Robust Face Recognition Based on a New Supervised Kernel Subspace Learning Method.

Face recognition is one of the most popular techniques to achieve the goal of figuring out the identity of a person. This study has been conducted to develop a new non-linear subspace learning method named "supervised kernel locality-based discriminant neighborhood embedding," which performs data classification by learning an optimum embedded subspace from a principal high dimensional space. In this approach, not only nonlinear and complex variation of face images is effectively represented using nonlinear kernel mapping, but local structure information of data from the same class and discriminant information from distinct classes are also simultaneously preserved to further improve final classification performance. Moreover, in order to evaluate the robustness of the proposed method, it was compared with several well-known pattern recognition methods through comprehensive experiments with six publicly accessible datasets. Experiment results reveal that our method consistently outperforms its competitors, which demonstrates strong potential to be implemented in many real-world systems.

N-Acetyltransferase-2 (NAT2) phenotype is influenced by genotype-environment interaction in Ethiopians.

BACKGROUND AND OBJECTIVES: N-acetyltransferase 2 (NAT2) metabolize several drugs including isoniazid. We investigated the effect of genotype, geographical difference, and smoking habit on NAT2 phenotype in Ethiopians. METHODS: Genotyping for NAT2 191G > A, 341 T > C, 590G > A, and 857G > A was performed in 163 unrelated healthy Ethiopians (85 living in Ethiopia and 78 living in Sweden). The NAT2 phenotype was determined using caffeine as a probe and log AFMU/(AFMU + 1X + 1 U) urinary metabolic ratio (MR) as an index. RESULTS: The frequencies of NAT2*4, *5, *6, *7, and *14 haplotypes were 14.1, 48.5, 30.1, 5.5, and 1.8%, respectively. The frequencies of rapid (NAT2*4/*4), intermediate (heterozygous *4), and slow (no *4 allele) acetylator genotypes were 1.8, 24.6, and 73.6%, respectively. The distribution NAT2 MR was bimodal with 70% being phenotypically slow acetylators. NAT2 genotype (p < 0.0001) and country of residence (p = 0.004) independently predicted NAT2 phenotype. Controlling for the effect of genotype, ethnic Ethiopians living in Ethiopia had significantly higher NAT2 MR than those living in Sweden (p = 0.006). NAT2 genotype-phenotype concordance rate was 75%. Distinct country-of-residence-based genotype-phenotype discordance was observed. The proportion of phenotypically determined rapid acetylators was significantly higher and slow acetylators was lower in Ethiopians living in Ethiopia (39% rapid, 61% slow) than in Sweden (20% rapid, 80% slow). Sex and smoking had no significant effect on NAT2 MR. CONCLUSIONS: We report a high prevalence of NAT 2 slow acetylators in Ethiopians and a conditional NAT2 genotype-phenotype discordance implicating a partial phenotype conversion and metabolic adaptation. Gene-environment interactions regulate NAT2 phenotype.

Polymorphisms in ABCB1 and CYP19A1 genes affect anastrozole plasma concentrations and clinical outcomes in postmenopausal breast cancer patients.

AIMS: Anastrozole, an aromatase inhibitor widely used in breast cancer, has recently been indicated to be a P-glycoprotein (ABCB1) substrate. We have aimed to determine whether ABCB1 single-nucleotide polymorphisms (SNPs) can affect anastrozole plasma concentrations in these patients. In addition, we assessed the impact of SNPs in CYP19A1 and TCL1A on the development of arthralgia and cancer recurrence in our series. METHODS: This study included 110 postmenopausal women with hormone receptor-positive breast cancer. Anastrozole plasma levels were determined by a liquid chromatography-electrospray ionization-quadrupole-time-of-flight mass spectrometry system. Patients were genotyped for SNPs in the ABCB1, TCL1A and CYP19A1 genes to search for associations with pharmacokinetic and pharmacodynamics parameters using logistic regression models. RESULTS: Anastrozole concentrations showed an almost nine-fold interindividual variability (mean 26.95 ± 11.91 ng ml-1 ). The ABCB1 2677-TT genotype was associated with higher plasma levels (32.22 ± 12.82 vs. 25.86 ± 11.56 ng ml-1 for GG/GT subjects; 95% confidence interval: -12.3 to -0.40), whilst the 3435-TT genotype showed a protective effect on the risk of arthralgia (odds ratio = 0.32 [0.11-0.89]; P = 0.029). The CYP19A1 rs1008805 GG genotype was strongly and inversely associated with arthralgia (odds ratio = 0.24 [0.09-0.65], P = 0.004); however, SNPs near the TCL1A gene were not linked to this adverse effect. None of the patients who had cancer recurrence harboured the CYP19A1 rs727479 AA genotype, which, in contrast, was present in 38% of patients who did not relapse (P for trend = 0.031). CONCLUSION: Our findings indicate that variability in anastrozole plasma levels may be attributable to the status of the ABCB1 gene locus. Furthermore, genetic variants in CYP19A1 were associated with arthralgia and cancer recurrence in our patients.

Optimization of an Optical Test Bench for Tire Properties Measurement and Tread Defects Characterization.

Tire characteristics and behavior are of great importance in vehicle dynamics since the forces transmitted in the tire-road contact are the main contributors to global vehicle performance. Several research groups have focused on the study and modeling of tires. Some of the most important factors that need to be known are tread characteristics and pressure distribution in the tire-ground contact patch. In this work, a test bench has been used to adequately determine the aforementioned factors. The measurement principle of the test bench is the frustration of total internal reflection (FTIR) of light. It makes use of a laterally illuminated glass on which the tire leans. An interposed plastic interface between them causes the reflection of light. Finally, a video camera captures the bright image formed through the glass. The brightness level in each pixel of the image is related to existing normal pressure. A study of the parameters that affect the test bench calibration such as type of interface material used, diffuse light, hysteresis, creep and transverse light absorption is performed. Experimental tests are conducted to relate tire inflation pressure and camber angle to the pressure distribution. Furthermore, the test bench is used to detect and evaluate the influence of defects in the tire on the contact pressures.

Robust Road Condition Detection System Using In-Vehicle Standard Sensors.

The appearance of active safety systems, such as Anti-lock Braking System, Traction Control System, Stability Control System, etc., represents a major evolution in road safety. In the automotive sector, the term vehicle active safety systems refers to those whose goal is to help avoid a crash or to reduce the risk of having an accident. These systems safeguard us, being in continuous evolution and incorporating new capabilities continuously. In order for these systems and vehicles to work adequately, they need to know some fundamental information: the road condition on which the vehicle is circulating. This early road detection is intended to allow vehicle control systems to act faster and more suitably, thus obtaining a substantial advantage. In this work, we try to detect the road condition the vehicle is being driven on, using the standard sensors installed in commercial vehicles. Vehicle models were programmed in on-board systems to perform real-time estimations of the forces of contact between the wheel and road and the speed of the vehicle. Subsequently, a fuzzy logic block is used to obtain an index representing the road condition. Finally, an artificial neural network was used to provide the optimal slip for each surface. Simulations and experiments verified the proposed method.

BDNF genetic variability modulates psychopathological symptoms in patients with eating disorders.

The brain-derived neurotrophic factor (BDNF) gene may influence eating behavior, body weight and cognitive impairments. We aimed to investigate whether BDNF genetic variability may affect anthropometric and psychological parameters in patients with anorexia or bulimia nervosa (AN, BN) and/or modulate the risk for the disorder. A total of 169 unrelated female patients and 312 healthy controls were genotyped for two common BDNF single-nucleotide polymorphisms (SNPs), Val66Met and C-270T, and several selected tag-SNPs. Associated personality characteristics and psychopathological symptoms were assessed by the EDI-2 and SCL-90R inventories, respectively. No single SNP or haplotype played a relevant role in the risk for AN or BN. The rs16917237 TT genotype was significantly associated with increased weight (74.63 ± 16.58 vs. 57.93 ± 13.02) and body mass index (28.94 ± 6.22 vs. 22.23 ± 4.77) in the BN group after correcting for multiple testing. Haplotype analyses using a sliding window approach with three adjacent SNPs produced four loci of interest. Locus 3 (rs10835210/rs16917237/C-270T) showed a broad impact on the measured psychopathological symptoms. Haplotypes CGC and CGT in this locus correlated with scores in all three scales of the SCL-90R inventory, both in AN and BN patients. In contrast, the results of the EDI-2 inventory were largely unaffected. These preliminary results suggest that variability in the BDNF gene locus may contribute to anthropometric characteristics and also psychopathological symptoms that are common but not exclusive of ED patients.

Influence of dopamine polymorphisms on the risk for anorexia nervosa and associated psychopathological features.

Dopamine neuronal functions make polymorphisms in dopaminergic pathways good candidates for playing a relevant role in anorexia nervosa (AN) and related psychopathological features. We have analyzed the effect of 8 polymorphisms in genes coding for dopamine receptors (DRD2, DRD3, and DRD4), transporters (DAT1) and metabolizing enzymes (COMT) in 78 women with AN and 186 control subjects. Associated psychopathological characteristics in patients with AN were assessed by the Eating Disorders Inventory Test-2 and SCL-90R self-reported questionnaires. The DRD4 variable number of tandem repeats (VNTR) 7R/7R and DRD4 -616CC genotypes were significantly associated with a greater risk for AN (odds ratio, 3.83; confidence interval, 1.05-13.98; P = 0.04; and odds ratio, 1.74; confidence interval, 1.01-2.97; P = 0.03, respectively). The analysis of physiological parameters in the patients with AN revealed that the short allele of a 120-base pair tandem repeat in the promoter region of the DRD4 gene was associated with higher weight (48.35 ± 6.79 vs 43.95 ± 5.78 kg; Bonferroni, P < 0.05), whereas the DRD4 -521TT genotype was associated with significantly higher body mass index (17.29 ± 2.25 vs 18.13 ± 2.41 kg/m2; Bonferroni, P < 0.05). The DRD4 C-616G and DAT1 VNTR polymorphisms correlated with several psychopathological features in patients with AN. Carriers of the mutant homozygous genotypes scored higher in all but one of the Eating Disorders Inventory Test-2 subscales. After correction for multiple testing, differences in Asceticism scores between DAT1 VNTR genotypes, as well as differences in Drive for Thinness and Body Dissatisfaction between C-616G genotypes remained significant (P < 0.05). The results show that certain genetic alterations in the dopamine pathways are able to modify the risk for AN as well as modulate psychopathological features that are often coupled to this disorder.

CYP1A1 gene polymorphisms increase lung cancer risk in a high-incidence region of Spain: a case control study.

BACKGROUND: A rural region in south-west Spain has one of the highest lung cancer incidence rates of the country, as revealed by a previous epidemiological 10-year follow-up study. The present work was undertaken to ascertain the role of CYP1A1 gene polymorphisms and their interaction with tobacco smoking in the development of the disease in this location. METHODS: One-hundred-and-three cases of lung cancer and 265 controls participated in the study. The participants were screened for the presence of four CYP1A1 polymorphisms, namely MspI, Ile462Val, T3205C, and Thr461Asn. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression models adjusting for age, sex, and smoking. RESULTS: The distribution of the variant CYP1A1 alleles was different from that described for other Caucasian populations, with CYP1A1*2A showing an uncommonly high frequency (p < 0.01). The CYP1A1*2B allele (carrying MspI and Ile462Val mutations) was strongly associated with high lung cancer risk (OR = 4.59, CI:1.4-12.6, p <0.01). The Ile462Val polymorphism was also shown to increase the risk for the disease (OR = 4.51, CI:1.8-11.9; p <0.01) and particularly for squamous-cell (OR = 5.01; CI: 1.6-14.3, p < 0.01) and small-cell lung carcinoma (SCLC) (OR = 6.97, CI: 1.2-81.3; p = 0.04). Moreover, the Thr461Asn polymorphism was found to be associated with SCLC in a Caucasian population for the first time to our knowledge (OR = 8.33, CI: 1.3-15.2, p = 0.04). CONCLUSION: The results suggest that CYP1A1 polymorphisms contribute to increase lung cancer susceptibility in an area with an uncommon high incidence rate.

GST polymorphisms interact with dietary factors to modulate lung cancer risk: study in a high-incidence area.

The aim of this study was to explore possible correlations between glutathione S-transferases (GST) polymorphisms, smoking, diet, and lung cancer susceptibility in a rural Spanish region with one of the highest incidence rates of the country. All lung cancer patients living in the area (103) and 247 matched controls were genotyped for the GST mu 1 (GSTM1) null, GST theta 1 (GSTT1) null, and GST pi 1 (GSTP1) Isoleucine (Ile) 105 valine (Val) polymorphisms and interviewed to gather information on smoking and dietary habits. Neither the presence of GST polymorphisms nor their interaction with smoking was independently associated to lung cancer risk. The intake of carotenoid-rich red and yellow vegetables was inversely associated with lung cancer (P < 0.05). Interestingly, this was observed only in carriers of the GSTM1 (P = 0.04), GSTT1 (P = 0.03), or GSTM1/T1 (P = 0.04) positive genotypes. Similarly, the consumption of citrus fruits was more frequent among cancer-free subjects who carried functional GSTM1 (P = 0.04) or both GSTM1 and GSTT1 enzymes (P = 0.04). The results show that the inverse association observed between the intake of dietary carotenoid-rich vegetables and lung cancer risk is dependent on the GST genotype. These results warrant further investigations to confirm the observed associations.

Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy.

Genetic factors contribute to the phenotype of drug response, but the translation of pharmacogenetic outcomes into drug discovery, drug development or clinical practice has proved to be surprisingly disappointing. Despite significant progress in pharmacogenetic research, only a few drugs, such as cetuximab, dasatinib, maraviroc and trastuzumab, require a pharmacogenetic test before being prescribed. There are several gaps that limit the application of pharmacogenetics based upon the complex nature of the drug response itself. First, pharmacogenetic tests could be more clinically applicable if they included a comprehensive survey of variation in the human genome and took into account the multigenic nature of many phenotypes of drug disposition and response. Unfortunately, much of the existing research in this area has been hampered by limitations in study designs and the nonoptimal selection of gene variants. Secondly, although responses to drugs can be influenced by the environment, only fragmentary information is currently available on how the interplay between genetics and environment affects drug response. Third, the use of a pharmacogenetic test as a standard of care for drug therapy has to overcome significant scientific, economic, commercial, political and educational barriers, among others, in order for clinically useful information to be effectively communicated to practitioners and patients. Meanwhile, the lack of efficacy is in this process is quite as costly as drug toxicity, especially for very expensive drugs, and there is a widespread need for clinically and commercially robust pharmacogenetic testing to be applied. In this complex scenario, therapeutic drug monitoring of parent drugs and/or metabolites, alone or combined with available pharmacogenetic tests, may be an alternative or complementary approach when attempts are made to individualize dosing regimen, maximize drug efficacy and enhance drug safety with certain drugs and populations (e.g. antidepressants in older people).

In vivo evaluation of CYP2A6 and xanthine oxidase enzyme activities in the Serbian population.

PURPOSE: The main aim of the study was to investigate the distribution of cytochrome P450 2A6 (CYP2A6) and xanthine oxidase (XO) enzyme activities in the Serbian population. Secondly, we tested the influence of genetics (CYP2A6 polymorphism), sex, and cigarette smoking on both enzymes. METHODS: One hundred forty healthy Serbian volunteers were genotyped for common CYP2A6 alleles. In 100 of them, CYP2A6 and XO activities were determined by the urinary 17U/17X and 1U/(1U + 1X) ratios, respectively, after oral administration of 100 mg caffeine as a probe. RESULTS: A 21-fold variation in the 17U/17X ratio was observed (range: 0.49-10.28, mean = 1.65, 95% CI: 1.49-1.83). The urinary 1U/(1U + 1X) ratios displayed four-fold variation, ranging from 0.17 to 0.71 (mean = 0.43, 95% CI: 0.41-0.45). CYP2A6 alleles *1A, *1B1, *9, *4 and *1B1x2 were found with frequencies of 0.579, 0.307, 0.082, 0.029, and 0.004 respectively. CYP2A6*5 was not detected. CYP2A6 genotype influenced interindividual variability in CYP2A6 enzyme activity (P = 0.04). Cigarette smoking inhibited CYP2A6 enzyme activity (P = 0.02), but had no effect on activity of XO (P = 0.16).There was no significant difference between men and women in terms of CYP2A6 or XO activity. CONCLUSIONS: Serbs displayed interindividual variations in CYP2A6 activity. CYP2A6 genotype and cigarette smoking, but not sex, influenced CYP2A6 enzyme activity. Unimodal distribution of XO enzyme activity in Serbs implies the absence of subjects with low enzyme activity in this population. XO activity is not influenced by sex or cigarette smoking.

Promoting appropriate drug use through the application of the Spanish drug-related problem classification system in the primary care setting.

BACKGROUND: According to the Second Consensus of Granada (2002), the term drug-related problem (DRP) is defined as a health problem resulting from pharmacotherapy and is considered a negative clinical outcome (ie, a therapeutic objective is not achieved or adverse effects are reported). DRP classification systems used in primary care settings can be useful tools to detect, evaluate, and resolve DRPs. OBJECTIVE: To encourage appropriate drug use in the ambulatory clinical setting through DRP detection and evaluation by means of the Spanish DRP classification system, and to document how pharmacists can help resolve DRPs through interventions with both general practitioners (GPs) and patients. METHODS: Four pharmacists investigated DRPs in polymedicated patients over a 6-month period. All detected DRPs were grouped into 3 major categories: necessity, effectiveness, and safety. To resolve DRPs, pharmacists performed interventions on GPs and patients. GPs received verbal and written information about DRPs; patient interventions were in the form of private meetings on health education. RESULTS: Four hundred twenty-two patients, 80% of whom were aged 65 years or older, were included in the study. Each patient was taking a mean +/- SD of 8.1 +/- 2.4 medications. Three hundred four medications were associated with 245 DRPs; medications indicated for digestive/metabolic or cardiovascular pathologies were the most prevalent. Most (60%) of the identified DRPs belonged to the effectiveness category, whereas safety issues accounted for 28.6%. The most frequently reported DRP was pathology resistant to treatment (19.6%), followed by nonadherence (16.3%). Of the 215 interventions carried out to resolve these DRPs, 173 (80.5%) were addressed to GPs, who agreed to change therapy regimens on 90.2% of the occasions. Forty-two (19.5%) interventions were addressed to patients. Furthermore, the interventions accepted by GPs and patients resolved 176 (82%) DRPs. CONCLUSIONS: The current Spanish DRP classification system is a useful tool to systematically detect and document DRPs in daily general practice. In addition, the interventions addressed by pharmacists to GPs and patients resolved most of the detected DRPs.

Effect of dopamine receptor D4 (DRD4) haplotypes on general psychopathology in patients with eating disorders.

Among the many candidate genes analyzed in eating disorder (ED) patients, those involved in dopaminergic functions may be of special relevance, as dopamine is known to play a significant role in feeding behavior, the distortion of body image, hyperactivity and reward and reinforcement processes. We aimed to determine the effect of functional polymorphisms and haplotypes in the Dopamine Receptor D4 (DRD4) gene on general psychopathological symptoms in ED patients. Two-hundred-and-seventy-three ED patients [199 with Anorexia Nervosa (AN) and 74 with Bulimia Nervosa (BN)] completed the SCL-90R inventory and were genotyped for four functional, clinically relevant DRD4 polymorphisms: three variants in the promoter region [120-bp tandem repeat (TR, long vs. short allele), C-616G and C-521 T] and a variable number of tandem repeats (VNTR) in exon 3 (7R vs. non-7R allele). After correcting for multiple testing, none of the assayed polymorphisms were individually associated with SCL-90R results. Four DRD4 haplotypes (*1-*4) were detected in the patients with a frequency > 0.1. In the BN group, haplotype *2 (non7R-TR long-C-C) was associated with higher scores in the three global SCL-90R indices (GSI, PSDI and PST) after Bonferroni correction (p ≤ 0.01 in all instances). Furthermore, carriers of this haplotype displayed higher scores (worst symptomatology) in Somatization, Obsessive-Compulsive, Anxiety, Phobic anxiety, Paranoid ideation and the test additional items (p-values for the differences between carriers vs. non-carriers ranging from 0.0001 to 0.0110). Certain combinations of DRD4 variants may contribute to psychopathological features in BN patients.

Evaluation of a drug-drug interaction alert structure through the retrospective analysis of statins-macrolides co-prescriptions.

The aim of this work was the evaluation of the existent drug interaction alert structure in Spain, which is based on yellow cards notifications and circulation of drug alert letters, through the retrospective analysis of CYP3A-metabolized statins and macrolides co-prescriptions in the Spanish province of Badajoz between May and September 2001. The period of study was planned to include the release of 2 drug alert letters released by the Spanish Drug Agency in June and July, addressed to all healthcare professionals, which warned against the concomitant prescription of statins and inhibitors of their metabolism, e.g. macrolides antibacterials. 4,600,764 prescriptions were examined, 664 of which corresponded to combinations of statins and macrolides. Although a decrease was detected in the number of these co-prescriptions throughout the study, 80 of these corresponding to 67 patients were still being prescribed in September, after the warnings by the Spanish Drug Agency had been released. 431 physicians prescribed these drugs simultaneously, with 22.9% of them having more than one patient at potential risk. Doctors working at rural healthcare centres or not directly attached to any healthcare facility were more prone to prescribe unsafe coprescriptions than those working at urban health centre. This study shows that the present drug alert system is not fully efficient when facing a situation like the one retrospectively reviewed in this study, in which a prompt action, in this case termination of potentially hazardous coprescriptions, was required. New systems developed to improve prescribing, including a new method based on personal contact between Drug Surveillance Centres and general practitioners, are discussed.

Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19).

OBJECTIVES: Fluvoxamine is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 and the smoking-inducible CYP1A2. Therapeutic doses of fluvoxamine inhibit both CYP1A2 and CYP2C19. In this study we used extensive metabolizers (EMs) and poor metabolizers (PMs) of debrisoquin (INN, debrisoquine) (CYP2D6) and two probes, caffeine (CYP1A2) and omeprazole (CYP2C19), to investigate whether nontherapeutic doses of fluvoxamine inhibit CYP1A2 but possibly not CYP2C19. METHODS: Single oral doses of 100 mg caffeine and 20 mg omeprazole were given separately to 5 EMs and 5 PMs of debrisoquin to assess the activity of CYP1A2 and CYP2C19, respectively. Initially, a single oral dose of fluvoxamine (25 mg to PMs and 50 mg to EMs) was given, followed by 1 week of daily administration of 25 mg x 2 to EMs and 25 mg x 1 to PMs. Caffeine (day 6) and omeprazole (day 7) were again administered at the steady state of fluvoxamine. Later the study protocol was repeated with a lower dose of fluvoxamine, 10 mg x 2 to EMs and 10 mg x 1 to PMs for 1 week. Concentrations of fluvoxamine, caffeine, omeprazole, and their metabolites were analyzed by HPLC methods in plasma and urine. RESULTS: The kinetics of fluvoxamine were not significantly different in EMs and PMs after a single oral dose of the drug. At the higher but not the lower steady-state dose of fluvoxamine, a significantly lower clearance in PMs compared with EMs was observed (geometric mean, 0.86 versus 1.4 L/h per kilogram; P <.05). At steady state, the 25 mg x 1 or x 2 fluvoxamine dose caused a pronounced inhibition of about 75% to 80% for both CYP1A2 and CYP2C19, whereas the inhibition after the lower 10 mg x 1 or x 2 dose was about 40% to 50%. The area under the plasma concentration-versus-time curve from 0 to 24 hours [AUC(0-24)] of caffeine increased 5-fold (P <.001) after the higher dose of fluvoxamine and 2-fold (P <.05) after the lower dose. The area under the plasma concentration-time curve from time zero to 8 hours [AUC(0-8)] ratio of 5-hydroxyomeprazole/omeprazole decreased 3.4-fold (P <.001) and 2.4-fold (P <.001), respectively. One EM subject had a very low oral clearance of fluvoxamine after both single and multiple dosing of the drug. This subject might have a deficient transporter protein in the gut, leading to an increased absorption of fluvoxamine. CONCLUSION: No convincing evidence was found that CYP2D6 is an important enzyme for the disposition of fluvoxamine. Other factors seem to be more important. A nontherapeutic oral daily dose of fluvoxamine is sufficient to provide a marked inhibition of both caffeine (CYP1A2) and omeprazole (CYP2C19) metabolism. It was not possible to separate the inhibitory effects of fluvoxamine on these enzymes, even after such a low daily dose such as 10 mg x 1 or x 2 of fluvoxamine.

Potential role of cerebral cytochrome P450 in clinical pharmacokinetics: modulation by endogenous compounds.

Cytochrome P450 (CYP) enzymes catalyse phase I metabolic reactions of psychotropic drugs. The main isoenzymes responsible for this biotransformation are CYP1A2, CYP2D6, CYP3A and those of the subfamily CYP2C. Although these enzymes are present in the human brain, their specific role in this tissue remains unclear. However, because CYP enzymatic activities have been reported in the human brain and because brain microsomes have been shown to metabolise the same probe substrates used to assess specific hepatic CYP activities and substrates of known hepatic CYPs, local drug metabolism is believed to be likely. There are also indications that CYP2D6 is involved in the metabolism of endogenous substrates in the brain. This, along with the fact that several neurotransmitters modulate CYP enzyme activities in human liver microsomes, indicates that CYP enzymes present in brain could be under various regulatory mechanisms and that those mechanisms could influence drug pharmacokinetics and, hence, drug response. In this paper we review the presence of CYP1A2, CYP2C9, CYP2D6 and CYP3A in brain, as well as the possible existence of local brain metabolism, and discuss the putative implications of endogenous modulation of these isoenzymes by neurotransmitters.

High CYP2A6 enzyme activity as measured by a caffeine test and unique distribution of CYP2A6 variant alleles in Ethiopian population.

CYP2A6 metabolizes clinically relevant drugs, including antiretroviral and antimalarial drugs of major public health importance for the African populations. CYP2A6 genotype-phenotype relationship in African populations, and implications of geographic differences on enzyme activity, remain to be investigated. We evaluated the influence of CYP2A6 genotype, geographical differences, gender, and cigarette smoking on enzyme activity, using caffeine as a probe in 100 healthy unrelated Ethiopians living in Ethiopia, and 72 living in Sweden. CYP2A6 phenotype was estimated by urinary 1,7-dimethyluric acid (17U)/1,7-dimethylxanthine or paraxanthine (17X) ratio. The frequencies of CYP2A6*1B, *1D, *2, *4, *9, and *1x2 in Ethiopians were 31.3, 29.4, 0.6, 0.6, 2.8, and 0.3%, respectively. The overall mean±SD for log 17U/17X was 0.12±0.24 and coefficient of variation 199%. No significant difference in the mean log 17U/17X ratio between Ethiopians living in Sweden versus Ethiopia was observed. Analysis of variance revealed CYP2A6 genotype (p=0.04, F=2.01) but not geographical differences, sex, or cigarette smoking as predictors of CYP2A6 activity. Importantly, the median (interquartile range) of 17U/17X ratio in Ethiopians 1.35 (0.99 to 1.84) was 3- and 11-fold higher than the previously reported value in Swedes 0.52 (0.27 to 1.00) and Koreans 0.13 (0.0 to 0.35), respectively (Djordjevic et al., 2013). Taken together, we report here the relevance of CYP2A6 genotype for enzyme activity in this Ethiopian sample, as well as high CYP2A6 activity and unique distribution of the CYP2A6 variant alleles in Ethiopians as compared other populations described hitherto. Because Omics biomarker research is rapidly accelerating in Africa, CYP2A6 pharmacogenetics and clinical pharmacology observations reported herein for the Ethiopian populations have clinical and biological importance to plan for future rational therapeutics efforts in the African continent as well as therapeutics as a global science.

Comparisons of CYP2A6 genotype and enzyme activity between Swedes and Koreans.

The aim was to compare cytochrome P450 2A6 (CYP2A6) genotype and enzyme activity between Swedes and Koreans, and to investigate the influence of genotype, sex, age, cigarette smoking and oral contraceptive (OC) use on enzyme activity. The study involved 190 Swedes and 144 Koreans. Genotyping for CYP2A6*1B, *1×2, *4, *5, *7, *8, *9, *10, *18 and *19 alleles was done. Using caffeine as a probe, in vivo CYP2A6 activity was estimated by the 17U/17X urinary ratio. Multiple regression analysis indicated ethnicity (p=0.0001) and CYP2A6 genotype (p=0.006), but not sex, age, cigarette smoking or OC use as predictors of CYP2A6 activity. There were significant differences in CYP2A6 genotype distribution and enzyme activity between Swedes and Koreans. Functional CYP2A6 alleles and rapid genotypes were more frequent in Swedes, whereas the defective alleles and slow genotypes were more frequent in Koreans (p≤0.0001). Distribution of log 17U/17X was bimodal in Koreans but unimodal in Swedes with a common antimode at 0.01, classifying 3.16% of Swedes and 18.75% of Koreans as slow metabolizers. CYP2A6 activity was higher in Swedes compared to Koreans (p<0.0001), even among carriers of rapid genotypes. We report major differences in CYP2A6 enzyme activity between Swedes and Koreans mainly due to CYP2A6 genetic variation but not exclusively.

Haplotypes in the 5'-untranslated region of the CYP1A2 gene are inversely associated with lung cancer risk but do not correlate with caffeine metabolism.

In this study, we analyzed the influence of CYP1A2 genetic variation and enzyme activity on lung cancer risk in a high-incidence area. A total of 95 lung cancer patients and 196 controls were genotyped for the -3860G/A, -3113A/G, -2467T/delT, -739T/G, and -163C/A polymorphisms in the 5'-untranslated region of the gene. In addition, a subset of 70 patients and 115 controls were phenotyped by high-performance liquid chromatography determination of the caffeine metabolic ratio (CMR). The -2467T/delT polymorphism and the CYP1A2*1V haplotype (-163C>A, -2467T>delT) were inversely associated with lung cancer risk (odds ratio [OR] = 0.47 [0.2-0.9]; P = 0.02 and OR = 0.13 [0.02-1.0]; P = 0.04; respectively). In addition, the CYP*1A/*1V and *1F (-163C>A)/*1D (-163C>A, -2467T>delT) diplotypes were absent in the patients group, whereas accounting for 7.1% (P = 0.017) and 5.6% (P = 0.037) of controls, respectively. Mean CMR was significantly higher in patients than in controls (10.50 ± 17.31 vs. 6.52 ± 6.26, P = 0.01) but regression analyses did not yield significant ORs for the association with lung cancer risk. Similarly, no significant correlations were found between any genetic variant and enzyme activity. Several CYP1A2 haplotypes and diplotypes containing the -2467delT variant were associated with lower lung cancer risk; however, they did not correlate with significant changes in CYP1A2 metabolic activity toward caffeine.