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The brain uptake of phenobarbital during prolonged status epilepticus (3 h) was studied in paralyzed, ventilated sheep. The first 30 min of status epilepticus was characterized by systemic hypertension, increased CBF, increased peripheral vascular resistance, a fall in brain pH, and an elevation in brain lactate concentrations. Subsequently, hemodynamic factors normalized and brain acidosis persisted. Phenobarbital administered during the early phase of status epilepticus produced higher levels of brain phenobarbital concentration, which was greatest at the earliest sample time (5 min following infusion), compared to nonseizure controls. This elevation persisted for the first 3 h following the infusion. Phenobarbital administration during the established phase of status epilepticus, when systemic blood pressure, peripheral vascular resistance, and CBF had returned to preseizure values, resulted in attenuated brain uptake not different from controls for the first 30 min. These results are explained by disruption of the blood-brain barrier to phenobarbital during the early (hypertensive) phase of status epilepticus.

Plasma concentrations and urinary excretion of meperidine and its metabolite normeperidine were determined after intravenous and oral administration to 11 men; five men had hepatic cirrohosis and six were normal. Systemic clearance of meperidine was smaller and bioavailability and half-life greater in the cirrhotic patients than in the normal subjects. Plasma concentrations and 24-hr urinary excretion of normeperidine was lower and persistence of normeperidine in plasma longer in the patients with cirrhosis. The route of administration did not alter the fraction of normeperidine generated from meperidine. The results suggest that in patients requiring repeated meperidine dosage the drug should be taken parenterally rather than orally to allow maximal analgesia and minimal formation of normeperidine. Patients with cirrhosis may be relatively protected from normeperidine toxicity because of impaired formation, but the risk of cumulative toxicity may be greater than in normal subjects because of slower elimination of the metabolite and greater sensitivity to the effects of narcotics on the central nervous system. Clinical Pharmacology and Therapeutics (1981) 30, 183–188; doi:10.1038/clpt.1981.146

An automated gas chromatographic method for determination of theophylline in plasma is described. A novel feature of this assay is the use of triethylsulfonium hydroxide as an on-column alkylating agent. A simple extraction procedure together with automated sample injection and data processing has facilitated processing of large numbers of samples generated in pharmacokinetic studies. The between-run coefficient of variation was 2.2% at 5 micrograms/ml (n = 5) and 3.9% at 15 micrograms/ml (n = 6). Within-run coefficient of variation was 2.4% at 5 micrograms/ml (n = 9) and 3.3% at 15 micrograms/ml (n = 6). Accuracy was 105% at a concentration of 5 micrograms/ml and 102% at 15 micrograms/ml.

Habitual tobacco smoking accelerates the metabolism of many drugs. With tobacco abstinence, it was expected that nicotine metabolism would be slower than when smoking. To test this hypothesis, the disposition kinetics of intravenous nicotine were studied in 20 healthy smokers while smoking, after abstaining from smoking for 1 week, and (in six subjects) when smoking again. Cardiovascular responses to nicotine were also measured. Unexpectedly, total and nonrenal clearance of nicotine increased by 36% and 39%, respectively, during abstinence. The increase in clearance after brief abstinence suggests that nicotine or its metabolites or another component of cigarette smoke inhibits nicotine metabolism in smokers. Cardiovascular responses to nicotine were greater after 1 week compared with overnight abstinence, consistent with loss of tolerance.

A method is described for extraction of the cocaine metabolite benzoylecgonine, conversion to the butyl ester derivative and gas chromatographic analysis using packed or capillary columns. Using a capillary column, cocaine and benzoylecgonine may be determined simultaneously. The extraction scheme has been designed to facilitate processing of large numbers of samples generated in pharmacokinetic studies. Structural analogues, m-toluylecgonine and m-toluylecgonine methyl ester, are used as internal standards. Concentrations as low as 10 ng/ml in 1-ml samples of plasma or urine are readily determined. Between-run coefficients of variation were 1.01% for cocaine and 4.18% for benzoylecgonine for concentrations of 75 and 350 ng/ml, respectively.

A number of procedures have been employed for the synthesis of sulfur-substituted aromatics; e.g., electrophilic substitution with sulfur-containing electrophiles such as sulfenyl halides1,2, chlorosulfonic acid3 and sulfoxides4, nucleophilic substitution of aryl halides with metal mercaptides5,6, replacement reactions involving diazonium intermediates7,8, and conversion of phenols to thiophenols via thermal rearrangement of thiocarbamates9. Aromatic systems with sulfur-containing substituents have also been prepared by nucleophilic addition to quinones10,11 or their mono12 or diketals13.

We measured daily nicotine intake in 11 habitual smokers who smoked their usual brand or commercial high-yield (Federal Trade Commission [FTC] yield 1.2 mg nicotine, 16 mg tar) or low-yield (0.4 mg nicotine, 5 mg tar) cigarettes. Daily nicotine intake was measured from metabolic clearance data in conjunction with blood and urinary concentrations of nicotine during 24-hr smoking periods. On the average, subjects consumed 35 mg nicotine while smoking their usual cigarettes and 26 mg while smoking either high- or low-yield commercial cigarettes different from their usual brand. This level of nicotine consumption from low-yield cigarettes was because smokers obtained 60% more nicotine per cigarette than predicted by FTC yield and they smoked 25% more cigarettes a day. Although there was considerable variability in nicotine intake between subjects, there was a correlation within subjects between intake while smoking their usual brand and experimental cigarettes. Nicotine intake between the two commercial high- or low-yield cigarettes also correlated (r = 0.86). These findings are consistent with a minimal level of acceptable daily intake of nicotine for individuals that is related to usual intake. We suggest that our protocol provides a better quantitative estimate of the yield of different cigarette brands and potential health hazards than those currently provided by the FTC.

The illicit synthesis of the popular drug 3,4-methylenedioxyamphetamine (MDA) has frequently called upon the precursor piperonylacetone, which is reductively aminated with ammonium hydroxide. The term "piperonylacetone" has been used for two distinct chemical entities in the chemical literature, vis., 3,4-methylenedioxyphenylacetone or 3,4-methylenedioxybenzylacetone. It is only the first of these two chemicals which will give rise to MDA. The second chemical has been made commercially available as piperonylacetone and, employing the usual recipes, produces 1-(3,4-methylenedioxyphenyl)-3-aminobutane. This amine could be mistaken for MDA if only simple presumptive tests are employed. This latter base is largely unexplored pharmacologically and toxicologically and, as it may reasonably appear in illicit drug traffic misrepresented as MDA, it may well represent a clinical problem of unforseeable consequences.

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.

Recent studies of quantitative and qualitative aspects of nicotine metabolism, and the use of metabolic data for estimating nicotine intake in humans are discussed. Previously reported methodology for determining nicotine bioavailability has been improved by using stable isotope-labeled nicotine administered intravenously. Combined gas chromatography-mass spectrometry with selected ion monitoring has been used to simultaneously determine concentrations of isotopically-labled nicotine and tobacco-derived nicotine in blood. Nicotine intake from cigarette smoking was estimated from clearance of labeled nicotine and blood concentrations of tobacco-derived nicotine. Progress in elucidating the metabolic profile of nicotine in humans, and the use of nicotine metabolites as markers of tobacco smoke consumption is summarized.

Pretreatment blood cotinine levels, expired carbon monoxide levels, and self-reported cigarette consumption were evaluated as predictors of smoking treatment outcome in 114 patients. Of these indices of nicotine intake, blood cotinine level was the most useful predictor. High blood cotinine level was the best predictor of dropping out before completion of treatment and of smoking at the end of treatment and at follow-ups. The usefulness of cotinine as a marker of tobacco dependence is discussed.

A 38-yr-old woman who by history ingested 13 g methylphenobarbital, alcohol, and 6 g acetaminophen became comatose slowly over 4 d. Acute hepatic injury appeared to impair the oxidative N-demethylation of methylphenobarbital to its product, phenobarbital. On the eighth day after ingestion she was treated because of protracted coma with Amberlite XAD-4 resin hemoperfusion. Hemoperfusion, which removed 0.83 g methylphenobarbital and 2.10 g phenobarbital, led to transient clinical improvement. When supportive patient management fails to produce a satisfactory clinical course in a methylphenobarbital-intoxicated patient, hemoperfusion could be a useful adjunct to therapy.

A wide variety in the origin, purposes, organization, and control exists among these institutions in Georgia. Most of them are two-year units. Among the public junior colleges there are five junior units of the University System of Georgia; one "branch" state college, maintained as an afternoon program of the Atlanta Division of the University of Georgia; one military college with state and city support; and three municipal colleges, with three entirely different programs and organizations. There are also eight private junior colleges, all church-related.

A method is described for the determination of meperidine and its pharmacologically active metabolite, normeperidine, in blood, plasma, and urine using gas chromatography with nitrogen-phosphorus detection. Structural analogs of both meperidine and normeperidine were used as internal standards. Unlike previously reported assays, this procedure was sensitive and convenient enough for use in pharmacokinetic studies of both meperidine and normeperidine following single doses of meperidine. The assay was sensitive to 5 ng of meperidine/ml and 2.5 ng of normeperidine/ml extracted from a 1-ml biological sample. The between-assay coefficients of variation at these concentrations were 9.4 and 10.4%, respectively.

More definitely stated, the problem is: What vocabulary and syntax, what reading material, and what choice of emphasis among the several accepted values of Latin study, are of most worth to the highschool student, irrespective of subsequent work in the subject? The study of this problem is the outgrowth of a group undertaking, in which the present writer participated, under the direction of Prof. J. J. Didcoct, Professor of Secondary Education, George Peabody College for Teachers, to organize a course in high-school Latin which would be educationally sound. Early in the development of the project it became apparent to the writer that a complete reorganization was necessary before highschool Latin could be brought into harmony with present educational objectives. He undertook accordingly to determine and set forth the educational principles which should govern such a reorganization and to outline the general lines of procedure. The principles and methods arrived at will not be presented in the present paper, but will be reported in a subsequent discussion. To state the main point briefly, the only legitimate important purpose of high-school Latin seems to be to aid the pupil in his mastery of English. Acceptance of this objective would lead a school to adopt: (1) a scientifically selected body of Latin subject-matter material which has been evaluated by a quantitative study of its contribution to the English language; (2) a radical change in methods of presentation. The first point mentioned, the selection of the material, involves: (a) determining the Latin vocabulary which is of the most value for derivatives in English; (b) selecting, or constructing, Latin reading material which will utilize most fully this vocabulary and at the same time will also involve the points of Latin grammar most applicable to ordinary English grammatical usage. This paper deals in a preliminary way only with the first phase of these objectives-the determination of a Latin vocabulary of positive and known value to the mastery of English words which people commonly use. The procedure is explained. The list itself, which the writer has in preparation, must await later publication.

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.

A method is described for the determination of methadone and its primary metabolite, 1,5-dimethyl-3,3-diphenyl-2-ethylidinepyrrolidine, in biologic fluids using gas chromatography with nitrogen-phosphorus detection. A simple extraction scheme is employed that is convenient for processing the large numbers of samples generated in pharmacokinetic studies. The method is sensitive enough for accurate determination of concentrations less than 5 ng/mL of both methadone and its primary metabolite in 1 mL of biologic specimens.

The disposition kinetics of nicotine and cotinine enantiomers was determined in rabbits. The clearance of (R)-nicotine was similar to that of (S)-nicotine, but clearance of (R)-cotinine was twice that of (S)-cotinine. Fractional conversions of both enantiomers of nicotine to cotinine were approximately 50%. These results suggest that in rabbits the biotransformation pathways of cotinine, but not nicotine, are influenced by stereochemistry. The disposition kinetics of nicotine enantiomers in beagle dogs was also studied. In dogs, the clearance of (R)-nicotine was slightly greater than the clearance of (S)-nicotine. Methods for the synthesis of (R)-nicotine and (R)-cotinine of high enantiomeric purity and a gas chromatographic method for determination of nicotine enantiomeric purity are described.

Two monothio analogues of mescaline and three monothio analogues of 2,3,4-trimethoxyphenethylamine (isomescaline) have been synthesized and characterized. Only the two mescaline analogues (3-and 4-thiomescaline) were found to be psychotomimetics in man, being 6 and 12 times more potent than mescaline, respectively. All five compounds can serve as substrates for bovine plasma monoamine oxidase in vitro, but no positive correlation is apparent between the extent of enzymatic degradation and human psychotomimetic potency.

(1982). 1-(3,4-Methylenedioxyphenyl)-3-aminobutane: A Potential Toxicological Problem. Journal of Toxicology: Clinical Toxicology: Vol. 19, No. 1, pp. 109-110.

Why do people habitually consume tobacco and how does tobacco use influence the health of the habitual user? Complete answers to these questions are many years away. But a beginning is an understanding of the human pharmacology of nicotine, which is the primary pharmacologically active substance in tobacco. Central issues include: (1) What are the pathways and rate of metabolism? (2) How does elimination rate influence effects of nicotine or smoking behavior? (3) What is the time course of nicotine in the body during regular tobacco use? (4) What is the relationship between dose, concentration, and effects? (5) How does tolerance influence effects of nicotine? We will review a number of studies conducted in our laboratory examining these issues.

Nicotine was given intravenously to subjects during acid and alkaline urine conditions in doses and a dosing schedule designed to simulate cigarette smoking. Total clearances were greater, terminal half-lifes shorter, but volumes of distribution much the same in acid (pH 7) urine conditions. The effect of urinary pH on total clearance was due entirely to changes in renal clearance, which accounted for 23% and 2% of total clearance in acid and alkaline urine conditions. Nicotine injections induced a sensation of arousal and increased heart rate and blood pressure over the short term, but with repeated injections tolerance to these effects developed rapidly. No differences in subjective or physiologic responses to intravenous nicotine were observed and we consider it unlikely that the effects of smoking a cigarette differ as a function of urinary pH. Clinical Pharmacology and Therapeutics (1980) 28, 517–522; doi:10.1038/clpt.1980.196

To examine the plausibility of the hypothesis that smoking a cigarette after a meal is motivated by accelerated metabolism of nicotine, we studied the influence of a high-protein meal on the disposition of nicotine in seven healthy smokers. Indocyanine green clearance, an estimate of hepatic blood flow, increased 31%, 50 minutes after the test meal. Consuming the meal during a steady state infusion of nicotine resulted in a small (18%) but consistent decrease in blood levels of nicotine. Our data demonstrate that food accelerates the metabolism of nicotine, but the time course and magnitude of the decline in levels of nicotine suggest that altered disposition of nicotine is not the primary motivation for smoking after meals.

A rapid and sensitive gas chromatographic method is described for the determination of cocaine in plasma. A close structural analogue of cocaine, m-toluylecgonine methyl ester, is used as an internal standard. The simplicity of the extraction scheme and the use of an automatic sampler makes the method convenient for large numbers of samples generated in pharmacokinetic studies.

When cigarette smokers with chronic lung disease become acutely ill or require surgery, they are often forced to stop smoking and may use nicotine gum. Smoking is known to accelerate the metabolism of theophylline, but the effects of short-term abstinence or nicotine gum on theophylline metabolism have not been reported. We studied the effects of brief tobacco abstinence and nicotine gum on theophylline elimination in healthy volunteers. Abstinence from smoking for 1 week resulted in a 37.6% decrease in clearance and a 35.8% increase in half-life. Nicotine gum had no effect on theophylline clearance. Our data indicate that at least partial normalization of the enzyme-inducing effects of smoking can be seen after brief cigarette abstinence. For smokers who are taking theophylline chronically, their dose of theophylline will need to be reduced by one fourth to one third after brief tobacco abstinence. Plasma concentration monitoring may be necessary for optimal dosing of theophylline in such patients.

Autoxidation of the bis(O-demethyl)-p-hydroquinone metabolite of the psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) at pH 7.4 leads exclusively to a bicyclic imino quinone. This imino quinone is a good alkylating agent, forming covalent adducts via 1,4 addition to thiols. The autoxidation appears to be dependent on trace metal catalysis and is dramatically inhibited by components of the 10000g supernatant fraction of rabbit liver homogenates. Incubation of tritium-labeled hydroquinone with bovine serum albumin under oxidizing conditions leads to significant amounts of nonextractable radioactivity which presumably is dependent on imino quinone alkylation of nucleophilic functionalities present on macromolecules. Incubation of tritium-labeled DOM with rabbit microsomes in the presence of NADPH leads to irreversible binding of the label to macromolecular components of the microsomes. Since this binding is NADPH dependent, it is likely that metabolic conversion of DOM to the hydroquinone is involved. The imino quinone oxidation product is highly lypophilic and is capable of crossing the blood-brain barrier. Intravenous administration of tritium-labeled imino quinone to rats resulted in significant nonextractable radioactivity in brain tissue. These properties of the hydroquinone metabolite parallel those reported for the structurally related sympatholytic compound 6-hydroxydopamine and have led to the hypothesis that the psychotomimetic properties of DOM may be mediated through 6-hydroxydopamine-type interactions of the hydroquinone with important macromolecules in the brain.

Publisher Summary This chapter discusses the nicotine dependence and tolerance in man. Pharmacokinetic and pharmacodynamic characteristics of a drug are important determinants of dependence liability, the temporal patterns of drug use, and the level of drug use. Ultimately, an understanding of pharmacokinetics and pharmacodynamics may be useful in developing effective treatment strategies. Several pharmacokinetic and pharmacodynamic characteristics appear to be necessary or optimal for a drug to produce dependence: the drug must be effectively absorbed into the blood stream, the drug must rapidly enter into the brain, and the drug must be psychoactive and that psycho activity related to levels of the drug in the brain. These characteristics allow for the drug abuser to manipulate the dose of his or her drug to optimize mood and psychological functioning and are most likely to result in the behavior described as criteria for drug dependence. This chapter examines the pharmacokinetic and pharmacodynamic characteristics of nicotine and how these characteristics might determine cigarette smoking behavior and tobacco addiction.

• Depression and dysphoria can follow the long-term use of cocaine. Little is known about the interaction of antidepressant drugs with cocaine and similar stimulants in humans. The physiologic and subjective effects of an oral 2-mg/kg dose of cocaine hydrochloride were measured in eight healthy cocaine-using men after pretreatment with a single, 100-mg oral dose of the triazolopyridine antidepressant trazodone hydrochloride or placebo in a double-blind study. The cocaineinduced effects of increased BP, increased pupil size, and decreased skin temperature were diminished by trazodone pretreatment. Trazodone alone did not alter plasma epinephrine or norepinephrine levels. An increase in plasma epinephrine levels after cocaine administration was not altered by trazodone pretreatment, but the increase in the norepinephrine level was larger. Trazodone alone produced mild sleepiness. Cocaine-induced euphoria was not altered by trazodone pretreatment, although feelings of tension and shakiness after cocaine administration were diminished.

Cotinine is the major metabolite of nicotine in man. We studied cotinine disposition kinetics in 28 healthy habitual cigarette smokers. Eight subjects received cotinine fumarate, 4 micrograms base/kg/min IV for 60 min. Mean (+/- SD) metabolic clearance was 60 +/- 12 ml/min and mean renal clearance was 12 +/- 5 ml/min, averaging 17% of total clearance. Steady-state volume of distribution was slightly greater than body weight (mean 88 +/- 17 l). Terminal t 1/2 averaged 15.8 +/- 4.0 hr in these eight subjects and 19.7 +/- 6.5 hr in another 12 subjects who abstained from smoking for 3 days. The effect of urinary acidification and alkalinization on renal clearance of cotinine during cigarette smoking was studied in another group of eight subjects. Compared with baseline (mean urinary pH 5.8, renal clearance 12.3 +/- 5.9 ml/min), renal clearance was increased about 50% by urinary acidification (pH 4.4, clearance 18.6 +/- 10 ml/min), but it was not affected by alkalinization (pH 6.7, clearance 14.0 +/- 10.4 ml/min). Infusion of cotinine to blood concentrations seen in moderately heavy smokers had no effect on heart rate, blood pressure, or skin temperature, measures that are sensitive to effects of nicotine. No spontaneous subjective effects were reported. We conclude that, at levels to which cigarette smokers are generally exposed, cotinine exerts no cardiovascular activity and weak, if any, psychologic activity.

To compare exposure to nicotine and related cardiovascular effects as well as urinary mutagenicity (a potential marker of systemic absorption of carcinogenic compounds) during use of oral snuff, chewing tobacco, and cigarettes, as desired.Crossover sequential treatments, balanced-order experimental study.Clinical research center.Eight healthy men who regularly smoked cigarettes and had previous experience with the use of both oral snuff and chewing tobacco.Four 3- or 4-day blocks during which participants used oral snuff, chewing tobacco, and cigarettes as desired, or abstained from all tobacco. Concentrations of nicotine and cotinine (the primary metabolite of nicotine), cardiovascular effects, and urine sodium, catecholamine and mutagenicity were measured over 24 hours at the end of each treatment block.Circadian exposure to nicotine and cardiovascular effects, including urinary catecholamine excretion, were similar for all forms of tobacco use. Urine sodium excretion was greater while using smokeless tobacco than while smoking, probably due to absorption of sodium from the smokeless tobacco. Urine mutagenicity was markedly increased while smoking cigarettes and tended to be increased (P less than 0.10) while chewing tobacco but not while using oral snuff.Systemic absorption of nicotine, sodium, and carcinogenic chemicals from smokeless tobacco may cause or aggravate human illness in addition to the known adverse effects on the oral cavity.

Ethanol and tobacco consumption are commonly associated. Both are risk factors for adverse cardiovascular events. To better understand the interactions, the influence of oral ethanol pretreatment (0.5 or 1.0 gm/kg over 60 minutes) on cardiovascular responses to and disposition kinetics of intravenous nicotine was studied in healthy volunteers. Ethanol increased heart rate, systolic blood pressure, and pressure-rate product in a dose-related manner. Nicotine had additive effects on heart rate and pressure-rate product. It also decreased skin temperature, reflecting cutaneous vasoconstriction, but this effect was antagonized by ethanol. Ethanol did not affect metabolic clearance but increased CLR of nicotine by 25%. Additive cardiovascular effects of ethanol and nicotine could contribute to arrhythmias and sudden death in patients with coronary heart disease. It is unlikely that an effect of ethanol on nicotine metabolism is responsible for increased cigarette smoking while drinking ethanol. Clinical Pharmacology and Therapeutics (1986) 40, 420–424; doi:10.1038/clpt.1986.200

Four methadone-maintained subjects were given diazepam (0.3 mg/kg) for 9 days. During the dual drug period, the effects and kinetics of methadone and of its major pyrrolidine metabolite were not altered. These findings indicate that, unlike its effects in rodents, diazepam does not inhibit the metabolism of methadone in man. Clinical Pharmacology and Therapeutics (1982) 31, 139–143; doi:10.1038/clpt.1982.22

The alpha-ethyl phenethylamine derivative 1-(1,3-benzodioxol-5-yl)-2-butanamine was prepared. An asymmetric synthesis was used to prepare the enantiomers of this compound and the related alpha-methyl homologue (MDA). The racemates and enantiomers of both compounds were evaluated in the two-lever drug discrimination assay in rats trained to discriminate saline from 0.08 mg/kg of LSD tartrate. Stimulus generalization occurred with the racemate and the R-(-) enantiomer of the alpha-methyl homologue and the S-(+) enantiomer of the alpha-ethyl primary amine. No generalization occurred with the other enantiomers or with the N-methyl derivatives of either series. Human psychopharmacology studies revealed that the N-methyl derivative of the title compound was nonhallucinogenic and that it had a new, novel psychoactive effect. It is suggested that this compound is the prototype of a new pharmacologic class that may have value in facilitating psychotherapy and that this class be designated as entactogens.

To elucidate the importance of nicotine in determining the effects of cigarette smoking, we studied 10 healthy subjects on a research ward who were either smoking their usual brand of cigarettes, smoking high- (HN, 2.5 mg) or low- (LN, 0.4 mg) nicotine research cigarettes, or abstaining. Blood nicotine concentrations were four times as high smoking HN than LN cigarettes. Values while smoking their own brands were intermediate. Cigarette smoking increased mean (24-hr) heart rate (HR), but HR effect did not differ as a function of nicotine exposure. Analysis of the hourly HR pattern showed that smoking increased HR more over the first few hours of the morning, but then followed a circadian pattern similar to that during abstention. HR remained elevated all night even though no cigarettes were smoked. Blood pressures tended to be higher while smoking, but plasma Cortisol concentrations throughout the day did not differ while smoking or abstaining. Thus the amount of nicotine consumed when assessed over the whole day has little influence on magnitude of cardiovascular responses to cigarette smoking. Insofar as nicotine contributes to risk, changing nicotine content per se may not alter the risk of sudden adverse cardiac events associated with cigarette smoking. Clinical Pharmacology and Therapeutics (1984) 36, 74–81; doi:10.1038/clpt.1984.142

Nicotine polacrilex gum is widely used as substitution therapy during cigarette smoking cessation. We studied circadian blood nicotine concentrations, daily intake of nicotine, and extraction of nicotine from gum in smokers switched experimentally to 2 or 4 mg nicotine gum, 12 pieces per day. Nicotine levels and intake were much lower while chewing gum than during ad libitum smoking. Extraction of nicotine from gum by the chewer was incomplete, averaging 53% and 72% for 2 and 4 mg gum, and variable (more than twofold) among individuals. The systemic dose of nicotine was less than expected based on analysis of nicotine in the chewed gum. Disproportionately higher metabolite-to-nicotine ratios while chewing gum compared with smoking suggested that some nicotine was swallowed and underwent first-pass metabolism. Nicotine and metabolite data were used to estimate buccal vs. gastrointestinal absorption. Relative buccal absorption vs. swallowing of nicotine appears to be an important determinant of systemic nicotine intake. Clinical Pharmacology and Therapeutics (1987) 41, 467–473; doi:10.1038/clpt.1987.58

Background The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours. Methods Twelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained. Results Selegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline. Conclusion No pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions.

In the hope of reducing the adverse health consequences of smoking, physicians frequently advise their patients who cannot quit to smoke fewer cigarettes. Habitual smokers may compensate for the reduced number of cigarettes, however, by taking in more smoke per cigarette. We measured the intake of tar (estimated as mutagenic activity of the urine), nicotine, and carbon monoxide during short-term cigarette restriction. With a reduction from an average of 37 cigarettes to an average of 5 cigarettes per day, the intake of tobacco toxins per cigarette increased roughly threefold and daily exposure to tar and carbon monoxide declined only 50 percent. We conclude that smoking fewer cigarettes may reduce exposure to toxins and related adverse health consequences. However, consistent with a tendency to maintain intake of nicotine, the magnitude of the benefit is much less than expected. Whether "oversmoking" persists during long-term restriction of cigarettes requires further investigation.

An unresolved public health issue is whether some modern cigarettes are less hazardous than others and whether patients who cannot stop smoking should be advised to switch to lower-yield cigarettes. We studied "tar" (estimated by urine mutagenicity), nicotine, and carbon monoxide exposure in habitual smokers switched from their usual brand to high- (15 mg of tar), low- (5 mg of tar), or ultralow-yield (1 mg of tar) cigarettes. There were no differences in exposure comparing high- or low-yield cigarettes, but tar and nicotine exposures were reduced by 49% and 56%, respectively, and carbon monoxide exposure by 36% while smoking ultralow-yield cigarettes. Similarly, in 248 subjects smoking their self-selected brand, nicotine intake, estimated by blood concentrations of its metabolite cotinine, was 40% lower in those who smoked ultralow but no different in those smoking higher yields of cigarettes. Our data indicate that ultralow-yield cigarettes do deliver substantial doses of tar, nicotine, and carbon monoxide, but that exposures are considerably less than for other cigarettes. ( JAMA 1986;256:241-246)

In Reply.— At present, no direct assays of human biologic fluids for "tar" exposure from cigarettes are available. Urine mutagenicity was selected as an indirect measure for several reasons: (1) The urine of most cigarette smokers is strongly mutagenic whereas the urine of nonsmokers (or of smokers after 24 to 48 hours of abstinence) is in most cases only weakly mutagenic. (2) The mutagenic components of tobacco smoke are found primarily in the tar rather than the gaseous phase of tobacco smoke.1(3) Tobacco smoke condensate (tar) from different brands of cigarettes has approximately the same mutagenic activity per milligram.2(4) The urine of a person smoking the same brand of cigarette has approximately the same mutagenicity from day to day.3Thus, there is a theoretical basis for assuming proportionality between tar exposure and urine mutagenicity. As we and others have pointed out, there is considerable variability

• Depression and dysphoria can follow the long-term use of cocaine. Little is known about the interaction of antidepressant drugs with cocaine and similar stimulants in humans. The physiologic and subjective effects of an oral 2-mg/kg dose of cocaine hydrochloride were measured in eight healthy cocaine-using men after pretreatment with a single, 100-mg oral dose of the triazolopyridine antidepressant trazodone hydrochloride or placebo in a double-blind study. The cocaineinduced effects of increased BP, increased pupil size, and decreased skin temperature were diminished by trazodone pretreatment. Trazodone alone did not alter plasma epinephrine or norepinephrine levels. An increase in plasma epinephrine levels after cocaine administration was not altered by trazodone pretreatment, but the increase in the norepinephrine level was larger. Trazodone alone produced mild sleepiness. Cocaine-induced euphoria was not altered by trazodone pretreatment, although feelings of tension and shakiness after cocaine administration were diminished.