Effect of domperidone on cimetidine and ranitidine absorption in rabbits

Cimetidine and ranitidine absorption were studied after oral administration to rabbits, alone or in combination with oral and intravenous domperidone. Blood samples were collected before and 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.5, and 6.0 h after cimetidine and ranitidine administration. Assays of cimetidine and ranitidine in plasma samples were carried out using HPLC method. Domperidone overall significantly reduced the area under the plasma concentration-time curve (AUC) by approximately 30 per cent for both drugs. However, domperidone had little effect on the maximum plasma concentration (Cmax), the time taken to reach the maximum plasma concentration (Tmax), and the elimination half-life (t1/2) of cimetidine and ranitidine. The results suggest that domperidone affects the extent but not the rate of cimetidine and ranitidine absorption by enhancing gastric emptying.     

The effect of nicotine on the delay of gastric emptying

The effect of cigarette smoking and its active component, nicotine, on the gastric emptying of solid food was assessed in a randomized double-blind crossover design. Ten regular smokers were studied after a 6 h fast and least 18 h after their last cigarette. Subjects smoked a total of three high (1.91 mg) or low (0.17 mg) nicotine cigarettes, before and after a technetium-labelled solid meal and were scanned by gamma camera periodically over a 2-h period. All calculations of gastric emptying revealed a significant delay after smoking high versus low nicotine cigarettes in: mean per cent isotope remaining in the stomach at each measurement point from 90-120 min; amount of meal remaining in the stomach at 2 h; and mean time at which 50% of the meal had emptied (T1/2). Delay in gastric emptying was significantly correlated with increase in serum nicotine concentration on the high nicotine day.     

Acute doses of d-amphetamine and bupropion increase cigarette smoking

RATIONALE: Bupropion is used clinically as a treatment for smoking cessation, but the processes by which it reduces smoking are poorly understood. Bupropion shares some neurochemical actions and behavioral effects with the psychostimulant amphetamine, and it has been shown that amphetamine increases smoking when administered acutely. The effects of single doses of bupropion on smoking have not been studied but, based on its similarities to amphetamine, we postulated that acute bupropion would also increase smoking. OBJECTIVE: To measure the effects of single doses of amphetamine and bupropion on smoking and craving for cigarettes in smokers. METHODS: Cigarette smokers who were not trying to quit participated in a three-session study in which they received placebo and a single dose of either d-amphetamine sulfate (10 and 20 mg; n=10) or bupropion hydrochloride (150 and 300 mg; n=12) after overnight abstinence. The three outcome measures were: i) subjective and behavioral effects of amphetamine and bupropion after a period of acute abstinence, ii) effects of amphetamine and bupropion on subjective responses to a single, smoked cigarette, and iii) effects of the drugs on number of cigarettes smoked during an ad libitum smoking period. RESULTS: After the acute abstinence and before smoking, both amphetamine and bupropion increased self-reported mood and euphoria, but did not change ratings of craving or withdrawal. After subjects smoked a single smoked cigarette, they reported that bupropion reduced ratings of "buzzed" and "intensity". During the period of ad libitum smoking both amphetamine and bupropion increased the number of cigarettes smoked. CONCLUSION: Acute doses of both bupropion and amphetamine increase smoking in non-treatment-seeking smokers without altering ratings of craving or withdrawal. Bupropion reduced some of the sensory responses to the smoked cigarette. It remains to be determined why bupropion increases smoking when administered acutely under controlled conditions, while it helps to reduce smoking in patients trying to quit.     

Smoke constituent exposure and stage of change in black and white women cigarette smokers

Differences in smoke constituent exposure by ethnicity and menthol preference and differences in decisional balance and habit strength by stage of change, ethnicity, and menthol preference were examined in this 2-factor study design. Ninety-five women, half of whom were Black and half of who smoked menthol cigarettes, participated in a cigarette smoking bout in the Clinical Research Center. Measures of smoking topography, plasma cotinine and nicotine, and expired carbon monoxide were obtained in addition to self-report of the pros and cons of smoking, time to first cigarette, and smoking history. Black women smoked significantly fewer cigarettes per day, but had higher cotinine levels compared to White women. Menthol smokers (n = 49) had significantly larger puff volumes, higher cotinine levels, and shorter time to first cigarette compared to nonmenthol smokers (n = 46). Precontemplators (n = 44) were significantly lower on beliefs about the negative aspects of smoking compared to contemplators and those in preparation stage. Black women, all stages combined, had higher negative beliefs about smoking than did White women. Implications for assessment of smoking patterns and intervention are discussed.     

Usefulness of salivary trans-3'-hydroxycotinine concentration and trans-3'-hydroxycotinine/cotinine ratio as biomarkers of cigarette smoke in pregnant women

Nicotine is rapidly and extensively metabolized in humans and negatively impacts the developing fetus. The concentrations of nicotine, cotinine, trans-3'-hydroxycotinine (hydroxycotinine), and norcotinine in pregnant smokers' oral fluid were evaluated to determine usefulness as biomarkers of cigarette smoking. Sixteen participants were divided into two groups: eight light smokers (LS) who smoked < or =10 cigarettes/day and eight heavy smokers (HS) who smoked > or =20 cigarettes/day. Oral fluid specimens (n=415) were collected throughout pregnancy and analyzed with solid-phase extraction followed by gas chromatography-mass spectrometry-electron impact selected ion monitoring. Median concentrations of nicotine, cotinine, and hydroxycotinine in oral fluid of LS ranged from 241.1 to 622.0, 80.6 to 387.5, and 14.4 to 117.7 ng/mL and for HS 146.5-1372.2, 66.0-245.8, and 38.3-184.4 ng/mL, respectively. Salivary cotinine and hydroxycotinine concentrations were significantly correlated in LS (r = 0.55, p < 0.01) and HS (r = 0.74, p < 0.01). Ratios of hydroxycotinine/cotinine in oral fluid from pregnant women averaged 0.30 +/- 0.18 (range, 0.07-1.05) for LS and 0.68 +/- 0.25 (range, 0.29-1.83) for HS. Based on these preliminary data, the best ratio to differentiate light from heavy pregnant smokers was 0.41. Salivary hydroxycotinine and cotinine concentrations are both good biomarkers of cigarette smoking. Determining the hydroxycotinine/cotinine ratio may differentiate light from heavy tobacco use and help predict increased fetal tobacco exposure.     

Nicotine content of cigarettes and the smoking habit: Their relevance to subjective ratings of preferences in smokers

One lettuce-leaf and three tobacco cigarettes with different nicotine content were smoked by 24 habitual smokers in the course of 4 successive sessions. Their previous smoking habits were found to be significantly related to their preferences for the various cigarettes. Whilst the heavy smokers (>10 cigarettes per day) preferred only the tobacco cigarettes and strongly disliked the lettuce-leaf, light smokers disliked mostly the highest nicotine cigarette. These ratings were also related to differences in the nicotine intake. It is suggested that these findings support the importance of nicotine in the smoking habit, although other factors may be related to the likableness of tobacco smoking. The relevance of this type of study is discussed.This work was supported by the Tobacco Research Council.     

Smoking behavior in low-yield cigarette smokers and switchers in the natural environment.

Urinary cotinine and puffing parameters were studied in 36 smoking students. Three smoking groups, formed according to the tar content of their preferred cigarette, were compared. Eighteen students had always smoked low-yield, 10 medium-yield and 8 were switchers from medium- to low-yield cigarettes. The subjects smoked their preferred brand (the first week), low-yield cigarettes (the second week) and medium-yield cigarettes (the third week). Day urine samples were collected for cotinine analysis during the two last days of the test weeks. Puffing indices were reported on the last day of every test week with a portable microcomputer assisted analyzer with flowhead cigarette holder. Urinary cotinine concentrations were rather constant within the groups, but lower among the low-yield cigarette smokers as compared to the switchers (p less than 0.05). Also the female smokers had lower cotinine concentrations than the male smokers (p less than 0.05). The compensatory behavior seen in every smoking group while they were smoking low-yield cigarettes was based on up-regulation in single puff volume, puff duration and total smoking time when compared to values with medium-yield cigarettes. The correlation between cotinine concentration and diurnal puff volume (1/day) was poor. It is concluded that the benefit possibly gained with low-yield cigarettes is not long lasting.     

Puffing behavior during the smoking of a single cigarette in a naturalistic environment.

The 36 participants in this study were habitual low-yield cigarette smokers, medium-yield cigarette smokers, and switchers from medium- to low-yield cigarettes. All participants smoked both low- (0.4 mg) and medium-nicotine (0.9 mg) cigarettes during the study. Puffing indices were recorded during the first two cigarettes, after an overnight abstinence of smoking, by a portable flowmeter processor unit in a naturalistic environment. The puff volumes per cigarette and per day were significantly lower while switching to higher-yield cigarettes, mainly due to a decrease in the number of puffs and longer interpuff intervals, but also due to a decline in puff duration and flow rate. However, the downregulation by puff volume was incomplete, at most two thirds, as calculated by machine smoking yields. Within the course of smoking a single cigarette, the flow rate was quite stable, puff duration and puff volume decreased toward the end of the cigarette, and interpuff interval was longest during the middle of the cigarette. Total puff volumes per cigarette were similar in the first two cigarettes of the day after an overnight abstinence of smoking, with no significant differences in other puff parameters. Diurnal cotinine excretion revealed that nicotine titration in switching situations was very accurate among switchers and medium-yield cigarette smokers, but not among the low-yield cigarette smokers, and so called oversmoking was found with the higher-nicotine brand. Preferred cigarette type had little effect on the puffing patterns of smokers in single cigarettes.     

Applications and Simulations of a Discontinuous Oral Absorption Pharmacokinetic Model

Purpose. To illustrate the application of a discontinuous oral absorption model to cimetidine and ranitidine plasma concentration versus time data to demonstrate the use of the model for drugs which display discontinuous oral absorption profiles, and to illustrate the effect of various model parameters on plasma drug concentration versus time profiles and bioavailability. Methods. A discontinuous oral absorption model was used to fit ranitidine and cimetidine serum concentrations following oral and intravenous administration. The model was also used to simulate bioavailability and plasma concentrations versus time profiles for various parameter values. Results. Serum concentrations following administration of ranitidine and cimetidine were well described by the model, and parameter estimates obtained were in agreement with literature values. Simulations demonstrate the effects of various absorption parameters and gastrointestinal tract transit parameters on bioavailability and plasma concentration profiles. Conclusions. This discontinuous oral absorption pharmacokinetic model can be a useful tool in characterizing absorption phases, disposition, and bioavailability of drugs exhibiting two absorption peaks following oral administration.     

Smoke yield of cigarettes and puffing behavior in men and women

Puffing behavior (number of puffs, puff interval, puff duration, peak pressure, latency to peak pressure, average and total puff volume) was measured in 67 dependent male and 43 dependent female smokers when they smoked two cigarettes of their habitual brand under laboratory conditions. Test-retest reliability for the two cigarettes was high, and factor analysis showed that puff shape, puff volume, and puff frequency accounted for about 50% of variation obtained with the different puffing variables. Expiratory tidal CO levels increased with the number of cigarettes smoked before the tests and with the intensity of the smoking habit, but pre- to postsmoking tidal CO differences were similar for smokers of all types of cigarettes (0.1–1.7 mg standard machine smoking nicotine yield). Volume compensation for differences of smoke yield of the cigarettes was generally more pronouced in women than in men and, additionally, it was more pronounced for cigarettes with standard smoke nicotine yield below 0.9 mg than for cigarettes with standard smoke nicotine yield above 0.9 mg for both sexes. Only for women, partial correlation procedures suggested that nicotine might be more important in determining puffing behavior than CO and condensate yield, but there were also no women smoking the strongest cigarettes (1.3–1.7 mg nicotine yield). For both sexes, no compensation by adjusting the number of cigarettes smoked daily was obtained. Personality ratings, pulmonary functions, and cardiovascular functions were not, or only inconsistently, correlated with puffing behavior or type of cigarette.     

Smoking modulates neuroendocrine responses to ipsapirone in patients with panic disorder.

Reduced 5-HT1A-receptor responsiveness has been reported in patients with panic disorder(PD) and/or agoraphobia (PDA). Although many of these patients are regular smokers, it has not been examined whether psychological or neurobiological effects induced by the selective 5-HT1A-receptor agonist, ipsapirone, are affected by the smoking status of the patients.In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone (0.3 mg/kg) and placebo were performed in 39 patients with PDA, and results were compared between patients who smoked (>10 cigarettes per day, n = 17) and patients who had been non-smokers for at least two years (n = 22).Patients who were smokers (but did not smoke during the challenge procedure) had significantly reduced baseline concentrations of cortisol and a significantly lower body temperature. In comparison to placebo, administration of ipsapirone was associated with significant increases of various psychological symptoms and plasma cortisol concentrations. The subgroup of PD patients who were smokers showed significantly higher cortisol responses to ipsapirone than non-smokers.In conclusion, smoking status has to be taken into account when assessing the responsiveness of 5-HT1A receptors in patients with psychiatric disorders. The prevention of smoking during challenge sessions might not be the ideal approach in heavy smokers, since sudden abstinence from smoking is likely to affect neurobiological and possibly psychological responses to ipsapirone.     

A comparative study of the effect of cimetidine and ranitidine on the rate of gastric emptying of liquid and solid test meals in man

Paired studies were carried out on 18 healthy male volunteers (20.9 +/- 1.9 years; mean +/- S.D.) to compare the effect of oral doses of the H2-receptor antagonists, ranitidine and cimetidine, on the rate of gastric emptying of radiolabelled solid and liquid test meals. Oral administration of ranitidine 300 mg accelerated the emptying of a liquid meal from the stomach, but it had no significant effect on the rate of emptying of a solid meal. Oral administration of either 400 or 800 mg cimetidine did not alter the rate of emptying of either the liquid or the solid meals from the stomach.     

WHOLE BLOOD AGGREGATION AND PLASMA LYSO-PAF RELATED TO SMOKING AND ATHEROSCLEROSIS

1. Aggregation of diluted whole blood (impedance method) and thromboxane B2 production during aggregation were measured in cigarette smokers and non-smokers, aged 41-68 years, with (n = 14) and without (n = 15) major symptomatic peripheral vascular disease. The plasma level of the lyso derivative of platelet activating factor (lyso-PAF) was also measured using a bioassay with 14C-serotonin labelled rabbit platelets, after extraction and acetylation to active PAF. 2. Aggregation to ADP and collagen was significantly less in non-smokers without vascular disease (n = 8) than in the other three groups (P less than 0.01; ANOVA). Thromboxane B2 production was not significantly different between the groups. There was no significant difference in plasma lyso-PAF between groups. No change was found in any variable after smokers smoked two cigarettes. 3. In these older age subjects, both vascular disease and the smoking habit were associated with greater whole blood aggregation. However, current smoking and the smoking of two cigarettes did not affect aggregation in subjects with vascular disease and plasma lyso-PAF levels were not consistently related to either smoking or vascular disease.     

Population characteristics and cigarette yield as determinants of smoke exposure

Relationships of population characteristics, smoking history, and cigarette yield with smoke exposure as measured by peripheral blood concentrations of thiocyanate, carboxyhemoglobin, nicotine and cotinine were sought in 170 male smokers. This population of smokers had significant elevations of serum thiocyanate, blood carboxyhemoglobin and plasma nicotine and cotinine concentrations as compared with an equal number of age- and sex-matched nonsmokers and these concentrations correlated significantly with past 24-hour cigarette consumption. Although the nicotine yield of the cigarette correlated significantly with plasma cotinine and marginally with plasma nicotine, the reduction in plasma nicotine and cotinine was not proportionate to the reduced yield of the cigarettes, suggesting that smokers partially compensate for the lower yields of their cigarettes. Blood levels of carboxyhemoglobin, nicotine and cotinine were also significantly associated with the weight of the subjects, presumably due to the relationship between weight and the volume of distribution. Univariate and multiple regression analyses provided evidence that coffee and alcohol consumption and years smoked also may be important determinants of smoke exposure.     

Lack of influence of cigarette smoking on triazolam pharmacokinetics.

The influence of cigarette smoking on the pharmacokinetics of a single dose of the triazolobenzodiazepine hypnotic triazolam was evaluated in 12 healthy nonsmoking male volunteers and in 12 male subjects, matched for age, height and weight, who smoked an average of 24 cigarettes a day (range: 15-30). Triazolam kinetics were determined from multiple serum concentrations measured during 15 h after a single 0.5 mg dose. There were no significant differences between nonsmoking controls and cigarette smokers in the peak serum triazolam concentration (4.64 vs 4.73 ng ml-1), the time of peak concentration (0.98 vs 1.0 h after dosage), elimination half-life (2.8 vs 2.5 h), or oral clearance of triazolam (506 vs 627 ml min-1). Likewise there were no significant differences between groups in the extent of triazolam binding to serum protein (18.8 vs 18.5% unbound). Altered pharmacodynamics of triazolam in cigarette smokers are not likely to be explained by altered pharmacokinetics.     

Sensory and physiologic effects of menthol and non-menthol cigarettes with differing nicotine delivery.

Many smokers choose menthol-flavored cigarettes, however, the influence of menthol on the effects of smoke-delivered nicotine is unknown. Research and commercial cigarettes, menthol and non-menthol, that delivered a wide range of nicotine were evaluated. Menthol (n=18) and non-menthol (n=18) cigarette smokers participated in a single session during which three cigarettes were smoked 45 min apart, in random order. Federal Trade Commission (FTC) nicotine yields of the three cigarettes were: research, low yield, 0.2 mg, commercial cigarettes (average), 1.2 mg; research, high yield, 2.5 mg. Commercial and high-yield cigarettes increased heart rate (HR) and blood pressure more than low-yield cigarettes; although, no differences in exhaled carbon monoxide (CO) occurred. Participants smoked commercial cigarettes faster and with fewer puffs than either of the research cigarette indicating production differences can affect topography. There was a significant group by cigarette interaction on satisfaction, and relief from cigarette craving. High-yield non-menthol cigarettes reduced craving and were rated as more satisfying than high-yield menthol cigarettes. No differences between menthol and non-menthol cigarettes on other subjective measures (strength, psychological reward, negative effects) were observed. Our findings indicate that nicotine delivery, but not mentholation, influences cardiovascular and most subjective measures. These results illustrate the importance of threshold levels of nicotine on subjective responses to cigarette smoking.     

Patterns of intermittent smoking: An analysis using Ecological Momentary Assessment

Non-daily smokers comprise a substantial proportion of US smokers, but there has been little study of their patterns of smoking, which are often assumed to reflect “social smoking.” We used Ecological Momentary Assessment methods to study smoking patterns in 27 non-daily smoking adults who recorded each cigarette smoked over three weeks by leaving a voice mail message indicating their circumstances at the time of smoking. All told, 689 cigarettes were recorded over 589 person-days of observation. On average, participants smoked on 67% of days, averaging 2.1 (SD = 0.91) cigarettes per day on days they smoked; 22% of all cigarettes were smoked in bouts (within an hour of another cigarette). Altogether, 19% of cigarettes were smoked when drinking alcohol and 29% when participants were socializing. Smoking patterns varied widely across participants. A pair of hierarchical cluster analyses distinguished three groups: Those who smoked primarily (81% of cigarettes) in the daytime (Early smokers; n = 15, 58% of total sample), those who smoked primarily (75% of cigarettes) at night (Late smokers; n = 7, 27%), and a distinct, classic “Social smoking” group (n = 4, 15% of total sample), who smoked mostly at night but also primarily when socializing or drinking (86% of their cigarettes), in the evening (71% of their cigarettes), on weekends (65% of their cigarettes), and in bouts (71% of their cigarettes). Overall, results suggest that non-daily smoking patterns are quite heterogeneous, and that many non-daily smokers may not be primarily social smokers.     

Does smoking influence the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine?

Twelve healthy habitual cigarette smokers and eight non-smokers participated in a double-blind placebo controlled study to determine the effect of smoking on the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine. In smokers, cigarette smoking was standardised and started 1 h before (A), or 2 h after (B) drug administration, or was prohibited (C). Intragastric pH-levels (IGpH) were measured with an ambulatory pH-recorder. Famotidine (40 mg orally) significantly raised median 22 h IGpH in non-smokers and smokers in all study periods. The smoking sequence (A, B, C) did not significantly influence median 22 h IGpH in both placebo-treated and famotidine-treated smokers, and no significant difference in median 22 h IGpH was shown between smokers and non-smokers. Plasma drug concentrations were similar in the various experiments, although famotidine was detected earlier in plasma from non-smokers compared with smokers (P less than 0.05). Smoking did not interfere significantly with the pharmacokinetics and pharmacodynamics of famotidine.     

Multiple plasma peaks of acetaminophen and ranitidine after simultaneous oral administration to rats

Acetaminophen (AAP) and ranitidine (RT) were coadministered orally to nine rats, and the possible contribution of the gastric emptying to the plasma concentration profiles of them was examined. The drugs showed multiple plasma peaks similar to the respective ones after separated administration of each durg. It implies that there is no significant interaction between AAP and RT in terms of the gastric emptying or drug absorption. There were no significant linear correlations of the peak patterns (peak height and peak time) between AAP andd RT. It is contrary to the expectation from the biphasic gastric emptying (BGE) theory previously suggested for AAP and RT. The BGE theory, therefore, seemed to have some draw-backs in explaining satisfactorily the multiple plasma peaks of AAP and RT. Two more doubts raised previously against the BGE theory were also discussed.     

Stimulant-induced changes in smoking and caloric intake: Influence of rate of onset

Rate-of-onset modulates the subject-rated effects of stimulants. Results of two studies from our laboratory demonstrate that immediate-release methylphenidate increases smoking and decreases caloric intake. Whether rate-of-onset influences the effects of methylphenidate on smoking and eating is unknown. The present experiment examined the influence of a range of doses of immediate- (7.5-30 mg) and sustained-release (18-72 mg) methylphenidate as well as placebo on smoking and eating. Eight cigarette smokers participated. A double-dummy drug administration procedure was used to maintain the double blind because immediate-release methylphenidate produces peak plasma concentrations 1.5-2 h and the sustained-release formulation produces peak plasma concentrations 6-8 h after oral administration. Smoking and eating were assessed for 4 h across the predicted peak effects of both methylphenidate formulations. Measures of smoking included total cigarettes, puffs, and carbon monoxide levels. Snacks and decaffeinated beverages were available ad libitum and caloric intake was monitored during the four-hour smoking session. Immediate- and sustained-release methylphenidate increased smoking and decreased caloric intake. The effects of methylphenidate generally did not vary as a function of formulation. The results of this study may have important implications for the treatment of disorders that require stimulant medications. Smoking should be monitored in patients that are prescribed stimulant medications, regardless of the formulation type.