https://apps.dtic.mil/sti/pdfs/ADA157550.pdf

The TRACE model of speech perception.

Signal detection theory (SDT) may be applied to any area of psychology in which two different types of stimuli must be discriminated. We describe several of these areas and the advantages that can be realized through the application of SDT. Three of the most popular tasks used to study discriminability are then discussed, together with the measures that SDT prescribes for quantifying performance in these tasks. Mathematical formulae for the measures are presented, as are methods for calculating the measures with lookup tables, computer software specifically developed for SDT applications, and general purpose computer software (including spreadsheets and statistical analysis software).

/pdf/calculation-of-signal-detection-theory-measures-4xcday6n3y.pdf

Calculation of signal detection theory measures

A shortened 10-item scale for clinical quantitation of the severity of the alcohol withdrawal syndrome has been developed. This scale offers an increase in efficiency while at the same time retaining clinical usefulness, validity and reliability. It can be incorporated into the usual clinical care of patients undergoing alcohol withdrawal and into clinical drug trials of alcohol withdrawal.

Assessment of Alcohol Withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar)

Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents. The focus is on studies in humans, but animal data are mentioned when relevant to the interpretation of human data. The pathways of nicotine metabolism are described in detail. Absorption, distribution, metabolism, and excretion of nicotine and related compounds are reviewed. Enzymes involved in nicotine metabolism including cytochrome P450 enzymes, aldehyde oxidase, flavin-containing monooxygenase 3, amine N-methyltransferase, and UDP-glucuronosyltransferases are represented, as well as factors affecting metabolism, such as genetic variations in metabolic enzymes, effects of diet, age, gender, pregnancy, liver and kidney diseases, and racial and ethnic differences. Also effects of smoking and various inhibitors and inducers, including oral contraceptives, on nicotine metabolism are discussed. Due to the significance of the CYP2A6 enzyme in nicotine clearance, special emphasis is given to the effects and population distributions of CYP2A6 alleles and the regulation of CYP2A6 enzyme.

Metabolism and Disposition Kinetics of Nicotine

Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and disposition characteristics of nicotine from tobacco and medicinal products are reviewed. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDPglucuronosyltransfease (UGT), and flavin-containing monooxygenase (FMO). In addition to genetic factors, nicotine metabolism is influenced by diet and meals, age, sex, use of estrogen-containing hormone preparations, pregnancy and kidney disease, other medications, and smoking itself. Substantial racial/ethnic differences are observed in nicotine metabolism, which are likely influenced by both genetic and environmental factors. The most widely used biomarker of nicotine intake is cotinine, which may be measured in blood, urine, saliva, hair, or nails. The current optimal plasma cotinine cut-point to distinguish smokers from non-smokers in the general US population is 3 ng ml−1. This cut-point is much lower than that established 20 years ago, reflecting less secondhand smoke exposure due to clear air policies and more light or occasional smoking.

/pdf/nicotine-chemistry-metabolism-kinetics-and-biomarkers-19i664xsss.pdf

Nicotine Chemistry, Metabolism, Kinetics and Biomarkers

Detection theory analysis of group data: Estimating sensitivity from average hit and false-alarm rates.

Background
Nicotine establishes and maintains tobacco dependence. Individuals with genetically deficient CYP2A6 nicotine metabolism are at lower risk to become smokers and, if dependent, will smoke fewer cigarettes. Hepatic CYP2A6 accounts for nicotine's low systemic bioavailability, precluding oral nicotine replacement to treat dependence.

Objective
We sought to determine whether CYP2A6 inhibition via oral methoxsalen decreases nicotine clearance, increases nicotine bioavailability, and decreases smoking.

Methods
Two within-subject designs in healthy tobacco-dependent volunteers were conducted: a single-blind kinetic study (n = 17) of methoxsalen 30, 10, or 3.5 mg or placebo given with nicotine 4 mg orally to abstinent smokers; and a double-blind randomized crossover study (n = 11) of methoxsalen 30 mg or placebo crossed with nicotine 4 mg given orally or placebo before 60 minutes’ abstinence and 90 minutes’ free smoking.

Results
Placebo plus nicotine 4 mg orally increased the mean 3-hour plasma nicotine level by 4 ng/mL over residual baseline nicotine level, whereas methoxsalen 10 or 30 mg plus nicotine increased it by 9 ng/mL (P < .01), demonstrating in vivo inhibition of CYP2A6 nicotine metabolism. Methoxsalen 30 mg plus nicotine 4 mg given orally decreased breath carbon monoxide concentration at the end of free smoking by 47% (4.6 versus 8.7 ppm; P < .01) and cigarettes smoked by 24% (3.1 versus 4.1, P < .01) compared with placebo plus placebo.

Conclusions
Methoxsalen inhibits nicotine first-pass metabolism of orally administered nicotine, and the combination directly reduces smoking in a laboratory setting. CYP2A6 inhibitors may have an important role in smoking cessation and tobacco exposure reduction.

Clinical Pharmacology & Therapeutics (2000) 68, 35–43; doi: 10.1067/mcp.2000.107651

Inhibition of cytochrome P450 2A6 increases nicotine's oral bioavailability and decreases smoking

The contribution of cytochrome P450 2D6 (CYP2D6) to the formation of hydrocodone's active metabolite, hydromorphone, was examined in vitro and in vivo. Human liver microsomes prepared from an individual homozygous for the D6-B mutation of the CYP2D6 gene catalyzed this reaction at a negligible rate. Urinary metabolic ratios of hydrocodone/hydromorphone were highly correlated with O-demethylation ratios for dextromethorphan, an established marker drug of CYP2D6 activity (rs = 0.85; n = 18). The kinetics of hydrocodone after a single oral dose and its partial metabolic clearance to hydromorphone were investigated in five extensive metabolizers of dextromethorphan, six poor metabolizers, and four extensive metabolizers after pretreatment with quinidine, a selective inhibitor of CYP2D6 activity. The mean values for partial metabolic clearance by O-demethylation in the three groups were 28.1 +/- 10.3, 3.4 +/- 2.4, and 5.0 +/- 3.6 ml/hr/kg, respectively. No statistically significant phenotypic differences in physiologic measures were observed. However, over the first hour after dosing, the extensive metabolizers reported more "good opiate effects" and fewer "bad opiate effects" than poor metabolizers and extensive metabolizers in whom CYP2D6 was inhibited by quinidine. These data establish the importance of CYP2D6 in the formation of hydromorphone from hydrocodone and suggest that the activity of this enzyme may limit the abuse liability of hydrocodone.

CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone

Amitriptyline has clinically important interactions with ethanol. Five healthy volunteers received 25 mg of amitriptyline orally, preceded by one hour and followed for eight hours by oral ethanol (or juice), dosed to achieve and maintain blood ethanol concentrations of 800 mg/l. In the presence of ethanol, amitriptyline free plasma concentrations were increased by a logarithmic mean of 204%, 186% and 127% at 1.5, 2, and 2.5 h, respectively, and amitriptyline free AUC0-8h was increased by 48% +/- 13% (means +/- SEM) (t = 5.21, p less than 0.01). Nortriptyline total AUC0-8h was increased by 26.6% +/- 12% (means +/- SEM) (t = 2.21, p less than 0.09). At the time of peak amitriptyline plasma concentrations, mean postural sway was increased over baseline by 92% with, and 2% without ethanol; likewise, mean short term memory (word recall) was decreased over baseline by 71% with, and 37% without ethanol. Ethanol increases free amitriptyline plasma concentrations most dramatically during the period of drug absorption; this is due to a decrease in amitriptyline hepatic clearance, resulting in decreased first-pass extraction. Together with the pharmacodynamic interaction, the kinetic changes provide a rationale for the toxicity of this combination and its deleterious effects on psychomotor skills.

Amitriptyline and ethanol: pharmacokinetic and pharmacodynamic interaction.

When disease impairs clearance of drugs, multiple-dose therapy may result in cumulation. The disposition of chlordiazepoxide (CDX), 50 mg infused intravenously over 10 min, was studied in 14 normal subjects and in 11 patients with biopsy-proven cirrhosis. In the normal subjects, mean (+/- SE) kinetic parameters were: t 1/2 beta, 10.0 (+/- 0.9) hr; Vd, 0.38 (+/- 0.04) l/kg; clearance, 0.54 (+/- 0.13) ml/min/kg. Clearance of total drug correlated inversely with serum albumin concentration in normal subjects (r = -0.63). Values in cirrhotic patients were: t 1/2 beta, 34.9 (+/- 8.7) hr; Vd, 0.34 (+/- 0.024) 1/kg; and clearance, 0.185 (+/- 0.34) ml/min/kg. Desmethylchlordiazepoxide (DMCDX), the major metabolite of CDX, appeared in blood of cirrhotic patients less rapidly than in normal subjects. Severity of liver disease did not indicate the impairment of CDX clearance. In 5 of the same cirrhotic patients, mean t 1/2 beta for oxazepam (7.1 +/- 1.0 hr) was 27% longer than in control subjects (5.6 +/- 0.7 hr); the difference is not significant. On kinetic grounds oxazepam may be preferable to chlordiazepoxide in cirrhotic patients since its elimination kinetics are not greatly altered in cirrhosis.

Chlordiazepoxide and oxazepam disposition in cirrhosis.

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