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Smoking mentholated cigarettes has been suggested to convey a greater cancer risk compared with smoking nonmentholated cigarettes. Two of the possible mechanisms by which mentholated cigarette smoking could increase risk are by increasing systemic exposure to tobacco smoke toxins and by affecting the metabolism of nicotine or tobacco smoke carcinogens. To examine these possibilities, we performed a crossover study in 14 healthy smokers, one-half of whom were African-Americans and one-half whites. Subjects were randomly assigned to smoke mentholated or nonmentholated cigarettes for 1 week, then to cross over to the other type of cigarettes for another week. Subjects were confined to a Clinical Research Center for 3 days of each week, during which time blood levels of nicotine and carbon monoxide were measured throughout the day and an intravenous infusion of deuterium-labeled nicotine and cotinine was administered to determine the rate and pathways of nicotine metabolism. The systemic intake of nicotine and carbon monoxide was, on average, not affected by mentholation of cigarettes. Mentholated cigarette smoking did significantly inhibit the metabolism of nicotine (clearance: 1289 versus 1431 ml/min, two sided, p = 0.02). Inhibition of nicotine metabolism occurred both by slower oxidative metabolism to cotinine and by slower glucuronide conjugation. Our data do not support the hypothesis that mentholated cigarette smoking results in a greater absorption of tobacco smoke toxins. Our finding of impaired metabolism of nicotine while mentholated cigarette smoking suggests that mentholated cigarette smoking enhances systemic nicotine exposure.

Cigarette smoking is the foremost modifiable risk factor for adverse pregnancy outcomes. Nicotine is a suspected fetal neuroteratogen. There is concern that nicotine may achieve toxic levels during pregnancy if nicotine replacement therapies are prescribed at doses used in the nonpregnant state. Ten healthy, volunteer, pregnant smokers received infusions of deuterium-labeled nicotine and cotinine during pregnancy and again postpartum. From blood and urine measurements, the following were determined: clearance (renal and nonrenal) of nicotine and cotinine, clearance of nicotine via the cotinine pathway (an indicator of CYP2A6 activity), and daily intake of nicotine from smoking. The clearance of nicotine and cotinine was significantly higher (60 and 140%, respectively), and the half-life of cotinine was much shorter (8.8 versus 16.6 h, P < 0.01) during pregnancy. Although plasma levels of cotinine were lower during pregnancy (119 versus 202 ng/ml, P < 0.05), daily intake of nicotine from smoking was similar during pregnancy and postpartum. For a given level of intake, the pharmacologic and toxicologic effects of nicotine during pregnancy are anticipated to be less than expected from nicotine metabolism data in nonpregnant women. Our data indicate that no downward dose adjustment needs to be made for nicotine replacement therapy during pregnancy. Conversely, higher than usual doses of nicotine may be necessary to optimize efficacy. Lower cotinine levels observed during pregnancy do not necessarily reflect less smoke exposure, and cut-off levels used to classify nonsmokers, passive smokers, and active smokers need to be established for pregnancy.

Following rapid IV injection (0.1 mg per kilogram) lidocaine HC1 concentrations were measured in the blood and brain of paralyzed, ventilated rats during bicuculline-induced status epilepticus and in identically prepared controls. The concentration of lidocaine in blood and brain was consistently higher in convulsing than in noncon- vulsing rats. At 1 minute, increased brain lidocaine reflected elevated blood concentrations; increased brain and blood partitioning after 1 minute is responsible for subsequent increases in brain lidocaine uptake. The therapeutic index of lidocaine is low; the concentration of lidocaine is increased in the convulsing brain. Our data suggest that conventional lidocaine doses may perpetuate rather than control refractory convulsions.

Buprenorphine administered sublingually is a promising treatment for opiate dependence. Utilizing a new, sensitive, and specific gas chromatographic electron‐capture detector assay, the absolute bioavailability of sublingual buprenorphine was determined in six healthy volunteers by comparing plasma concentrations after 3‐ and 5‐minute exposures to 2 mg sublingual and 1 mg intravenous buprenorphine. The amount of unabsorbed buprenorphine in saliva was measured after 2‐, 4‐, and 10‐minute exposures to 2 mg sublingual buprenorphine in 12 participants. Pharmacokinetic parameters were analyzed by analysis of variance; bioequivalence was evaluated by the Schuirmann two‐sided test. The 3‐ and 5‐ minute sublingual exposures each allowed 29 ± 10% bioavailability (area under the plasma concentration—time curve unextrapolated) and were bioequivalent. Buprenorphine recovered from saliva after 2‐, 4‐, and 10‐minute exposures was, on average, 52% to 55% of dose. Increased saliva pH was correlated with decreased recovery from saliva. Study results indicate that bioavailability of sublingual buprenorphine is approximately 30%. Sublingual exposure times between 3 and 5 minutes produce equivalent results. Buprenorphine remaining in saliva causes an almost twofold overestimation of bioavailability.

Cocaine abuse is a common clinical problem among opioid-dependent patients who are in methadone maintenance treatment. In an open prospective study, 16 DSM-III-R, cocaine-dependent, methadone maintenance treatment patients were treated with fluoxetine, at a mean dose of 45 mg/day for 9 weeks. Eleven subjects (69) were infected with the human immunodeficiency virus. Cocaine use was significantly reduced by the end of treatment, although most subjects did not achieve abstinence. Comparison of intake to week 9 showed a significant decrease in self-reported cocaine use, craving, and quality of high. Actual cocaine use was measured by a quantitative analysis of cocaine and benzoylecgonine (BE) concentrations in plasma and urine. Median BE and cocaine concentrations in urine decreased significantly from intake to week 9 of fluoxetine treatment. This decrease would not have been detected if BE had been measured only qualitatively, as present or absent in the urine. Fluoxetine was well tolerated in combination with methadone and did not appear to alter methadone concentrations in plasma. Few adverse effects were noted. No subjects had to discontinue fluoxetine. Fluoxetine may be a promising treatment approach for cocaine abuse in methadone maintenance patients. Quantitative detemination of exact cocaine and BE concentrations in biofluids may be a more accurate method of measuring cocaine use outcome than qualitative urinalysis.

Daily intake of nicotine in 22 subjects was estimated from metabolic clearance data obtained after intravenous infusion of nicotine and from blood and urinary nicotine concentration data obtained over 24 hr when the subjects were smoking cigarettes. Daily intake of nicotine averaged 37.6 mg (±17.7, SD) but varied widely among subjects (10.5 to 78.6 mg). Men metabolized nicotine faster than did women, but daily intake of nicotine did not differ. Intake correlated strongly with cigarettes smoked per day (r = 0.59) but not with machine-determined yield. Nicotine intake per cigarette averaged 1.04 mg ( ±0.36) but did not correlate with machine-determined yield. Correlations between several commonly used biochemical markers of tobacco smoke and nicotine intake were examined; the afternoon (4:00 P.M.) blood level of nicotine was the best marker.Clinical Pharmacology and Therapeutics (1984) 35, 499–504; doi:10.1038/clpt.1984.67

Caffeine metabolism is known to be accelerated in cigarette smokers, but the effects of smoking on the kinetics and pattern of metabolism in a daily consumption pattern have not been described. We investigated the effects of tobacco abstinence on the rate and pattern of caffeine metabolism in nine habitual smokers who consumed six cups of coffee per day, each cup containing 2 mg/kg caffeine. Abstinence from smoking for 4 days resulted in a 46% increase in the 24-hour AUC. Thus, significant, although probably not complete, normalization of the enzyme-inducing effects of cigarette smoking can be seen after 4 days abstinence. During abstinence, 24-hour urine ratios of dimethylxanthines to caffeine and mono-dimethylxanthines to dimethylxanthines were reduced, suggesting that cigarette smoking accelerates both demethylation steps. Other metabolic pathways were unaffected.

Zavarygin et al. compiled a list of 15 deuterium abundance measurements; two were discarded because the remaining 13 measurements are then consistent with Gaussianity. Those authors found that the weighted-mean baryon density (?bh2) determined from the 13 measurements is mildly discrepant (1.6?) with that determined from the Planck 2015 cosmic microwave background anisotropy data in a flat cosmogony. We find that a median statistic central estimate of ?bh2from all 15 deuterium abundance measurements is a more accurate estimate; is very consistent with ?bh2estimated from Planck 2015 data in a flat cosmogony, but is about 2?lower than that found in a closed cosmogonical model from the Planck 2015 data.