Propranolol antagonism of phenylpropanolamine-induced hypertension.

Phenylpropanolamine (PPA) overdose can cause severe hypertension, intracerebral hemorrhage, and death. We studied the efficacy and safety of propranolol in the treatment of PPA-induced hypertension. Subjects received propranolol either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and propranolol pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous propranolol after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the stroke volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous propranolol reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by propranolol 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that propranolol antagonizes this increase by reversing the effect of PPA on cardiac output. That propranolol antagonizes the pressor effect of PPA is in contrast to the interaction in which propranolol enhances the pressor effect of norepinephrine. This is probably because PPA has less beta 2 activity than does norepinephrine.

An abstinence syndrome following chronic administration of delta-9-terahydrocannabinol in rhesus monkeys.

Chaired, chronically catheterized rhesus monkeys were administered IV delta-9-tetrahydrocannabinol (THC), 0.5 mg/kg every 6 h for 3 weeks. Following the first THC injection, the animals appeared heavy-lidded, immobile, and unresponsive to observation. Tolerance developed to these behaviors during the 3 weeks of THC administration, although the animals remained subdued compared to baseline. Following discontinuation of THC, animals showed an increase in gross movement, eye contact, and tooth baring of greater frequency and/or duration than observed before THC. This presumably represents a cannabis abstinence syndrome.

Effects of cotinine on information processing in nonsmokers.

Cotinine, the major proximate metabolite of nicotine, is present in smokers in higher concentrations and for a longer time than nicotine, yet its effects on information processing have not previously been reported. We studied the cognitive effects of cotinine in non-smokers. Sixteen subjects were tested on three doses of cotinine (0.5, 1.0, and 1.5 mg cotinine base/kg), and placebo, on a choice reaction time (RT) task and on a verbal recall task with short and long lists. Cotinine significantly impaired recall on the long list and displayed non-significant but generally consistent dose-related slowing of RT and N100 latency. The acute effects of cotinine were small, and probably do not account for the cognitive deficits observed in tobacco withdrawal, although the cognitive effects of chronic cotinine administration need to be investigated.

Caffeine effects on learning, performance, and anxiety in normal school-age children.

OBJECTIVE: The purpose of this investigation was to study the acute effects of caffeine on learning, performance, and anxiety in normal prepubertal children. METHOD: Twenty-one children were evaluated in a double-blind, placebo-controlled crossover design. Subjects were studied during four sessions, 1 week apart, under the following conditions: baseline, placebo, 2.5 mg/kg caffeine, and 5.0 mg/kg caffeine. Subjects were randomized to order of placebo and the two dosages of caffeine. Dependent measures included tests of attention, manual dexterity, short-term memory, and processing speed. Anxiety rating scales were also administered. Saliva samples were analyzed for caffeine levels. RESULTS: Caffeine improved performance on two of four measures of the Test of Variables of Attention and on a test of manual dexterity in the dominant hand. There was a trend toward increased current level of self-reported anxiety after caffeine on a visual analogue measure of anxiety. Children reported feeling significantly less "sluggish" after caffeine ingestion than after placebo ingestion. CONCLUSIONS: In a small sample size, there was indication that caffeine enhanced performance on a test of attention and on a motor task. Children also reported feeling less "sluggish" but somewhat more anxious. Because caffeine is so widely available and frequently consumed by children, these results are important and need replication.

Saliva cotinine levels as a function of collection method.

Saliva cotinine is commonly used to estimate nicotine intake but laboratories use different methods of collection. In three small trials, comparisons were made between (1) sugar vs. unstimulated saliva production (n = 29), (2) wax chewing vs. unstimulated production (n = 15) and (3) between two consecutive unstimulated saliva samples (n = 10). Sugar-stimulated saliva cotinine scores were 26% below unstimulated levels (p < 0.001); correlation between measures was high (r = 0.90; p < 0.001). Wax stimulated saliva yielded levels 6% below unstimulated (p < 0.05; correlation: r = 0.98; p < 0.001). No differences were observed between two unstimulated samples taken within a approximately 20-minute period (correlation: r = 0.99; p < 0.001). It is postulated that changes in salivary flow can account for the findings.

Clinical pharmacology of oral cotinine.

Cotinine is the major proximate metabolite of nicotine. The aims of our study were to assess the pharmacokinetics of oral cotinine comparing the use of saliva and plasma concentrations, and to characterize the subjective and cardiovascular effects of oral cotinine in nonsmokers. The clearance and half-life of cotinine measured using plasma or saliva concentrations were similar. There was no change in heart rate or blood pressure, and no differences in subjective response with cotinine compared to placebo. We conclude that administration of oral cotinine with measurement in saliva samples is easy, safe, and provides an accurate estimate of systemic clearance and half-life of cotinine.

Mouth versus deep airways absorption of nicotine in cigarette smokers.

Nicotine from the alkaline smoke of cigars is absorbed through the buccal mucosa, but such absorption from the more acidic smoke of American cigarettes has not been reported. Forty-one male and 52 female smokers were studied under normal ventilation and smoking conditions, and under high ventilation and controlled smoking conditions that restricted intake to the mouth only, with no inhalation. The major finding is that there is virtually no intake of nicotine through the buccal mucosa while smoking American cigarettes. Confirming prior reports, plasma nicotine and expired CO levels showed no correlation with the analytical yields of nicotine and CO of the cigarettes smoked. Fifteen nonsmokers (7 male, 8 female) participated in this study as controls. Data from these subjects provided additional information regarding absorption of nicotine and carbon monoxide during passive smoking. Within the highly ventilated environment, there was no significant change of CO and nicotine levels of nonsmokers. However, within the normally ventilated environment, there was minimal increase in both substances, statistically significant only for nicotine. These results suggest that nicotine may be a better indicator of exposure to second-hand smoke than carbon monoxide.

Bupropion in breast milk: an exposure assessment for potential treatment to prevent post-partum tobacco use.

OBJECTIVES: To assess potential infant exposure to bupropion and its active metabolites in breast milk such as would occur during treatment to prevent post-partum relapse to tobacco use, and to compare the concentrations of bupropion in urine and saliva with plasma and breast milk. DESIGN AND SETTING: Cohort study, outpatient clinical research centre. SUBJECTS: Ten healthy post-partum volunteers who agreed to take bupropion for seven days, pump and discard their breast milk, and have samples of breast milk, plasma, saliva, and urine analysed. INTERVENTION: Bupropion 150 mg a day for three days and then 300 mg a day for four days. MAIN OUTCOME MEASURES: Concentrations of bupropion and its active metabolites (hydroxybupropion, erythrohydrobupropion, threohydrobupropion) in breast milk, plasma, saliva, and urine. Determination of average infant exposure. RESULTS: The calculated average dosage of bupropion in breast milk was 6.75 microg/kg/day. Therefore, the average infant exposure is 0.14% of the standard adult dose of bupropion, corrected for the difference in body weight. Considering the sum of bupropion and its active metabolites, the average infant exposure is expected to be 2% of the standard maternal dose on a molar basis. The concentration of bupropion and its active metabolites in breast milk was not associated with age, body mass index, use of oral contraceptive pills, age of infant, or the frequency of breast feeding at the time the study was initiated. The coefficient of determination (r2) between the concentration of bupropion in breast milk and in urine was 0.77 (p < 0.01). CONCLUSIONS: Bupropion and its active metabolites are present in the breast milk of lactating women. The concentrations of bupropion in breast milk and urine were highly correlated. These results indicate that the daily dose of bupropion and metabolites that would be delivered to an infant of a woman taking a therapeutic dose of bupropion is small. These results suggest that the effectiveness of bupropion to prevent post-partum relapse to tobacco use should be evaluated without excluding women who plan to breast feed.

Clonidine for smoking cessation.

BACKGROUND: Clonidine was originally used to lower blood pressure. It acts on the central nervous system and may reduce withdrawal symptoms in various addictive behaviours, including tobacco use. OBJECTIVES: The aim of this review is to determine clonidine's effectiveness in helping smokers to quit. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register. Date of the most recent search: October 1998. SELECTION CRITERIA: We considered randomised trials of clonidine versus placebo with a smoking cessation endpoint assessed at least 12 weeks following the end of treatment. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of subjects, the dose and duration of clonidine therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least twelve weeks follow-up in patients smoking at baseline. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed effects model. MAIN RESULTS: Six trials met the inclusion criteria. There were three trials of oral, and three of transdermal clonidine. Some form of behavioural counselling was offered to all participants in five of the six trials. There was a statistically significant effect of clonidine in one of these trials. The pooled odds ratio for success with clonidine vs placebo was 1.89 (95% confidence interval 1.30 to 2.74). There was a high incidence of dose-dependent side-effects, particularly dry mouth and sedation. REVIEWER'S CONCLUSIONS: Based on a small number of trials, in which there are potential sources of bias, clonidine is effective in promoting smoking cessation. Prominent side-effects limit the usefulness of clonidine for smoking cessation.

Clonidine for smoking cessation.

BACKGROUND: Clonidine was originally used to lower blood pressure. It acts on the central nervous system and may reduce withdrawal symptoms in various addictive behaviours, including tobacco use. OBJECTIVES: The aim of this review is to determine clonidine's effectiveness in helping smokers to quit. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register for trials of clonidine. Date of the most recent search: May 2004. SELECTION CRITERIA: We considered randomized trials of clonidine versus placebo with a smoking cessation endpoint assessed at least 12 weeks following the end of treatment. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of subjects, the dose and duration of clonidine therapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was abstinence from smoking after at least 12 weeks follow up in patients smoking at baseline. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed effect model. MAIN RESULTS: Six trials met the inclusion criteria. There were three trials of oral, and three of transdermal clonidine. Some form of behavioural counselling was offered to all participants in five of the six trials. There was a statistically significant effect of clonidine in one of these trials. The pooled odds ratio for success with clonidine versus placebo was 1.89 (95% confidence interval 1.30 to 2.74). There was a high incidence of dose-dependent side-effects, particularly dry mouth and sedation. REVIEWERS' CONCLUSIONS: Based on a small number of trials, in which there are potential sources of bias, clonidine is effective in promoting smoking cessation. Prominent side-effects limit the usefulness of clonidine for smoking cessation.

Elimination of cotinine from body fluids: implications for noninvasive measurement of tobacco smoke exposure.

Cotinine elimination from plasma, saliva, and urine was studied over 11 days in five subjects (three nonsmokers and two occasional smokers). Half-lives for cotinine averaged 16-19 hours in the different body fluids (range 10 to 27 hours between subjects). There was no tendency for the half-life in saliva to be longer than in plasma or urine. We conclude that choice of body fluid for cotinine assay in smoking studies should depend on practical rather than pharmacokinetic considerations.

Cotinine in the serum, saliva, and urine of nonsmokers, passive smokers, and active smokers.

Cotinine was measured in the serum, saliva, and urine of nonsmokers, passive smokers, and active smokers. Serum and saliva could not discriminate between nonsmokers and passive smokers. Mean urine cotinine was higher in passive smokers than nonsmokers but there was a great deal of intersubject overlap. Cotinine in all body fluids could separate active smokers from the other two groups. Among smokers, light smokers had lower levels than heavier smokers.

The effect of cigarette smoking on penile erection.

Clinical observations suggest that cigarette smoking impairs erectile function in patients with moderate arterial insufficiency. To evaluate the effects of smoking on the physiology of erection, we studied six healthy adult mongrel dogs in which bipolar cuff electrodes were implanted around the cavernous nerves. After threshold stimulation parameters for penile erection were established, cigarette smoke collected in a 60-ml. syringe was released slowly near the dog's mouth, to be inhaled by natural breathing. Stimulation of the cavernous nerve was repeated and blood samples for nicotine, cotinine and blood gases were obtained before and after each cigarette. The systolic and intracorporeal pressure, flow through the internal pudendal artery, and venous flow from the corpora cavernosa were recorded at baseline and with each electrostimulation after smoke inhalation. Five of the six dogs were unable to achieve full erection after inhalation of smoke from two to three cigarettes. Some decrease of flow through the internal pudendal artery occurred and the venous restriction ability was almost completely abolished by smoking. Further, when nicotine was injected intravenously into two additional dogs, the same phenomenon was observed. These findings support the idea that cigarette smoking may contribute to impotence in some patients.