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The heart rate response to nicotine may be an important component of the process leading to dependence. The present study is the first to determine the extent to which genetic and environmental sources play a role in various components of the heart rate response. One hundred and ten monozygotic and 29 dizygotic twin pairs received an i.v. infusion of nicotine and cotinine over 30 min. Before, during, and for 30 min after infusion, heart rate was measured via an electronic monitor. The clearance of nicotine was determined as a measure of the rate of nicotine metabolism. Average resting heart rate before infusion was 64.7 beats per minutes (bpm), and at the termination of infusion, heart rate had increased to an average of 72.7 bpm. At 30 min after infusion, heart rate had decreased to 67.5 bpm. Age, current smoking status, body mass index, and nicotine clearance were associated significantly with heart rate levels over the full 60 min of measurement. After adjustment for several covariates, including dose of administered nicotine and rate of nicotine clearance, the variance in several characteristics of the heart rate response curve was examined for the relative contribution from genetic and environmental sources. In the total sample, as much as 30.3% of the variance in the acceleration of heart rate was due to additive genetic sources. In nonsmokers, 34.8% and 31.0% of variance in the acceleration and deceleration of heart rate, respectively, was due to genetic sources. Heart rate acceleration and deceleration may be a reflection of central nervous system responsiveness to nicotine. The contribution from genetic sources to heart rate response characteristics should be investigated further as a potential endophenotype for use in genetic studies of nicotine dependence.

Objective: To determine the relationship between joint variation in 2 dopaminergic genes and the likelihood of nonsmoking following treatment with bupropion sustained release (SR)., Design: Three hundred twenty-three participants in a bupropion SR smoking cessation effectiveness trial with 12-month follow-up were genotyped for variants of dopamine receptor gene DRD2 and dopamine transporter SLC6A3., Main Outcome Measures: Self-reported 7-day point prevalence of nonsmoking., Results: Neither genotype alone was associated with 7-day point-prevalent nonsmoking at the 12-month follow-up. However, in the presence of the DRD2 A1 allele, SLC6A3 status was significantly associated with the likelihood of nonsmoking at the 12-month follow-up (individuals with DRD2 A1+ and SLC6A3 9- were more likely to be smoking). In the absence of the DRD2 A1 allele, the association between SLC6A3 status and nonsmoking was nonsignificant., Conclusion: Although these results are suggestive, a more compelling test is needed of the hypothesis that dopaminergic gene interaction underlies, in part, the likelihood of smoking following treatment with bupropion SR. Most likely this will come from larger studies involving prospective randomization to treatment based on genotype., (Copyright (c) 2007 APA, all rights reserved.)

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.

Trichostrongylus colubriformis is an important cause of parasitic gastroenteritis in ruminants, where it causes protracted diarrhoea, rapid loss of weight, loss of production and death. The in vitro efficacy of extracts of Peltophorum africanum was determined against this parasitic nematode. Eggs and larvae of T. colubriformis were incubated at 23 degrees C in the extracts of the leaf, bark and root of P. africanum at concentrations of 0.008-25 mg ml-1 for 2 and 5 days, respectively. Thiabendazole and water were used as positive and negative controls, respectively. Inhibition of egg hatching and larval development increased significantly (P<0.05) with increasing concentrations of the extracts. Concentrations of 0.2-1.0 mg ml-1 of the extracts of leaf, stem bark, and root bark of P. africanum completely inhibited the hatching of eggs and development of larvae. No eggs and larvae of T. colubriformis could be observed in wells incubated with all the three extracts at concentrations of 5 and 25 mg ml-1. The in vitro model results support the traditional use of P. africanum against nematode parasites. Further research is required to isolate and structurally identify the active anthelmintic compounds, and to improve methods of plant extraction of the effective anthelmintic components that will be readily adaptable for use by rural communities against helminthosis.

Background and Objective: The liver enzyme cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Variants in the CYP2A6 gene have been associated with altered nicotine metabolism and with effects on smoking behavior. Our objective was to determine the relationship between variant CYP2A6 genotypes and the disposition and metabolism of nicotine administered intravenously., Methods: Intravenous infusions of deuterium-labeled nicotine and cotinine were administered to 278 healthy twin volunteers, most of whom were white. They were genotyped for CYP2A6*1, CYP2A6*2, CYP2A6*4, CYP2A6*7, CYP2A6*8, CYP2A6*9, CYP2A6*10, and CYP2A6*12., Results: On the basis of the fractional clearance of nicotine to cotinine and on the plasma ratio of 3'-hydroxycotinine to cotinine, both shown to be indicators of CYP2A6 enzymatic activity, subjects were classified into 3 groups. Group 1 included wild-type variant CYP2A6*1/*1 (n=215) and was assumed to have 100% activity. Group 2 included *1/*9 (n=21) and *1/*12 (n=12), which averaged about 80% of normal activity. Group 3 included *1/*2 (n=10), *1/*4 (n=2), *9/*12 (n=3), *9/*4 (n=2), and *9/*9 (n=3), which averaged about 50% of normal activity. The mean total plasma clearance of nicotine (+/-SD) was 18.8+/-6.0, 15.5+/-4.9, and 11.7+/-5.1 mL.min-1.kg-1 in groups 1, 2, and 3, respectively, and group 1 had significantly faster clearance than group 2 (P<.05) and group 3 (P<.01). Overall, groups 2 and 3 also had lower total clearance of cotinine, had longer half-lives for nicotine and cotinine, and excreted in the urine a greater fraction of the nicotine dose as unchanged nicotine and nicotine glucuronide and excreted less as 3'-hydroxycotinine compared with group 1., Conclusions: We provide novel pharmacokinetic and metabolic data on nicotine after systemic dosing in relation to common CYP2A6 genotypes. Our data will enhance the interpretation of CYP2A6 genotypic data as used in association studies of smoking behavior and its health consequences.

Background: China has the world's largest concentration of smokers (350 million) and rising alcohol consumption, yet little is known about tobacco and alcohol use aetiology. In 2000, the Chinese National Twin Registry was established to provide a genetically informative resource for investigation of health behaviour including tobacco and alcohol use., Methods: Using standard twin methodology, this study aimed to examine the relative contribution of genetic and environmental influences on cigarette smoking and alcohol drinking in a sample of adult Chinese twins (n = 1010 individual twins). More than half of the male twins were smokers (58%), and 32.5% reported alcohol consumption. Among male smokers, 46.4% smoked 20 or more cigarettes per day (heavy smokers) and among drinkers, 32.8% consumed one or more drinks per day. Nearly all female twins were non-smokers (99.2%) and non-drinkers (98.7%); therefore, genetic analysis was limited to male data., Results: In men, current smoking was significantly heritable [75.1%, 95% confidence interval (CI) 56.7-87.5] with no evidence for a significant contribution of shared environmental effects. Heavy smoking was more strongly influenced by genes (66.2%, 95% CI 0-88.4) than shared environment (8.7%, 95% CI 0-71.0). Similarly, current drinking was more strongly influenced by genetic effects (59.5%, 95% CI 0-87.8) than by shared environmental effects (15.3%, 95% CI 0-72.1). Amount of alcohol consumed was influenced to a similar degree by genetic (42.4%, 95% CI 0-91.8) and shared environmental factors (39.2%, 95% CI 0-82.7)., Conclusions: These results support findings from twins of Western origin on the aetiology of tobacco and alcohol use and encourage further work in Chinese twins.

An Ehrlichia ruminantium culture system was utilized for the anti-rickettsial evaluation of two ethnoveterinary plants, Elephantorrhiza elephantina and Aloe marlothii. Well-established E. ruminantium cultures were incubated with the plant leaf acetone extracts and compared to oxytetracycline and untreated controls. Effectivity was established by comparing the percentage parasitised cells and the calculation of both EC50 and extrapolated EC90 in microg/ml. The plant extracts were also screened for antibacterial activity using bioautography. Elephantorrhiza elephantina and A. marlothii demonstrated anti-ehrlichial activity with an EC50 of 111.4 and 64.5 microg/ml and EC90 of 228.9 and 129.9 microg/ml, respectively. The corresponding EC50 and EC90 for oxytetracycline was 0.29 and 0.08 microg/ml. Both plants appeared to produce their inhibitory activity by a similar mechanism, unrelated to that of the tetracyclines. Both the plant acetone extracts demonstrated antibacterial activity against Escherichia coli and Staphylococcus aureus (ATCC strains).

There is ample scientific and empirical evidence supporting the use of plant-derived antioxidants for the control of neurodegenerative disorders. Antioxidants may have neuroprotective (preventing apoptosis) and neuroregenerative roles, by reducing or reversing cellular damage and by slowing progression of neuronal cell loss. Although demand for phytotherapeutic agents is growing, there is need for their scientific validation before plant-derived extracts gain wider acceptance and use. We have evaluated antioxidant potential of Peltophorum africanum (weeping wattle), a plant widespread in the tropics and traditionally used, inter alia, for the relief of acute and chronic pain, anxiety and depression. The dried leaves, bark and root of P. africanum were extracted with acetone. Thin layer chromatograms were sprayed with 0.2% 2,2-diphenyl-1-picryl hydrazyl (DPPH) in methanol for screening for antioxidants. Quantification of antioxidant activity was assessed against 6-hydroxy-2, 5,7,8-tetramethylchromane-2-carboxylic acid (Trolox) and L-ascorbic acid (both standard antioxidants), using two free radicals, 2,2'-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) and DPPH, respectively. Results of our study show that the bark and root extracts had higher antioxidant activity than L-ascorbic acid and Trolox, a synthetic vitamin-E analogue. The respective TEAC (Trolox Equivalent Antioxidant Capacity) values for the bark and root extracts, and Trolox were 1.08, 1.28 and 1.0. EC(50) values for L-ascorbic acid (5.04 microg/mL) was more active than the leaf 6.54 (microg/mL), but much less active than the bark (4.37 microg/mL) and root (3.82 microg/mL) extracts. Continued work on P. africanum, and other plants rich in antioxidants, may avail neuroscientists with potent neuroprotective antioxidant therapeutics.

Three endemic vulture species Gyps bengalensis, Gyps indicus and Gyps tenuirostris are critically endangered following dramatic declines in South Asia resulting from exposure to diclofenac, a veterinary drug present in the livestock carcasses that they scavenge. Diclofenac is widely used globally and could present a risk to Gyps species from other regions. In this study, we test the toxicity of diclofenac to a Eurasian (Gyps fulvus) and an African (Gyps africanus) species, neither of which is threatened. A dose of 0.8 mg kg(-1) of diclofenac was highly toxic to both species, indicating that they are at least as sensitive to diclofenac as G. bengalensis, for which we estimate an LD50 of 0.1-0.2 mg kg(-1). We suggest that diclofenac is likely to be toxic to all eight Gyps species, and that G. africanus, which is phylogenetically close to G. bengalensis, would be a suitable surrogate for the safety testing of alternative drugs to diclofenac.

Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, gamma-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor.

Genome-wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter-marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19).

Objective: The impact of CYP2A6*21 (K476R) on in vivo nicotine metabolism and disposition was investigated., Methods: A two-step allele-specific PCR assay was developed to detect the 6573A>G single nucleotide polymorphism (SNP) in CYP2A6*21. Nicotine metabolism phenotypes from a previously described intravenous labeled nicotine and cotinine infusion study [1] was used to assess the impact of CYP2A6*21. Genomic DNA samples from 222 (111 monozygotic and dizygotic twin pairs) Caucasian subjects were genotyped for CYP2A6 alleles (CYP2A6*1X2, -*1B, -*2, -*4, -*7, -*9, -*10, -*12, and -*21). The pharmacokinetic parameters were compared between individuals with no detected CYP2A6 variants (CYP2A6*1/*1, n = 163) and individuals heterozygous for the CYP2A6*21 allele (CYP2A6*1/*21, n = 9)., Results: The frequency of the CYP2A6*21 allele was found to be 2.3% in Caucasians (n = 5/222 alleles, evaluated in one twin from each twin pair). In vivo pharmacokinetic parameters, such as nicotine clearance (1.32+/-0.37 vs. 1.18+/-0.20 L/min), fractional clearance of nicotine to cotinine (1.02+/-0.36 vs. 0.99+/-0.23 L/min), nicotine half-life (111+/-37 vs. 116+/-29 min), and the trans-3'-hydroxycotinine to cotinine ratio (1.92+/-1.0 vs. 1.55+/-0.58) indicated no substantial differences in nicotine metabolism between those without the variant (CYP2A6*1/*1, n = 163) and those with the variant (CYP2A6*1/*21, n = 9), respectively., Conclusions: CYP2A6*21 does not have a detectable impact on nicotine metabolism in vivo. Our data suggest that CYP2A6*21 may not be important for future studies of nicotine metabolism and the resulting impacts on smoking behaviors.

Background: Several studies have reported that female smokers have a higher risk of lung cancer than male smokers. This could be related to sex differences in nicotine metabolism and related smoking behavior. This study tested the hypothesis that women metabolize nicotine more rapidly than men and that, among women, oral contraceptive users metabolize nicotine more rapidly than nonusers of oral contraceptives., Methods: Two hundred seventy-eight healthy volunteers who were twins and 16 who were siblings of twins, recruited from the Northern California Twin Registry, received an infusion of deuterium-labeled nicotine and cotinine with frequent blood sampling. The plasma clearances of nicotine and cotinine, the clearance of nicotine to cotinine (an index of cytochrome P450 [CYP] 2A6 activity), and the ratio of trans-3'-hydroxycotinine to cotinine (another indicator of CYP2A6 activity) were measured., Results: The clearances of nicotine and cotinine, the clearance of nicotine to cotinine, and the trans-3'-hydroxycotinine/cotinine ratio were significantly higher in women than in men (nicotine clearance, 15.6 +/- 4.3 mL.min(-1).kg(-1) in men versus 18.8 +/- 6.6 mL.min(-1).kg(-1) in women; P < .001); they were also higher among women taking oral contraceptives than in those who were not taking oral contraceptives (nicotine clearance, 22.5 +/- 6.6 mL.min(-1).kg(-1) in women taking oral contraceptives versus 17.6 +/- 6.1 mL.min(-1).kg(-1) in those who were not; P < .05). Women who were menopausal or postmenopausal were not different from men. Among oral contraceptive users, nicotine metabolism was accelerated among those taking combined and estrogen-only contraceptives but not progesterone-only contraceptives., Conclusions: Sex hormones influence nicotine metabolism. Nicotine and cotinine metabolism is faster in women than in men and is faster in women taking oral contraceptives compared with those who are not. Accelerated nicotine metabolism appears to be a result of estrogen. Sex-related differences in nicotine clearance could affect smoking behaviors, as well as response to nicotine medications, and could be a marker for altered metabolism of nicotine-derived carcinogens.

Estrogens are essential for normal reproductive activity in female and male vertebrates. In female reptiles, they are essential for ovarian differentiation during a critical developmental stage. To understand the molecular mechanisms of estrogen action in the Nile crocodile (Crocodylus niloticus), we have isolated cDNA encoding the estrogen receptor alpha (ERalpha) from the ovary. Degenerate PCR primers specific to ER were designed and used to amplify Nile crocodile cDNA from the ovary. The full-length Nile crocodile ERalpha cDNA was obtained using 5' and 3' rapid amplification cDNA ends (RACE). The deduced amino acid sequence of the Nile crocodile ERalpha showed high identity to the American alligator ERalpha (98%), caiman ER (98%), lizard ER (82%) and chicken ERalpha (92%), although phylogenetic analysis suggested profound differences in the rate of sequence evolution for vertebrate ER sequences. Expression of ERalpha was observed in the ovary and testis of juvenile Nile crocodiles. These data provide a novel tool allowing future studies examining the regulation and ontogenic expression of ERalpha in crocodiles and expands our knowledge of estrogen receptor evolution.

To assist in determining whether employer-sponsored smoking cessation programs can be justified on cost-effectiveness grounds, a review was performed to examine the costs imposed on employers by smoking and the extent to which employers can recover those costs through successful smoking cessation programs. The magnitude of the costs (or cost savings) imposed by employee tobacco use depends on workplace factors, including medical coverage (before and after retirement), disability and life insurance benefits, level of exposure to workplace pollutants associated with smoking-related diseases, employee turnover rate, current smoke-free area policy, smoking breaks policy, cost of providing smoking areas, and type of retirement pension plan.

Nicotine replacement therapy (NRT) is an effective treatment for smoking cessation, but as with all such pharmacotherapies, the majority of smokers who use NRT products do not stop smoking or remain abstinent long term. Treatment outcome is affected by a range of individual-specific factors, as well as the pharmacokinetic profile of each NRT formulation. This has led to speculation that abstinence rates could be improved if NRT treatments were individually tailored to best match each individual's needs and preferences. There are also populations for whom special product and dosage considerations are warranted to maximise treatment safety.This paper reviews the rationale for NRT treatment, standard dose recommendations and recommendations for how to best match NRT treatment to the specific needs of individual smokers. We also review emerging evidence that genetic profiling may one day be a useful consideration for tailoring NRT treatment.

The relationship between apolipoprotein E (APOE) epsilon4 and change in cognition was examined in older men (n = 247; age = 75.0 +/- 3.5 years) and women (n = 79; age = 70.8 +/- 4.9 years) free of history of stroke. Participants were examined again 4.0 +/- 0.5 years later. Exclusion criteria were (1) initial scores on the Mini-Mental State Examination of 23 or less or (2) the presence of the APOE 2/4 genotype. Men with epsilon4 showed greater decline in some measures of executive function and verbal memory compared to those without epsilon4; women with epsilon4 showed greater decline in Trail Making test performance relative to women without the allele. A significant gender x APOE epsilon4 interaction was seen for change in performance on short delay cued recall. These results suggest that APOE epsilon4 is associated with cognitive decline differently in older adult men and women.

The pharmacokinetics of diminazene aceturate following intramuscular (i.m.) administration at 4.2 mg/kg was evaluated in 8 healthy German Shepherd dogs. Blood samples were collected at 19 intervals over a period of 21 days. Diminazene plasma concentrations were measured using a validated HPLC method with UV detection and a sensitivity of 25 ng/ml. The in vitro and in vivo binding of diminazene to blood elements was additionally determined. Diminazene pharmacokinetics showed a large inter-individual variation after i.m. administration. It had a short absorption half-life (K01-HL of 0.11 +/- 0.18 h), resulting in a C(max) of 1849 +/- 268.7 ng/ml at T(max) of 0.37 h and a mean overall elimination half-life (T1/2beta) of 5.31 +/- 3.89 h. A terminal half-life of 27.5 +/- 25.0 h was measured. At 1 h after i.m. injection, 75% of the diminazene in whole blood was in the plasma fraction. The results of this study indicate that diminazene is rapidly distributed and sequestered into the liver, followed by a slower terminal phase during which diminazene is both redistributed to the peripheral tissues and/or renally excreted. It is recommended that diminazene administered i.m. at 4.2 mg/kg should not be repeated within a 21-day period.

A commonly available Babesia caballi culture system was utilized for anti-babesial screening of four commonly used ethnoveterinary plants, Rhoiscissus tridentata, Elephantorrhiza elephantina, Aloe marlothii and Urginea sanguinea, in vitro. Well-established B. caballi cultures were initially incubated with either imidocarb diproprionate and diminazene aceturate to validate the model, where after the studies were performed on the four plants. Effectivity was established as the degree of inhibition using a colour change method as well as by evaluating percentage parasitized cells on thin culture smears and calculating the degree of residual infectivity. The model was effective in demonstrating the in vitro efficacy of the well known anti-babesial drugs imidocarb and diminazene indicating an EC50 value of 0.08 and 0.3 microg/ml, respectively. Only the E. elephantina rhizomes acetone extracts were effective at a concentration of 100 microg/ml. It was also shown that the colour change method of evaluation was not very sensitive for determining activity of crude plant extracts.

This review focuses on the current status and future directions of pharmacogenetics research into responses to treatments for nicotine dependence and smoking cessation. Research remains in its infancy and, although the potential for individualized treatment tailored to genotype is promising, there are practical, ethical and social considerations that must be addressed before such research is translated into clinical practice. In particular, future studies that need to be conducted before such research is translated into clinical practice and potential limitations and barriers to this translation are described.

Plasma sex hormone concentrations have been used as biomarkers in epidemiological studies of many conditions including cancer, obesity, bone density, and coronary heart disease. The objective of this analysis was to estimate genetic and nongenetic influences on endogenous sex hormones (testosterone, estradiol, estrone, and SHBG) in a large sample of 532 adult white male twins (134 monozygotic and 132 dizygotic twin pairs) from the National Heart, Lung, and Blood Institute Twin Study. Participants were aged 59-70 yr at the time of plasma collection, and hormone concentrations were determined with RIA. Genetic models were fitted by the method of maximum likelihood. Testosterone and SHBG concentrations have substantial genetic variation, with additive genetic factors accounting for 57 and 68% of the total phenotypic variation, respectively. In contrast, variation in estrone (37% shared environmental and 63% individual specific environmental effects) and estradiol concentrations (25% genetic effect, 44% shared environmental effects, and 31% individual specific environmental effects) were largely influenced by nongenetic factors. Assessment of the relative contribution of genetic and nongenetic influences on hormone concentrations may help in the search for genes underlying variation and covariation in complex traits affected by plasma sex hormone concentrations.

Peltophorum africanum (Fabaceae) is a deciduous tree widespread in southern Africa. The plant has many ethnomedical and ethnoveterinary uses. Root and bark decoctions are used to treat diarrhoea, dysentery, sore throat, wounds, back and joint pains, HIV-AIDS, venereal diseases and infertility. Pastoralists and rural farmers use the root and bark extracts to treat diarrhoea, dysentery, infertility, and to promote well-being and resistance to diseases in cattle. To evaluate these ethnobotanical leads, dried leaves, stem bark and root bark were extracted with ethanol, acetone, dichloromethane and hexane. Polyphenols in the extract were determined by the Folin-Ciocalteu method with gallic acid as standard. Qualitative antioxidant activity was screened by spraying thin layer chromatograms (TLC) of the extracts with 0.2% 1,1-diphenyl-2-picryl hydrazyl (DPPH), and quantified with Trolox equivalent antioxidant capacity (TEAC) assay. Minimum inhibitory concentration (MIC) and total antibacterial activity (TAA) were determined by serial microplate dilution for Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis, with gentamicin as standard and tetrazolium violet as growth indicator. Acetone and ethanol extracted the largest quantity of material. Polyphenols concentration was 49.2% in acetone extract of the root and 3.8% in dichloromethane extract of the leaf. Antioxidant activity of at least 5 antioxidant compounds as measured by TEAC ranged from 1.34 (ethanol extract of the root) to 0.01 (hexane extract of the leaf). The total antibacterial activity (volume to which active compounds present in 1 g plant material can be diluted and still inhibit bacterial growth) was 1263 ml/g for ethanol extract of the root against S. aureus, and 800 ml/g for acetone extract of the root against P. aeruginosa. There was substantial activity against both Gram-positive and Gram-negative bacteria, with MIC values of 0.08 mg/ml for S. aureus and 0.16 mg/ml for P. aeruginosa. There is therefore a rationale for the traditional use of root and bark of P. africanum in treating bacterial infection related diseases.

Information about levels of nicotine dependence in ex-smokers when they smoked, or in current smokers at an earlier date, is useful for clinical and research purposes. To estimate the accuracy of retrospective reports of dependence, 28 individuals who completed either the Fagerström Tolerance Questionnaire (FTQ) or Fagerström Test for Nicotine Dependence (FTND) in smoking cessation trials conducted 5 to 12 years earlier were asked to respond again to the same questions, thinking back to their smoking behavior just prior to their on-study quit attempt. Concordance and Kappa values for the items ranged from 50.0% to 95.0% and 0.00 to 0.92, respectively. The mean difference between the baseline and follow-up total scale scores was 0.05 for the FTQ and 0.38 for the FTND, and the correlation between these assessments was 0.62 for the FTQ (p<0.005) and 0.72 for the FTND (p<0.05). These preliminary results suggest that retrospectively assessed FTQ/FTND scale scores have acceptable reliability.

To conduct a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty nine twin pairs [110 monozygotic (MZ) and 29 dizygotic (DZ)] underwent a 30-min infusion of stable isotope-labelled nicotine and its major metabolite, cotinine, followed by an 8-h in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine and metabolites by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry and subsequent characterization of pharmacokinetic and metabolism phenotypes. DNA was genotyped to confirm zygosity and for variation in the gene for the primary enzyme involved in nicotine metabolism, CYP2A6 (alleles tested: *1, *1x2, *2, *4, *7, *9 and *12). Univariate biometric analyses quantified genetic and environmental influences on each pharmacokinetic measure in the presence and absence of covariates, including measured CYP2A6 genotype. The best-fitting model identified a substantial amount of variation in the weight-adjusted rate of total clearance of nicotine attributable to additive genetic influences [59.4%, 95% confidence interval (CI)=44.7-70.7]. The majority of variation in the clearance of nicotine via the cotinine pathway was similarly genetically influenced (60.8%, 95% CI=46.9-71.5). Heritability estimates were reduced to 54.2% and 51.8%, respectively, but remained substantial after taking into account the effect of variation in CYP2A6 genotype. These results suggest the involvement of additional genetic factors (e.g. uncharacterized or novel CYP2A6 alleles as well as other genes in the metabolic pathway) that remain to be identified.

The A1 allele of the dopamine D2 receptor gene (DRD2) is associated with a reduced number of dopamine binding sites in the brain and with the increased likelihood of substance abuse and addictive behavior. In a study of smokers enrolled in an open-label, randomized effectiveness trial, we investigated whether variants in the DRD2 receptor gene are associated with smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling. Adherence to treatment and point-prevalent smoking status were assessed at 3 and 12 months, respectively, following a target quit date. Compared to women who carry both A2 alleles, women with at least one A1 allele were more likely to report having stopped taking bupropion due to medication side effects (odds ratio (OR)=1.91, 95% confidence interval (CI)=1.01-3.60; P<0.04) and at 12 months were somewhat more likely to report smoking (OR=0.76, 95% CI=0.56-1.03; P<0.076). Significant associations or trends were not observed in men. In women, individual variability in responsiveness to bupropion-based treatment may be partially due to differences in genetic variants influencing dopamine receptor function.

Sleep disturbance is commonly reported as a prominent subjective symptom by quitting smokers. However, little research on this issue has used objective measures of sleep quality. Previous research has relied mainly on retrospective report of sleep disturbance, with few studies investigating sleep during the initial period after quitting tobacco use. Studies that have used objective measurements suggest that sleep fragmentation is a common occurrence during the withdrawal period. In sleep medicine, sleep disturbance is viewed as a consequence of frequent arousals and is now considered to have particularly deleterious daytime consequences, including sleepiness and dysphoric mood. Recent work also indicates that such awakenings affect the cardiovascular system by providing repetitive bursts of sympathetic nervous system activation, possibly contributing to elevated levels of cardiovascular and cerebrovascular morbidity. Pharmacological treatments designed to facilitate smoking cessation are ineffective for sustained abstinence in many smokers, which may be related to sleep disturbance. Indeed, preliminary evidence suggests that the administration of nicotine replacement therapy (NRT) or bupropion can result in disrupted sleep, particularly in women. However, to better understand the role that nicotine withdrawal and bupropion or NRT treatment, independently and in combination, might play in sleep disturbance, it is necessary to develop a better understanding of the nature of the sleep disturbance than can be provided by self-report. This is particularly important for the development of treatment approaches targeted to ameliorate sleep disruption as part of an overall smoking cessation strategy. The present review seeks to report the current state of knowledge based on extant findings and argues for the need to conduct more detailed polysomnographic investigations of the potentially vicious cycle of smoking cessation leading to sleep disturbances that may prove iatrogenic to sustained cessation.

Tobacco use is the single most preventable cause of death, disability, and disease in the United States and is projected to be the leading cause of death and disability across all developed countries by the year 2020. Understanding nicotine dependence, its causes, consequences, and effective treatments is critical to the nation's public health agenda. This article presents a brief overview of nicotine dependence with particular emphasis placed on understanding what nicotine dependence is, why it occurs, how it is measured, and how it can be managed through effective treatments.

This article describes a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty-nine twin pairs (110 monozygotic and 29 dizygotic) were recruited and assessed for smoking status, zygosity, and health conditions known or suspected to affect drug metabolism. Participants underwent a 30-minute infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, followed by an 8-hour in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine, and metabolites by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry and subsequent characterization of pharmacokinetic phenotypes. DNA was genotyped to confirm zygosity and for variation in the primary gene involved in nicotine metabolism, CYP2A6. Univariate and multivariate biometric analyses planned for the future will determine genetic and environmental influences on each pharmacokinetic measure individually and in combination with each other, and in the presence and absence of covariates, including measured genotype. When the analyses are completed, this study will result in a more complete characterization of the impact of genetic and environmental influences on nicotine and cotinine metabolic pathways than has heretofore been reported. The approach taken, with its use of a quantitative model of nicotine metabolism, highly refined metabolic phenotypes, measured genotype, and advanced tools for biometric genetic analysis, provides a model for the use of twins in next-generation studies of complex drug-metabolism phenotypes.

Unlabelled: The net benefit (i.e., benefits minus costs) of sustained-release (SR) bupropion for smoking cessation from an employer's perspective has previously been evaluated in clinical trials including frequent, in-person behavioral counseling and manufacturer recommended dosing but not in actual practice settings and lower dosing., Objectives: The objective of this research was to determine the return on investment (ROI) and internal rate of return (IRR) from an employer's perspective of two dosing schedules of bupropion SR in combination with behavioral interventions of minimal intensity (tailored mailings, TM) or moderate intensity (proactive telephone calls, PTC) in an actual practice setting., Methods: An open-label, randomized trial with 1-year follow-up was conducted in a large health system (Group Health Cooperative) based in Seattle, WA. Participants included 1524 adult smokers interested in quitting smoking. Participants were randomly assigned to receive 150 mg of bupropion SR daily and PTC (n=382), 150 mg of bupropion SR daily and TM (n=381), 300 mg of bupropion SR daily and PTC (n=383) or 300 mg of bupropion SR daily and TM (n=378). Sufficient medications for 8 weeks of dosing were provided to patients. The primary outcome measure of the field trial was self-reported point-prevalence 7-day nonsmoking status at 12 months, and the primary outcome measures of the economic analysis were employer net benefit, employer ROI, and the ROI-associated IRR using 2002 dollars., Results: Using net benefit, the 300-mg/PTC and the 150-mg/PTC treatments were approximately equally preferred. Using ROI or IRR, both the 150-mg/TM and 150-mg/PTC treatments were about equally preferred, with IRR values of 31.7% and 31.4%, respectively. Under a pessimistic scenario regarding effectiveness and costs, 150 mg/PTC became more cost-effective than 150 mg/TM, and employer IRR for 150 mg/PTC was 13%. Under an optimistic scenario IRR exceeded 45% for all treatments., Conclusions: These results suggest that employers can receive competitive returns on investment from sponsoring smoking cessation programs, that 150 mg of bupropion doses yield better returns than 300-mg doses, and that PTC treatments should be preferred to TM if smoking cessation rates in the targeted employee population are lower than those in the study population.

The objective of this study was to establish a repeatable, standardized laboratory procedure for monitoring the development of antimicrobial resistance in bacteria isolated from animals and food of animal origin in South Africa, with reagents prepared in-house. The emergence of resistance and the spread of resistant bacteria can be limited by implementing a veterinary antimicrobial drug policy, in which inter alia systematic monitoring and prudent use play essential roles. The bacteria included in this study represented three different categories, namely zoonotic bacteria (Salmonella), indicator bacteria (Escherichia coli, Enterococcus faecalis and Enterococcus faecium) and veterinary pathogens (Mannheimia haemolytica). Thirty isolates of each species were collected with the aim of standardizing the laboratory methodology for a future national veterinary surveillance and monitoring programme. Susceptibility to ten selected antimicrobial drugs was determined by means of minimum inhibitory concentrations (MICs) using the microdilution method. The method according to the National Committee for Clinical Laboratory Standards was used as the standard. Multi-well plates containing varying dilutions of antimicrobial drugs and prepared in-house for MIC determinations, yielded repeatable results. Storage of plates for 2 months at -70 degrees C did not influence results meaningfully. Within this limited sample of bacteria, MIC results did not indicate meaningful resistance against any of the ten selected antimicrobial drugs. The findings of the study will be used to establish a national veterinary antimicrobial resistance surveillance and monitoring programme in South Africa. To allow for international comparison of data, harmonisation of the surveillance and monitoring programme in accordance with global trends is encouraged. Ideally it should be combined with a programme monitoring the quantities of antimicrobial drugs used. The aim is to contribute to slowing down the emergence of resistance and the problems associated with this phenomenon by means of the rational use of antimicrobial drugs.

We examined the association between endogenous sex hormones (estradiol, estrone, testosterone, and SHBG) and coronary heart disease (CHD) in white male twins. Stored plasma samples were available for 566 participants of the National Heart, Lung, and Blood Institute Twin Study, a longitudinal study of cardiovascular disease in male twins. Twenty-eight of these individuals were lost to follow-up, and outcome data were missing. Of the remaining 538 participants, 78 had CHD at baseline, and 154 subsequently developed CHD over 20 yr of follow-up. We observed no differences in mean unadjusted or age- and body mass index-adjusted log-transformed sex hormone concentrations for participants with and without CHD (all P > 0.08). Quartile and median split analyses revealed no significant association between any of the sex hormones and either prevalent or incident CHD. The discordant monozygotic twins showed no significant case-control group difference in estradiol, estrone, testosterone, and SHBG (all P > 0.3). The positive and negative concordant twin pairs had similar values for each of the sex hormones (all P > 0.3). We observed no relationship between endogenous sex hormone concentrations and prevalent or incident CHD in this sample of male twins.

Objectives: To determine the differential cost effectiveness of 2 dosing regimens of bupropion sustained release (SR) in combination with behavioral interventions of minimal intensity (tailored mailings [TM]) or moderate intensity (proactive telephone calls [PTC]) for smoking cessation in an actual practice setting., Study Design: Open-label, randomized trial, with 1-year follow-up, conducted in a large health system based in Seattle, Washington., Methods: A total of 1524 adult smokers interested in quitting smoking were randomly assigned to receive 150 mg bupropion SR daily and PTC (n = 382), 150 mg bupropion SR daily and TM (n = 381), 300 mg bupropion SR daily and PTC (n = 383), or 300 mg bupropion SR daily and TM (n = 378). Sufficient medication for 8 weeks of dosing was provided to patients. The primary outcome measure was self-reported point-prevalence 7-day nonsmoking status at 12 months after the target quit date., Results: Although the 300-mg dose was associated with a higher 12-month nonsmoking rate relative to the 150-mg dose with both PTC and TM, the additional cost resulted in lower cost effectiveness. The PTC behavioral intervention was more expensive than TM, but the additional effectiveness resulted in almost equivalent cost effectiveness at the 150-mg dose. Costs per additional 12-month nonsmoker (above that expected for placebo) for the 150-mg dose groups averaged 950 dollars and per additional lifetime quitter averaged 1508 dollars; for the 300-mg groups these costs were 1342 dollars and 2129 dollars, respectively. Cost per life-year and quality-adjusted life-years (QALYs) saved varied substantially by age and treatment, but were no greater than 1100 dollars for all treatment groups when averaged across the age and sex distribution for the study population., Conclusions: Although the cost per life-year and QALYs saved were sufficiently low for all doses to rate these smoking cessation interventions as among the most cost effective of life-saving medical treatments, within the regimens tested 150 mg bupropion combined with either PTC or TM was the most cost effective.

Aims: To examine heterogeneity in outcome following treatment for smoking cessation with combined bupropion SR and behavioral counseling in women and men., Design, Setting, Participants: This study included 875 women and 649 men recruited from a large health-care system and randomized to one of four combinations of treatment [two dosage levels of bupropion SR (Zyban, 150 mg and 300 mg) were crossed with two counseling programs of lower and higher intensity to create a four-cell design]., Measurements and Findings: A comprehensive set of relevant individual characteristics prior to treatment and treatment characteristics was included in the analysis. Smoking outcome at 12 months was defined as point-prevalence of any regular smoking within the 7 days prior to follow-up contact. Classification and regression tree analysis identified six subgroups in women that ranged in proportion of non-smokers from 9.8% to 42.9% and six subgroups in men that ranged in proportion of non-smokers from 17.3% to 50.0%., Conclusions: These results indicate the presence of a substantial amount of variation in treatment outcome among women and men receiving combined bupropion SR and counseling. Variation in outcome could be reduced by providing treatments tailored to subgroups of individuals who are at exceptionally high risk for smoking following cessation.

Drug use is a complex behavior influenced by multiple biological, family, and sociocultural factors. The concurrent use/misuse of multiple drugs is often seen and drug use also co-occurs with other psychiatric conditions. Behavior and molecular genetic studies support an important posited role of genes in drug use. This posited genetic risk does not appear to be conferred by one or two major genes manifesting large effects, but rather by a number of genes manifesting smaller effects. Genetic factors explain, on average, only about half of the total variability in drug use, with the remaining variability influenced by environmental factors. Also, genetic risk may be differentially expressed in the presence vs. absence of particular environmental conditions. Thus, investigation of environmental factors and their interaction with genetic risk is a necessary component of genetic research. While the full potential of genetic investigations for the prevention of drug misuse has yet to be realized, an example of the impact of risk factor modification under various conditions of gene-environment interaction is provided, and the implications for use of genetic information in drug-misuse prevention are discussed. The multifactorial nature of drug use necessitates coordinated investigation from multiple disciplines and timely dissemination of scientific findings. In addition, this work demands adherence to the highest standards of confidentiality and ethical use of genetic information to best inform future prevention efforts.

Numerous questions remain regarding the intergenerational transmission of tobacco use and dependence, and some of these questions are best approached from a transdisciplinary perspective. For example, considering both genetic and environmental influences on cigarette smoking promises to be a fruitful venue for future investigations. In this paper, we consider the evidence regarding intergenerational influences on the transmission of tobacco use and nicotine dependence in both humans and animal models; our focus will be on genetic influences, in utero exposure to nicotine, and some postnatal influences. Research gaps that exist between scientific disciplines are highlighted, and some directions for future research are suggested.

To date, only one study has been published on individual characteristics associated with outcome following standard treatment with bupropion SR for smoking cessation. To investigate treatment outcome beyond the 6-week end-of-treatment point, the present study examined characteristics associated with more clinically relevant smoking endpoints following treatment with bupropion SR in a large health care system. A total of 1,524 smokers (649 men and 875 women) of average age 45.1 years were randomized to receive one of four combinations of bupropion SR (150 or 300 mg) and behavioral counseling (tailored mailings or proactive telephone counseling) and assessed for point-prevalent smoking status at 3 and 12 months. Multiple logistic regression analyses of potential risk factors for 12-month point-prevalent smoking and for persistent smoking (point-prevalent smoking at both follow-ups) following treatment were conducted for men and women combined and separately. Risk factors for smoking at both endpoints in the combined sample included treatment with tailored mailings, female gender, younger age, higher levels of tobacco dependence, shorter previous quit attempts, previous use of nicotine replacement therapy, and report of current depressive symptoms or lifetime depression. Risk factors for smoking following treatment identified in women only included treatment with the lower dose of bupropion SR, younger age, and higher perceived stress, whereas those that were unique to men included the presence of lifetime depression. The results are discussed in terms of their implications for the need for more effective treatments in general, and the role of individual differences in the likelihood of returning to smoking following treatment for quitting.

Background: The efficacy of bupropion hydrochloride sustained release (SR) (Zyban) for smoking cessation has been evaluated in clinical trials that included frequent in-person behavioral counseling, but not in actual practice settings., Objective: To determine the differential effectiveness of 2 doses of bupropion SR in combination with behavioral interventions of minimal to moderate intensity in an actual practice setting., Design: Open-label randomized trial, with 1 year of follow-up., Setting: A large health system (Group Health Cooperative) based in Seattle., Participants: Adult smokers (N = 1524) interested in quitting smoking., Interventions: Participants were randomly assigned to receive 1 of 4 combinations of bupropion SR (150 or 300 mg) and behavioral counseling (minimal or moderate intensity)., Main Outcome Measures: The primary outcome measure was self-reported point-prevalence 7-day nonsmoking status at 3 and 12 months following the target quit date. Secondary outcomes included adverse and abstinence effects reported since beginning treatment with bupropion SR., Results: At 3 months, a significantly higher rate of nonsmoking was observed among those receiving the larger bupropion SR dose (P=.005). At 12 months, moderate intensity counseling was associated significantly with a higher rate of nonsmoking (P=.001). At 3 months, the higher dose was associated with a significantly increased frequency of self-reported symptoms such as difficulty sleeping (P=.02), difficulty concentrating (P=.02), shakiness/tremor (P=.002), and gastrointestinal problems (P=.005)and a decreased frequency of reported desire to smoke (P=.001)., Conclusions: In this actual practice setting, the combination of bupropion SR and minimal or moderate counseling was associated with 1-year quit rates of 23.6% to 33.2%. This suggests that existing health care systems can substantially decrease tobacco use rates among their enrollees if they provide these modest interventions.

This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements.

The standard tool for assessing tobacco dependence is the Fagerström Tolerance Questionnaire (FTQ) or its more recent variant, the Fagerström Test for Nicotine Dependence (FTND). Although both of these scales reportedly assess physiological dependence on nicotine, they might not tap some facets of dependence, particularly psychosocial factors. To determine whether tobacco dependence exhibits multidimensional properties, we examined two existing, independent data sets, one from SRI International (n=443) and another from the University of Michigan (n=445). Based on our knowledge from existing literature, standard psychometric statistical analyses, and results from exploratory factor analysis using SRI's data set, we identified two competing models for dependence representing a hybrid of the FTQ/FTND and the Smoking Motives Questionnaire. We then examined these models using confirmatory factor analysis with data from the University of Michigan. We characterized the final model by five first-order factors, each consisting of two to four items, and one higher-order factor. The first-order factors were termed stimulation, automaticity, sedation, psychosocial motives, and morning smoking; the higher-order factor, tobacco dependence, underlay each of the first-order factors. The ranges of interitem correlations and Cronbach's alpha estimates of internal consistency for the first-order factors were .34 - .68 and .64 - .81, respectively. Results of these analyses support the hypothesis that tobacco dependence is multidimensional.

Although investigators have used family history methods to investigate familial clustering of disorders such as depressive disorder, alcoholism, coronary heart disease, and cancer, research of this type is relatively new to the field of smoking. We examined agreement between proband report of parental smoking behavior and parent's self-reported smoking behavior in 126 proband-parent pairs. Probands were either never, current, or exsmokers; parents were either current or exsmokers. Agreement between proband and parent was better for smoking behaviors when the parent was a current smoker. We found good proband-parent agreement for some smoking behaviors when the parent was a current smoker (e.g., age started smoking [mean (SD) difference between proband and parental report, 1.36 years (9.07 years)], and cigarettes per day and brand smoked [kappa=.49 and.56, respectively]) but poor agreement for items that may represent more complex or less observable indicators of nicotine dependence, regardless of parental smoking status. Reliability was excellent for probands of either current- or exsmoker parents for smoking status (kappa=.92). As a result of probands' difficulty in reliably answering several items that comprise the Fagerström Tolerance Questionnaire (FTQ) (e.g., number of minutes to parent's first cigarette of the day, whether parent smoked more in the morning than during the rest of the day) and the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) diagnosis (e.g., sleep difficulties and difficulty concentrating during nicotine withdrawal), reliability for an FTQ score >/=7 (kappa=.067) and the DSM-IV nicotine dependence diagnosis (kappa=.28) was poor. Our findings should aid investigators in defining the limits of proband reports of parental smoking behavior and identify opportunities for the development of better approaches for the assessment of familial nicotine dependence.

Background: Little is known about the effectiveness of bupropion SR for smoking cessation outside the context of clinical efficacy trials, where in-person screening and treatment occur at a higher level than provided in a typical health care system. This article describes the methods for recruitment, screening for exclusions, and resulting sample in a field trial of bupropion SR undertaken in a managed-care setting., Methods: A total of 2979 telephone interviews were conducted to screen and identify eligible volunteers using a detailed protocol that allowed for consultation with study physicians when necessary. The volunteers' primary care physicians were given the option to override their eligibility, and pharmacy databases were used to verify medication reporting., Results: A total of 1909 (64%) volunteers were considered eligible for the study. The most common reason for exclusion was use of contraindicated medications (32%), followed by recent use of one of the behavioral cessation programs (14%), brain injury that reduced seizure threshold (14%), current depression (14%), and high levels of alcohol use (13%)., Conclusions: The methods used in this field trial show that it is possible to enroll subjects in an effectiveness trial that is successful from the standpoint of the consumer, provider, and health care system.

Cotyledoside, a bufadienolide cardiac glycoside, was administered intravenously to sheep in 2 studies. In experiment 1, sheep (n = 4) received 0.0135 mg/kg daily on 5 consecutive days and in the 2nd experiment, sheep (n = 4) received 0.027 mg/kg as a single dose. Jugular blood was collected at different time intervals and kinetic parameters were determined. The data fitted a 1-compartmental model. In both experiments a short half-life (t1/2) and mean residence time (MRT), a relative small volume of distribution (Vd(ss)) and rapid clearance were calculated. In the 1st experiment, t1/2 and MRT increased significantly (P < 0.007) from Day (D) 0 to D4. It is suggested that the rapid decline in plasma cotyledoside concentrations in sheep denotes rapid distribution of cotyledoside to the tissues or extracellular spaces and possible accumulation at the biophase.

Self-report measures of depressive symptoms, such as the Center for Epidemiological Studies-Depression Scale (CES-D), correlate with current and lifetime smoking status. In one previous study of adult female twins, genetic factors accounted for the covariation of liability to a diagnosis of major depressive disorder and liability to lifetime smoking (Kendler, Neale, MacLean, Heath, Eaves, & Kessler, 1993b, Archives of General Psychiatry, 50, 36-43); however, it remained unclear whether genetic effects also account for the covariation between subclinical depressive symptomology and smoking behavior. In this study, we use twin structural equation modeling to explore whether genetic and/or environmental influences contribute to the covariation between depressive symptoms, as measured by the CES-D, and current and lifetime smoking status among 120 monozygotic and 114 dizygotic Caucasian male twin pairs (aged 59-69). In this sample, depressive symptoms showed small but significant correlations with current and lifetime smoking status. Univariate twin analyses indicated that additive genetic and non-shared environmental factors contributed significantly to liability to current and lifetime smoking. However, the majority of variance in CES-D scores was attributable to non-shared (individual) environment. In bivariate analyses, non-shared environmental factors accounted for the majority of covariation between liability to depressive symptoms (CES-D scores > or = 8; above the 75th percentile) and liability to current and lifetime smoking status. Taken together with the previous literature, these results suggest that the etiology of covariation among depressive symptoms and smoking behavior may vary by measurement and severity of depressive symptomology.

A workgroup formed by the Society for Research on Nicotine and Tobacco reviewed the literature on abstinence measures used in trials of smoking cessation interventions. We recommend that trials report multiple measures of abstinence. However, at a minimum we recommend that trial: (a) report prolonged abstinence (i.e., sustained abstinence after an initial period in which smoking is not counted as a failure) as the preferred measure, plus point prevalence as a secondary measure; (b) use 7 consecutive days of smoking or smoking on > or = 1 day of 2 consecutive weeks to define treatment failure; (c) include non-cigarette tobacco use, but not nicotine medications in definitions of failure; and (d) report results from survival analysis to describe outcomes more fully. Trials of smokers willing to set a quit date should tie all follow-ups to the quit date and report 6- and/or 12-month abstinence rates. For these trials, we recommend an initial 2-week grace period for prolonged abstinence definitions; however, the period may vary, depending on the presumed mechanism of the treatment. Trials of smokers who may not be currently trying to quit should tie follow-up to the initiation of the intervention and should report a prolonged abstinence measure of > or = 6-month duration and point prevalence rates at 6- and 12-month follow-ups. The grace period for these trials will depend on the time necessary for treatment dissemination, which will vary depending on the treatment, setting, and population. Trials that use short-term follow-ups (< or = 3 months) to demonstrate possible efficacy should report a prolonged abstinence measure of > or = 4 weeks. We again recommend a 2-week grace period; however, that period can vary.