effects of nicotine on salty or bland food consumption. Excessive gains in body weight after cessation of nicotine administration were greater for females than for males.

Sex differences in nicotine's effects on consummatory behavior and body weight in rats.

Nicotine administration and cessation have greater effects on body weight and eating behavior in female than in male rats. These generalizations are based on studies of body weight and eating behavior for 2-3 week periods before, during, and after nicotine administration. Therefore, the sex differences may reflect differences in sensitivity to nicotine or simply differences in the time course of nicotine's effects. The present research was designed to replicate these previous studies and to examine long-term effects of nicotine cessation on body weight. Nicotine or saline was administered SC to female and male Sprague-Dawley rats for 16 days. Body weight, food consumption, and water consumption were measured before, during, and after nicotine administration. In addition, body weight was measured for 4 months after cessation of nicotine. There was an inverse relationship between nicotine and body weight. Also, there was an inverse relationship between nicotine and general consummatory behavior for females but not for males. The body weight of females that had received nicotine were indistinguishable from controls up to 4 months after cessation of nicotine. The body weight of males that had received 12 mg nicotine per kg per day remained lower than controls.