Acid-base analysis of individuals following two weight loss diets.

OBJECTIVE: To examine the effects of low-carbohydrate, ketogenic (LCKD) and low-fat (LFD) diets on acid-base status. DESIGN: Prospective analysis of volunteers from two clinical trials. PARTICIPANTS: Subset of 39 volunteers from a randomized trial comparing the effects of an LCKD with an LFD, and a single-arm trial of an LCKD. SETTING: Outpatient research clinic. INTERVENTION: LCKD (initially <20 g of carbohydrate daily) or LFD (<30% of energy from fat, 500-1000 kcal energy reduction) instruction. MEASUREMENTS: Arterial blood gas analysis, serum chemistries (electrolytes, urea nitrogen/creatinine, glucose, ketone bodies, lactate), anion gap, and urine ketone bodies measured at weeks 0, 2, 8, and 24. RESULTS: Participants had a mean (+/-standard deviation) age of 43.5+/-9.3 years; 28 (72%) were female, 29 (74%) were Caucasian. Using linear mixed-model analysis to examine blood test changes from baseline to 24 weeks, the LFD group experienced a decrease in arterial blood pH from a mean of 7.43 at week 0 to 7.40 at week 24 (P=0.03), and the LCKD group experienced a decrease from 7.42 at week 0 to 7.40 at week 24 (P=0.01). The lowest pH measurements observed were 7.34 in the LFD group and 7.37 in the LCKD group. Although serum bicarbonate appeared to decrease from baseline at weeks 2 and 8 in the LCKD group, the change at 24 weeks was not statistically significant in either diet group, and only four of 131 (two of 92 from the LCKD group) measurements were less than 22 mmol/l. The proportion of participants with elevated urine and serum ketone body levels rose in the LCKD group only, was highest at week 2, and decreased over the subsequent time points. CONCLUSION: In individuals following an LCKD or an LFD, blood pH decreased mildly and the LCKD group experienced a small, transient decrease in serum bicarbonate in conjunction with mild ketosis. This suggests that an LCKD induced a mild compensated metabolic acidosis, but no individual showed evidence of significant metabolic derangement.

Diet therapy for narcolepsy.

The effects of a low-carbohydrate, ketogenic diet (LCKD) on sleepiness and other narcolepsy symptoms were studied. Nine patients with narcolepsy were asked to adhere to the Atkins' diet plan, and their symptoms were assessed using the Narcolepsy Symptom Status Questionnaire (NSSQ). The NSSQ-Total score decreased by 18% from 161.9 to 133.5 (p = 0.0019) over 8 weeks. Patients with narcolepsy experienced modest improvements in daytime sleepiness on an LCKD.

Improvement of gastroesophageal reflux disease after initiation of a low-carbohydrate diet: five brief case reports.

The 5 individuals described in these case reports experienced resolution of GERD symptoms after self-initiation of a low-carbohydrate diet. Their observations suggest that carbohydrate restriction may have contributed to their symptom relief. However, this conclusion is confounded by concurrent reduction of caffeine intake in 3 of the individuals and reduction of acidic and high-osmolal food intake in all of them. Observations from some of these individuals suggest that carbohydrates may be a precipitating factor for GERD symptoms and that other classic exacerbating foods such as coffee and fat may be less pertinent when a low-carbohydrate diet is followed. However, these conclusions are preliminary. These findings primarily suggest that prospective research should be performed on the effect of low-carbohydrate diets on GERD symptoms. Trials that control for all of the confounders mentioned above and that contain objective endpoints are needed to further investigate these issues.

Oral nicotine solution for smoking cessation: a pilot tolerability study.

This study was conducted to determine the preliminary tolerability of an oral nicotine solution with minimal behavioral intervention for smoking cessation. Twenty-five healthy volunteers who smoked at least 10 cigarettes per day and were motivated to quit smoking were enrolled in an open-labeled trial with a 12-week treatment and a 6-month follow-up period. After reviewing self-help materials and setting a quit-smoking day, subjects were provided nicotine solution to mix with their beverages to control smoking urges, and returned for refills eight times over 12 weeks. Abstinence (point prevalence) was defined as self-report of 0 cigarettes smoked for the previous 7 days verified by exhaled carbon monoxide (CO) <10 ppm. The oral nicotine solution was well tolerated when mixed with an individual's chosen beverage. Subjects controlled the concentration of nicotine consumed, which ranged from 0.25 to 10 mg nicotine base per 170-354 ml of beverage. One week after the quit date the mean venous nicotine level was 13.4 ng/ml and mean serum cotinine level was 418.0 ng/ml in six non-smokers. Abstinence rates at 4 weeks, 3 months, and 6 months were 28.0%, 24.0%, and 20.0%, respectively. It was concluded that an oral nicotine solution was tolerable and provided nicotine replacement at levels that may prove useful for smoking cessation. Further research to clarify appropriate dosages and optimal beverages for mixture, and controlled trials to assess safety and efficacy, appear in order.

Individual differences in smoking reward from de-nicotinized cigarettes.

Most studies of cigarette smoking and smoking cessation have focused on the psychopharmacological effects of nicotine; relatively few have explored the role of sensory aspects of cigarette smoke. Sensory aspects of cigarette smoke play a role in the maintenance of smoking behavior, and may be particularly important for certain smokers. This paper presents the results of a pooled analysis of nine studies conducted in our laboratory, in order to explore the influence of demographic and smoking-related variables on ratings of de-nicotinized as compared to nicotine-containing cigarettes. A major finding of this analysis is that ratings of smoking derived from de-nicotinized, but not nicotine-containing, cigarettes appear to vary with level of tobacco dependence, suggesting that sensory factors may be more important to highly dependent, as compared to less-dependent, smokers. The implications of these findings for smoking cessation treatment and for future research are discussed.

Use of bupropion SR in a pharmacist-managed outpatient smoking-cessation program.

We administered bupropion sustained-release (SR) in a pharmacist-managed outpatient smoking-cessation program. Patients were referred to the program by their primary care physician. All patients completed initial visit questionnaires, received behavioral counseling by a clinical pharmacist, and were provided educational materials on smoking cessation. Seventy-one patients received bupropion SR for treatment of nicotine dependence and were followed for 6 months. Point prevalence abstinence rates were 28.2% and 25.4% at 8 weeks and 6 months, respectively. The trend was toward lower cessation rates in patients with a documented psychiatric diagnosis at 6 months (p=0.064). Bupropion SR was fairly well tolerated, with the most common adverse effects being dry mouth and bad taste. The agent appears to have better success for smoking cessation in patients free of psychiatric comorbidities, but further research is required to support this finding.

Acute effects of nicotine and mecamylamine on tobacco withdrawal symptoms, cigarette reward and ad lib smoking.

Separate and combined effects of nicotine and the nicotinic antagonist mecamylamine were studied in 32 healthy volunteer smokers after overnight abstinence from smoking. Subjects participated in three sessions (3 h each), during which they wore skin patches delivering either 0 mg/24 h, 21 mg/24 h or 42 mg/24 h nicotine. Thirty-two subjects were randomly assigned to two groups receiving oral mecamylamine hydrochloride (10 mg) vs. placebo capsules. Two and one-half hours after drug administration, subjects were allowed to smoke ad lib, rating the cigarettes for rewarding and aversive effects. Transdermal nicotine produced a dose-related reduction in the subjective rewarding qualities of smoking. Nicotine also reduced craving for cigarettes and this effect was attenuated, but not eliminated, by mecamylamine. Mecamylamine blocked the discriminability of high vs. low nicotine puffs of smoke, and increased nicotine intake substantially during the ad lib smoking period. Some of the psychophysiological effects of each drug (elevation in blood pressure from nicotine, sedation and decreased blood pressure from mecamylamine) were offset by the other drug. The results supported the hypothesis that nicotine replacement can alleviate tobacco withdrawal symptoms even in the presence of an antagonist such as mecamylamine. Mecamylamine did not precipitate withdrawal beyond the level associated with overnight cigarette deprivation, suggesting its effects were primarily due to offsetting the action of concurrently administered nicotine as opposed to blocking endogenous cholinergic transmission.

Dissociating nicotine and nonnicotine components of cigarette smoking.

To dissociate the sensorimotor aspects of cigarette smoking from the pharmacologic effects of nicotine, smokers rated the subjective effects of nicotine-containing or denicotinized cigarettes, and intravenous (IV) nicotine or saline infusions. Three groups of participants (n=20 per group) received either: (1) continuous nicotine, (2) pulsed nicotine, or (3) saline. Each group was exposed to an IV condition once while smoking a denicotinized cigarette and once while not smoking, in a 3x2 mixed design. A fourth group (n=20) received saline while smoking their usual brand of cigarette. The dose and rate of nicotine administration were individualized based on previous measures of ad lib smoke intake. Denicotinized cigarette smoke significantly reduced craving and was rated significantly more satisfying and rewarding than the no-smoking conditions. IV nicotine reduced craving for cigarettes, and increased ratings of lightheadedness and dizziness. However, no significant satisfaction or reward was reported after IV nicotine. The combination of IV nicotine and denicotinized cigarette smoke produced effects similar to those of smoking the usual brand of cigarette. The results suggest that sensorimotor factors are critical in mediating the immediate subjective response to smoking, and that the immediate subjective effects of nicotine administered in doses obtained from cigarette smoking are subtle. Thus, addressing smokers' needs for both for the sensorimotor aspects of smoking as well as for the direct CNS effects of nicotine may be critical in enhancing smoking cessation treatment outcome.

Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction.

An understanding of drug addiction requires knowledge of the effective drug concentrations to which receptors in the nervous system are exposed. It has often been thought that smoking of abused substances such as nicotine or cocaine produces much higher drug concentrations in the arterial blood than those achieved following any other route of administration. However, to date no studies have sampled arterial blood following cigarette smoking with the rapidity necessary to evaluate this hypothesis. We measured arterial plasma nicotine concentrations in samples collected every 5 s from 13 cigarette smokers during cigarette smoking and during administration of nicotine by intravenous injections. Our results show that, for both routes of administration, concentrations of nicotine in arterial blood were more than 10 times lower than expected. Thus, the delivery of nicotine into arterial blood is substantially slower than would be predicted if nicotine were absorbed as rapidly as has generally been assumed. A plausible explanation of these results is that lung uptake of nicotine considerably slows the entry of nicotine into the systemic circulation, as has been shown for other amines. These results have significant implications for theories of addiction to nicotine as well as other drugs such as cocaine that may be subject to binding by lung tissue.

Factors influencing morning report case presentations.

BACKGROUND: One of the most widely accepted didactic conferences among residency training programs is morning report. This study examines several factors that may influence the content of case presentations at morning report. METHODS: This prospective survey is of cases presented over a 1-year period at two morning reports--a university hospital and its affiliated Veterans Affairs (VA) hospital. RESULTS: Of 286 morning reports, 227 questionnaires (79%) were completed. The most common subspecialty categories represented in the cases were cardiology (20.3% of cases), infectious disease (13.2%), gastroenterology (11.5%), pulmonary (11.0%), hematology (10.1%), and general medicine (6.2%). The case mix was not significantly different by type of hospital nor by chief resident. The discussion was inpatient oriented in 88.6% of cases. CONCLUSION: Morning report case mix was similar at a university and its affiliated VA hospital and was predominantly inpatient oriented.

Naltrexone blockade of nicotine effects in cigarette smokers.

RATIONALE: The role of endogenous opiate systems in cigarette smoking remains unclear. In laboratory animals, opiate antagonists block many of the effects of nicotine, but in humans they do not consistently alter smoking behavior. OBJECTIVE: This study explored the effects of naltrexone, alone and in combination with nicotine, on smoking behavior. METHODS: In a double-blind, double-dummy, within-subjects design, 19 regular smokers received four treatments of 1 week duration: naltrexone tablet (50 mg) plus placebo skin patch, placebo tablet plus nicotine skin patch (21 mg/24 h), naltrexone tablet plus nicotine skin patch, and placebo tablet plus placebo skin patch. During each treatment, subjects rated their responses to nicotine-containing and denicotinized cigarettes in the laboratory, and to their own brand of cigarette smoked ad libitum outside the laboratory. RESULTS: Pretreatment with the nicotine patch attenuated smoking-induced decreases in craving, negative affect, and rates of ad lib smoking, and potentiated the aversiveness of a cigarette. Naltrexone reversed these effects of the nicotine patch, and produced negative effects on mood. CONCLUSIONS: The blockade of nicotine's effects by naltrexone supports a role for opioid mechanisms in cigarette smoking.

Blockade of smoking satisfaction using the peripheral nicotinic antagonist trimethaphan.

The present study was conducted to investigate the role of peripheral nicotinic receptors in mediating the rewarding effects of cigarette smoking. Twelve cigarette smokers rated cigarettes after intravenous infusion of the short-acting peripheral nicotinic receptor antagonist trimethaphan and after placebo (saline) infusions. Subjects were blinded to the infusion and cigarette conditions. Cigarette conditions included subjects' usual brand of cigarette, denicotinized tobacco cigarettes, and nicotine-injected cigarettes that had a tar delivery equal to that of the denicotinized cigarettes but with an enhanced nicotine delivery equal to that of subjects' usual brands. The latter cigarettes were rated as extremely harsh due to the high nicotine/tar ratio. Trimethaphan significantly attenuated the airway sensations associated with nicotine, and eliminated the difference in smoking satisfaction between the usual brand of cigarette and the other two cigarettes. These findings suggest that nicotinic receptors on peripheral nerve endings in the respiratory tract modulate smoking satisfaction and may be important in the maintenance of cigarette addiction.

Nicotine-mecamylamine treatment for smoking cessation: the role of pre-cessation therapy.

The nicotinic antagonist mecamylamine was evaluated in a randomized smoking cessation trial. Four groups of participants (n = 20 per group) received nicotine plus mecamylamine, nicotine alone, mecamylamine alone, or no drug for 4 weeks before cessation. After the quit-smoking date, all subjects received nicotine plus mecamylamine treatment for 6 weeks. Nicotine skin patches (21 mg/24 hr) and mecamylamine capsules (2.5-5.0 mg twice per day) were used. Precessation mecamylamine significantly prolonged the duration of continuous smoking abstinence; abstinence rates at the end of treatment were 47.5% with mecamylamine and 27.5% without mecamylamine. Nicotine + mecamylamine reduced ad lib smoking, smoking satisfaction, and craving more than either drug alone. Moreover, the orthostatic decrease in blood pressure caused by mecamylamine was offset by nicotine. Mecamylamine before smoking cessation may be an effective adjunct to nicotine patch therapy.

Smoking behavior on the first day of a quit attempt predicts long-term abstinence.

BACKGROUND: The nicotine patch has been widely used for smoking cessation, but not all smokers quit using the patch. Knowing which smokers are likely to succeed with the nicotine patch may improve the efficiency of nicotine patch use. OBJECTIVE: To identify predictors of smoking abstinence using baseline characteristics, smoking behavior, and withdrawal symptoms. METHODS: Using 2 randomized clinical trials of pharmacologic treatment, brief counseling, and quit date formats in the outpatient research clinic setting, predictors of smoking cessation were derived in 1 sample (n = 159), then prospectively validated in an independent sample (n = 48). Subjects smoked 1 pack of cigarettes per day or more and were motivated to quit smoking. Self-report of abstinence at 6 months verified by exhaled carbon monoxide of 8 ppm or less was used. RESULTS: Abstinence at 6 months was 24% in the derivation set and 25% in the validation set. Using logistic regression, a model containing quit date abstinence (odds ratio, 10.6; 95% confidence interval [CI], 2.9-38.7) and baseline nicotine dependence (odds ratio, 0.75; 95% CI, 0.6-1.0 per unit increase in Fagerstrom score) provided the optimal predictive ability and was validated in the independent set. Quit date abstinence improved the likelihood of 6-month abstinence by 4.1 over baseline (95% CI, 2.6-6.4) for low-nicotine-dependent smokers and 1.2 (95% CI, 0.6-2.2) for high-nicotine-dependent smokers. Quit date smoking altered the likelihood of 6-month abstinence by 0.2 (95% CI, 0.0-0.8) for low-dependent smokers and 0.1 for high-dependent smokers (95% CI, 0.0-0.6). CONCLUSIONS: Abstinence on the quit date and low-nicotine dependence improve the likelihood of smoking abstinence at 6 months. Smoking on the quit date may be an indication for postponing the cessation attempt or adjusting the therapy for smoking cessation.

The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.

BACKGROUND: Transdermal nicotine therapy is widely used to aid smoking cessation, but there is uncertainty about its safety in patients with cardiac disease. METHODS: In a randomized, double-blind, placebo-controlled trial at 10 Veterans Affairs medical centers, we randomly assigned 584 outpatients (of whom 576 were men) with at least one diagnosis of cardiovascular disease to a 10-week course of transdermal nicotine or placebo as an aid to smoking cessation. The subjects were monitored for a total of 14 weeks for the primary end points of the study (death, myocardial infarction, cardiac arrest, and admission to the hospital due to increased severity of angina, arrhythmia, or congestive heart failure); the secondary end points (admission to the hospital for other reasons and outpatient visits necessitated by increased severity of heart disease); any side effects of therapy; and abstinence from smoking. RESULTS: There were 48 primary and 78 secondary end points noted in a total of 95 subjects. At least one of the primary end points was reached by 5.4 percent of the subjects in the nicotine group and 7.9 percent of the subjects in the placebo group (difference, 2.5 percent; 95 percent confidence interval, -1.6 to 6.5 percent; P=0.23). In the nicotine group, 11.9 percent of the subjects had at least one of the secondary end points, as compared with 9.7 percent in the placebo group (difference, 2.2 percent; 95 percent confidence interval, -2.2 to 7.4 percent; P= 0.37). After 14 weeks the rate of abstinence from smoking was 21 percent in the nicotine group, as compared with 9 percent in the placebo group (P=0.001), but after 24 weeks the abstinence rates were not significantly different (14 percent vs. 11 percent, P= 0.67). CONCLUSIONS: Transdermal nicotine does not cause a significant increase in cardiovascular events in high-risk outpatients with cardiac disease. However, the efficacy of transdermal nicotine as an aid to smoking cessation in such patients is limited and may not be sustained over time.

Dissociating the nicotine and airway sensory effects of smoking.

This study examined the subjective and cardiovascular effects of two of the components of cigarette smoking when given separately: nicotine and airway sensations. Using a within-subjects design, six healthy volunteer smokers, age 18-45 years, who smoked at least 20 cigarettes per day were given six conditions in a randomized, counterbalanced order. The effects of IV nicotine, IV saline, and denicotinized cigarettes were compared to a standard 1-mg cigarette. The standard cigarette produced more of a calming effect and more irritability reduction than either the nicotine or airway sensations alone. The denicotinized cigarette was similar to the standard cigarette condition, except the cigarette condition was associated with higher feelings of "exhilaration." Many of the positive subjective effects from a denicotinized cigarette were comparable to that of a standard cigarette. These data support the hypothesis that replacement of the sensory cues of smoking with "airway sensory replacement" may be useful for smoking cessation.

Accuracy and reliability of apical S3 gallop detection.

This study assessed physician performance in detecting the apical S3 gallop using a cardiology patient simulator. Six physicians (two cardiology fellows, two medicine residents, and two attending physicians) performed two sets of 24 cardiac examinations that included the presence or absence of an apical S3 gallop. All the examiners were able to significantly alter the prior odds of an apical S3 gallop's being present, but the cardiology fellows had higher sensitivities. Sensitivity was lower for detecting soft S3 gallops, and specificity was lower when a diastolic murmur was also present. Physician performance in detecting apical S3 gallops is variable, but can be excellent.