Effects of passive smoking on theophylline clearance

Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long-term exposure to cigarette smoke, and seven age-matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48-hour postinfusion period. Clearance for passive smokers was 6.01 x 10(-2) L/hr.kg and for nonsmokers, clearance was 4.09 x 10(-2) L/hr.kg (p less than 0.025). Terminal elimination half-life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p less than 0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p less than 0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p less than 0.004) and urine (p less than 0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r = 0.73, p less than 0.01) and urine (r = 0.79, p less than 0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system.     

Effects of caffeine on cigarette smoking and subjective response

We examined the effects of oral caffeine on cigarette smoking and subjective response in a group of six smokers who smoked cigarettes ad libitum in a naturalistic laboratory environment. A within-subject, repeated-measures design was used, and each subject received placebo, caffeine base (50 to 800 mg), or d-amphetamine sulfate (25 mg) on several occasions before 90-min daily smoking sessions. There was no evidence of an increase in the number of cigarettes smoked or the amount of smoke inhaled per session after caffeine. Caffeine increased salivary caffeine concentrations, arm tremor, and self-reported measures of mood and subjective response. The major subjective effects of caffeine were increases in tension-anxiety and dysphoric-somatic effects. In contrast, d-amphetamine induced increases in the number of cigarettes smoked and in the amount of smoke inhaled per session. The major subjective effects of 25 mg of d-amphetamine were increases in measures of well-being, euphoria, and mental efficiency. Results demonstrate that caffeine and d-amphetamine have different effects on cigarette-smoking behavior as well as on subjective response and suggest that the positive correlation between cigarette smoking and coffee drinking is not the result of a simple pharmacologic effect of caffeine.     

Influences of smoking and caffeine consumption on trigeminal pain processing

Background

Many human and animal studies have shown the influence of nicotine and caffeine on pain perception and processing. This study aims to investigate whether smoking or caffeine consumption influences trigeminal pain processing.

Methods

Sixty healthy subjects were investigated using simultaneous recordings of the nociceptive blink reflex (nBR) and pain related evoked potentials (PREP) following nociceptive electrical stimulation on both sides of the forehead (V1). Thirty subjects were investigated before and after smoking a cigarette, as well as before and after taking a tablet of 400 mg caffeine.

Results

After smoking PREP showed decreased N2 and P2 latencies indicating central facilitation at supraspinal (thalamic or cortical) level. PREP amplitudes were not changed. NBR showed a decreased area under the curve (AUC) indicating central inhibition at brainstem level. After caffeine intake no significant changes were observed comparing nBR and PREP results before consumption.

Conclusions

Smoking influences trigeminal pain processing on supraspinal and brainstem level. In the investigated setting, caffeine consumption does not significantly alter trigeminal pain processing. This observation might help in the further understanding of the pathophysiology of pain disorders that are associated with excessive smoking habits such as cluster headache. Previous smoking has to be taken into account when performing electrophysiological studies to avoid bias of study results.     

A urinary metabolite ratio that reflects systemic caffeine clearance

Systemic caffeine clearance and urinary metabolite profiles were determined in 15 subjects with diverse exposure histories to cytochrome P-450 inducers (cigarette smoke) and inhibitors (oral contraceptive steroids). A correlation was observed between caffeine clearance and a urinary ratio based on the molar recovery of paraxanthine 7-demethylation products relative to a paraxanthine 8-hydroxylation product (r = 0.91; P less than 0.001). Analysis of urinary metabolites was undertaken in a larger population to assess the effects of gender, age, oral contraceptives, and smoking on the ratio. No gender differences were observed in either adults or children; children (n = 21) showed a higher (P less than 0.001) mean metabolite ratio than adults (n = 61), oral contraceptive users (n = 9) had lower (P less than 0.05) ratios than women not taking oral contraceptives (n = 30), and smokers (n = 26) had higher (P less than 0.001) ratios than nonsmokers (n = 61). The data indicate that a urinary metabolite ratio based on paraxanthine 7-demethylation/8-hydroxylation products reflects systemic caffeine clearance and likely monitors cytochrome P-450 activity inducible by polycyclic aromatic hydrocarbons.     

Effect of quinolones on caffeine disposition

Six healthy volunteers received a single caffeine dose after pretreatment with norfloxacin, pipemidic acid, or placebo in a crossover, randomized, single-blind clinical trial. Quinolones altered the pharmacokinetics of caffeine, with a significant increase in the AUCs and a decrease in plasma clearance. The elimination half-life increased significantly with pipemidic acid. The apparent volume of distribution, mean renal clearance, and time to reach maximum caffeine concentrations remained unaltered. There was a decline in caffeine metabolite levels in the 24-hour urine samples for both quinolone treatments, suggesting that pipemidic acid and, to a lesser degree, norfloxacin inhibit metabolism of the N-demethylation pathways of caffeine. The practical consequence of this observation could be caffeine accumulation during repeated intake of coffee. In two additional healthy volunteers under a controlled multiple-dose regimen of caffeine ingestion, administration of pipemidic acid for 2 days caused a fourfold increase in the plasma concentrations of caffeine.     

The effect of cigarette smoking on salivation and esophageal acid clearance

To further define the influence of cigarette smoking on the pathophysiology of gastroesophageal reflux disease, studies were done to evaluate acid clearance in the esophagus and the salivary titratable base secretion of chronic smokers as compared to those of nonsmokers, and to ascertain the acute effects of smoking on these variables. Eight nonsmoking volunteers and 16 cigarette smokers without symptoms of gastroesophageal reflux disease were studied. All studies were initiated after a 6-hour fast, with the smokers also having refrained from smoking. Of the 16 smokers half smoked three cigarettes in the course of the experiments and half did not smoke. The immediate effects of cigarette smoking were a prolongation of the acid clearance time and a diminution of the secretion of salivary titratable base. However, both of these effects were overshadowed by greater baseline differences between the populations of smokers and nonsmokers. As a population the smokers had only 60% of the titratable base secretion of nonsmokers and acid clearance times that were 50% longer than those of nonsmokers. These effects were presumably long-lasting effects of cigarette smoking, although the duration of the effect was not defined. The observed differences in acid clearance are most likely the result of diminished salivary base secretion, since good correlation existed between these parameters.     

咖啡因对鼠牙胚发育的影响

背景：孕期饮用咖啡会导致孕妇钙吸收障碍,影响胎儿牙胚发育。目的：观察咖啡因对鼠牙胚发育的影响。方法：将Wistar孕鼠随机分为2组,在咖啡因组大鼠受孕7d后的饮水中添加咖啡因,对照组孕鼠饮水中不加咖啡因。孕20d时,两组各处死一半孕鼠取胎鼠,苏木精-伊红染色观察牙胚组织形态;另一半孕鼠连续用药至产仔后20d,测定仔鼠血清中钙离子水平,并取仔鼠第一磨牙进行扫描电镜观察。结果与结论：咖啡因组仔鼠血清中钙离子水平低于对照组（P〈0.05）。苏木精-伊红染色可见咖啡因组胎鼠与相同时期对照组胎鼠相比,牙胚组织体积减小,发育迟缓。电镜结果显示咖啡因组孕鼠所产仔鼠的第一磨牙酸蚀后表面空隙比对照组多。提示对孕鼠使用咖啡因可以影响其仔鼠牙胚的发育,导致牙胚发育迟缓,使釉质基质钙化不全,发育后的牙齿不耐酸蚀。     

Effect of hypophysectomy on caffeine elimination in rats

Two groups of 8-week-old Sprague-Dawley male rats were used: 8 hypophysectomized (H[-]), operated on day 0, treated by daily sc tetracosactid (ACTHs: 10 micrograms), and thyroxine (T4:5 micrograms/100 g); 7 sham-operated, treated by sc saline solution. ACTHs, T4, saline solution were administered on days 7-16. The animals received po caffeine (CAF) 4 mg/kg as citrate salt on day 15. Ten blood samples were drawn from the tail. Plasma CAF concentrations were determined by HPLC. CAF apparent clearance and apparent volume of distribution were lower in H(-) rats than in controls: 0.281 +/- 0.072 vs 0.455 +/- 0.165 l/kg/h (-38%; P less than 0.05) and 0.520 +/- 0.239 vs 1.28 +/- 0.266 l/kg (-59%; P less than 0.01) respectively. CAF half-life was lower in H(-) rats than in controls: 1.33 +/- 0.621 vs 2.12 +/- 0.676 h (-37%; P less than 0.01). CAF is a drug with a low hepatic extraction ratio and low plasma protein binding. CAF clearance is therefore primarily dependent on intrinsic clearance, which depends on the activity of the enzymes involved in CAF metabolism. These data suggest that hepatic CAF metabolism is reduced in H(-) rats treated by SC ACTHs and T4. The decrease in CAF apparent volume of distribution is probably related to dehydration, as suggested by increase in urine flow and hematocrit. The CAF half-life was probably low because the volume of distribution was proportionally more decreased than the clearance. Our results suggest that the pituitary gland plays a role in the regulation of hepatic CAF metabolizing enzymes.     

Effect of rifampin on apparent clearance of everolimus

OBJECTIVE: To assess the influence of the CYP3A4 enzyme inducer rifampin on the pharmacokinetics of the immunosuppressant everolimus to provide guidance for their coadministration. METHODS: In this open-label, single-sequence, crossover study, 12 healthy subjects received a single oral 4-mg dose of everolimus alone and again after an 8-day pretreatment with rifampin 600 mg/d. Urinary excretion of 6beta-hydroxycortisol was measured at various time points during rifampin treatment as a marker of CYP3A4 induction. RESULTS: Urine excretion of 6beta-hydroxycortisol was significantly elevated during treatment with rifampin compared with prestudy, indicating enzyme induction. When everolimus was coadministered during rifampin treatment, the apparent clearance of everolimus was significantly increased, on average by 172%. This was manifested as a decrease in maximum concentration in all subjects, on average by 58% (range 14-73%). The AUC remained unaffected in 1 subject (although 6beta-hydroxycortisol indicated enzyme induction) and decreased in the other 11 subjects. The average decrease in AUC in the full study population was 63% (range 0-82%). Everolimus half-life was reduced significantly, from an average of 32 hours to 24 hours. CONCLUSIONS: In everolimus-treated patients for whom rifampin is indicated, alternative agents with less enzyme induction potential than rifampin could be considered. Alternatively, the dose of everolimus could be individually titrated based on everolimus therapeutic drug monitoring during rifampin therapy.     

红细胞压积对血液透析尿素清除率的影响

目的采用猪血离体实验方法探讨红细胞压积(Hct)对血液透析尿素清除率的影响。方法采集新鲜猪血3000ml,加入适量尿素配成含一定尿素浓度的血样本,离心分离血浆与血球,然后按一定比例将血浆与血球重新混合成Hct分别为0、10%、20%、30%、40%、50%、60%、70%的8个全血样本,每份300ml。在相同的血液透析条件下每个血样透析3min,同时收集透析废液,分别测定透析前后血样本及透析废液中的尿素浓度,通过血尿素浓度计算尿素清除量及尿素下降率(URR);通过透析液尿素浓度计算其尿素含量,并与前者比较其一致性。结果随着Hct的增加,URR依次为97.7%、95.6%、90.5%、85.8%、84.1%、75.9%、62.5%、54.8%(相关系数r=-0.9654)(P<0.01);通过透析前后血及透析废液尿素浓度计算出的尿素清除量结果一致。结论随着Hct的增加,尿素的透析清除率将有较明显的下降。同时,该实验为多种血液透析相关研究建立了一种较为合理的血液透析离体实验方法。     

Selective induction of propranolol metabolism by smoking: additional effects on renal clearance of metabolites

The objective of this study was to examine the effect of cigarette smoking on the activities of the three primary pathways governing propranolol metabolism in human subjects, i.e., glucuronidation, side-chain oxidation and ring oxidation. A single 80-mg dose of propranolol p.o. together with 40 muCi of 4-[3H]propranolol was given to six smoking and seven nonsmoking, young, white, male subjects and the oral clearance of propranolol and the partial clearances through these pathways were determined. The oral clearance of propranolol was increased by 77% (P less than .02) in smokers compared with nonsmokers. This apparent induction of propranolol metabolism was due to a 122% increase in side-chain oxidation (P less than .001) and a 55% increase in glucuronidation (P less than .01). There was no significant effect of smoking on aromatic ring oxidation. Smokers had a 30% greater renal clearance of total metabolites (P less than .05), due mainly to a 53% greater renal clearance of the acidic propranolol metabolite naphthoxylactic acid (P less than .001). These data show a selective effect of smoking on propranolol metabolism and suggest that side-chain oxidation and glucuronidation are mediated by isoenzymes inducible by aromatic hydrocarbons. The selective effect of smoking on the renal clearance of the major propranolol metabolite naphthoxylactic acid may be due to induction of a renal transport protein.     

Effect of oral contraceptives on plasma clearance.

The effects of chronic steroid contraceptive therapy on drug clearance from plasma were studied by using plasma antipyrine, phenylbutazone, and cholecalciferol half-lives in women. After 3 mo of oral steroid therapy (Norinyl, 2 mg; norethindrone + mestranol), the antipyrine half-life was increased in 3 of 6 subjects, phenylbutazone half-life was not consistently altered, and vitamin D3 half-life was increased in 3 of 4 patients. After 1 to 7 yr of oral steroid theraphy, the antipyrine half-life was longer while taking the contraceptive than when the contraceptive treatment was discontinued in 4 of 6 subjects, whereas that of phenylbutazone was not consistently altered.