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The purpose of this note is to present a simple proof (without using the Gauss egregium theorem) of the following fact: To make a length preserving projection of the Earth is impossible.

Let T=c1T1+c2T2+c3T3- c4(T1T2+T3T1+T2T3), where T1, T2, T3 are three n x n tripotent matrices and c1, c2, c3, c4 are complex numbers with c1, c2, c3 nonzero. In this article, necessary and sufficient conditions for the nonsingularity of such combinations are established and some formulae for the inverses of them are obtained. Some of these results are given in terms of group invertible matrices., We would like to thank the referee for his/her careful reading. The first author was supported by the Vicerrectorado de Investigacion U.P.V. PAID 06-2010-2285.

In this paper, we present some learning objects for the study of Kepler’s laws that graphically show the orbits and the movements of various planets. One of them shows the orbit of a planet from the point of view of a fixed planet, showing that the orbit is quite involved. No differentials equations are required, but only elementary vector calculus. The learning objects have been implemented in Matlab. © 2010 Wiley Periodicals, Inc. Comput Appl Eng Educ 21: 1–7, 2013; View this article online at wileyonlinelibrary.com/journal/cae; DOI 10.1002/cae.20446

We find expressions for many types of generalized inverses of an arbitrary square complex matrix by using two representations given in [Benítez J. A new decomposition for square matrices. Electron. J. Linear Algebra. 2010;20:207 225] and in [Hartwig RE, Spindelböck K.Matrices for which A∗ and A commute. Linear Multilinear Algebra. 1984;14:241 256]., The authors wish to thank Prof. Oskar Maria Baksalary for the comments that improved the manuscript. They are also grateful to three anonymous referees for remarking that some proofs can be simplified. The first author is supported by work funded by Vicerrectorado de Investigacion U.P.V. PAID 06-2010-2285. The second author is supported by the NSFC Grant (11061005, 61165015) and the Ministry of Education Science and Technology Key Project under Grant 210164 and Grants (HCIC201103) of Guangxi Key Laborarory of Hybrid Computational and IC Design Analysis Open Fund and Key issues for Department of Education of Guangxi (201202ZD031).

Genetic and environmental factors are determinants of the interindividual and interethnic variability in drug metabolism. The metabolism of several important drugs (e.g. haloperidol) cosegregates with that of debrisoquine. Thus, interethnic differences in debrisoquine hydroxylation polymorphism (CYP2D6) might be partly responsible for the variation in haloperidol disposition between races. The influence of tobacco, ethanol, caffeine, gender, and oral contraceptive use on the debrisoquine metabolic ratio (MR) has been analyzed in 633 Spanish healthy volunteers. MR was also determined in panels of healthy volunteers. 18 smokers were studied during a tobacco abstinence period, and 31 women three times during the same menstrual cycle. Among EMs, debrisoquine MR was significantly (P < 0.05) lower during smoking cessation (mean antilog +/- SD, 0.48 +/- 0.29) compared to a smoking period (0.61 +/- 0.23). During the lutheal phase of the menstrual cycle, debrisoquine MR was also significantly (P < 0.01) lower (0.33 +/- 0.41) compared to the ovulatory-phase (0.41 +/- 0.34) and the phase before ovulation (0.44 +/- 0.36). Among EMs, it is suggested that debrisoquine MR may be modified by tobacco smoking and sexual hormones. The clinical relevance of these findings remains unclear.

The goal of this study was to assess in human liver microsomes the inhibitory capacity of commonly used antipsychotics on the most prominent CYP450 drug metabolizing enzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A). Chlorpromazine was the only antipsychotic that inhibited CYP1A2 activity (IC50=9.5 μM), whilst levomepromazine, chlorpromazine, and thioridazine significantly decreased CYP2D6-mediated formation of 1′-hydroxybufuralol (IC50 range, 3.5–25.5 μM). Olanzapine inhibited CYP3A-catalyzed production of 1′, and 4′-hydroxymidazolam (IC50=14.65 and 42.20 μM, resp.). In contrast, risperidone (IC50=20.7 μM) and levomepromazine (IC50=30 μM) showed selectivity towards the inhibition of midazolam 1′-hydroxylation reaction, and haloperidol did so towards 4′-hydroxylation (IC50 of 2.76 μM). Thioridazine displayed a Ki of 1.75 μM and an inhibitory potency of 1.57 on CYP2D6, suggesting a potential to induce in vivo interactions. However, with this exception, and given the observed Ki values, the potential of the assayed antipsychotics to produce clinically significant inhibitions of CYP450 isoforms in vivo seems limited.

As a contribution to the identification of the relevant species for biological activity and the understanding of structure–activity relationships of [VIVO(L-2H)(NN)] antitrypanosomal complexes (NN is a bidentate polypyridyl DNA intercalator; L is a tridentate salicylaldehyde semicarbazone derivative), new [VVO2(L-2H)] complexes and [VIVO(L-2H)(NN)] complexes including bipy or dppz (dipyrido[3,2-a: 2′,3′-c]phenazine) co-ligands are prepared and characterized in the solid state and in solution. Their activity is evaluated on Trypanosoma cruzi. The lipophilicity, as structural descriptor related to bioactivity, of the whole [VIVO(L-2H)(NN)] series is determined. Furthermore, the antiproliferative effect of those new compounds showing activity against T. cruzi is evaluated on the genetically related parasite T. brucei with the aim to develop broad spectrum agents. The new [VIVO(L-2H)(dppz)] complexes are about ten to fifteen times more toxic to T. cruzi than the bipy analogues and show quite good in vitro activity on T. brucei brucei. They are shown to interact with DNA, suggesting that this biomolecule may be the parasite target. The stability of the VIVO-complexes in solution is accessed by several techniques. Globally the data suggest that the relevant species for biological activity are the [VIVO(L-2H)(NN)] compounds, their order of activity being dependent on the NN nature, but not much on the substitution on the salicylaldehyde semicarbazone moiety. A parabolic relationship between biological response and lipophilicity (determined as RM = log [(1 / Rf) − 1] by a TLC method) is obtained. From this correlation an optimum RM value, close to 1.44, was found, which may be used as design guide for future development of antitrypanosomal compounds. Fil: Fernández, Mariana. Universidad de la República; Uruguay Fil: Becco, Lorena. Universidad de la República; Uruguay Fil: Correia, Isabel. Universidade Técnica de Lisboa; Portugal Fil: Benítez, Julio. Universidad de la República; Uruguay Fil: Piro, Oscar Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina Fil: Echeverría, Gustavo Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; Argentina Fil: Medeiros, Andrea. Universidad de la República; Uruguay. Instituto Pasteur de Montevideo; Uruguay Fil: Comini, Marcelo. Instituto Pasteur de Montevideo; Uruguay Fil: Lavaggi, María Laura. Universidad de la República; Uruguay Fil: González, Mercedes. Universidad de la República; Uruguay Fil: Cerecetto, Hugo. Universidad de la República; Uruguay Fil: Moreno, Virtudes. Universidad de Barcelona; España Fil: Costa Pessoa, Joao. Universidade Técnica de Lisboa; Portugal Fil: Garat, Beatriz. Universidad de la República; Uruguay Fil: Gambino, Dinorah. Universidad de la República; Uruguay

Polymorphic hydroxylation of debrisoquine (DBQ) is a Mendelian genetic trait related to the risk of suffering some spontaneous disorders. To elucidate whether such a relation exists between this polymorphism and chronic inflammatory bowel disease (CIBD), 67 (39 males) patients with ulcerative colitis (UC), 52 (35 males) patients with Crohn's disease (CD) and 837 healthy controls (391 males) received 10 mg debrisoquine. DBQ and its metabolite, 4-OH-DBQ, were measured in urine to calculate metabolic ratio. Subjects with MR < 12.6 (log 10 MR < 1.1) were extensive metabolizers (EM) of DBQ, whereas those with MR < 12.6 were poor metabolizers (PM). Four UC (5.97%), 1 CD (1.92%) patients and 42 controls (5.03%) were PM of DBQ (nonsignificant difference). When analysing the EM subjects separately, log10 MR were lower in controls (mean = -0.295, SD 0.427, P = 0.0015)) and in Crohn's disease patients (man = -0.281, SD 0.495, P = 0.03) than in ulcerative colitis patients (mean = -0.085, SD = 0.495). There is no relationship between oxidative phenotype of DBQ and the risk for CIBD. Nevertheless, the EM phenotype includes both homo- and heterozygote genotypes for functioning alleles exerting a gene-dose effect that gives a higher oxidative capability to homozygote EMs, reflected in a lower MR value. Genotyping studies are needed to disclose whether heterozygote EMs are over-represented among UC patients and to identify any nonfunctioning allele possibly linked to the risk of developing this disease.

The association of the arylamine N-acetyltransferase polymorphism and breast cancer has been investigated by analysis of genomic DNA from 160 breast cancer patients and 132 healthy women. Five mutations of the NAT2 gene were studied by using allele-specific PCR amplification and restriction mapping with the endonucleases FokI and Ddel. Eight allelic variants of the NAT2 gene were identified in both, patients with breast cancer and control groups, with relative frequencies. Wild-type 0.194 and 0.219, 341C+481T+803G 0.433 and 0.345, 341C+481T 0.048 and 0.076, 282T+590A 0.205 and 0.222, 282T 0.059 and 0.044, 590A 0.011 and 0.024, 803G 0.016 and 0.052, 857A 0.035 and 0.019, respectively. The prevalences for the poor acetylator genotypes were 53 and 51% for the patients with breast cancer and the control group, respectively. Seven patients with the rare lobular breast cancer showed reduced frequency for NAT2 mutations (p < 0.05) and all of them had the extensive acetylator genotype (p < 0.01). This preliminary observation suggests that extensive acetylation may be related to lobular breast cancer. No genetic support for association of the NAT2 polymorphism and other histologic types of breast cancer was found. Any differences in the acetylator rate between breast cancer patients and healthy subjects may be secondary to breast cancer itself, but not involved in the pathogenesis of the disease.

Let A be a square complex matrix. Let P be one of the following properties: (a) A is an EP matrix, (b) the column space of A is complementary to the column space of A, and (c) the orthogonal complement of the column space of A is the column space of A. We study the canonical angles between the column space of A and the column space of A when A satisfies property P. Also, we research the following problem: Let { Am}m= 1¿ be a sequence of matrices satisfying property P that converges to some matrix A. When does A satisfy property P? © 2012 Elsevier Inc. All rights reserved., Supported by Grant No. 144003 of the Ministry of Science, Technology and Development, Republic of Serbia.

[EN] Let {Am} ¿ m=1 be a sequence of complex group invertible matrices that converges to A. We characterize when A is group invertible and {A # m} ¿ m=1 converges to A # in terms of the canonical angles between Am and A ¿ m , where X # denotes the group inverse of the matrix X . We compare this characterization with some known characterizations of the continuity of the Drazin inverse., Supported by Spanish Project MTM2010-18539. Supported by grants (HCIC201103) of Guangxi Key Laboratory of Hybrid Computational and IC Design Analysis Open Fund.

AHP (analytic hierarchy process) is used to construct coherent aggregate results from preference data provided by decision makers. Pairwise comparison, used by AHP, shares a common weakness with other input formats used to represent user preferences, namely, that the input mode is static. In other words, users must provide all the preference data at the same time, and the criteria must be completely defined from the start. To overcome this weakness, we propose a framework that allows users to provide partial and/or incomplete preference data at multiple times. Since this is a complicated issue, we specifically focus on a particular aspect as a first attempt within this framework. For that reason, we re-examine a mechanism to achieve consistency in AHP, i.e. a linearization process, which provides consistency when adding a new element to the decision process or when withdrawing an obsolete criterion under the dynamic input mode assumption. An algorithm is developed to determine the new priority vector from the users' new input. Finally, we apply the new process to a problem of interest in the water field, specifically, the adoption of a suitable leak control policy in urban water supply. © 2012 Elsevier B.V. All rights reserved., This work has been performed under the support of the project IDAWAS, DPI2009-11591 of the Direccion General de Investigacion del Ministerio de Ciencia e Innovacion (Spain), with the supplementary support of ACOMP/2011/188 of the Conselleria d'Educacio of the Generalitat Valenciana, and the support given to the first author by Spanish project MTM2010-18539. The third author is also indebted to the Universitat Politecnica de Valencia for the sabbatical leave granted during the first semester of 2011. The use of English in this paper was revised by John Rawlins.

We studied the possible interaction between rifampin and doxycycline in 20 patients with brucellosis treated randomly with either doxycycline and streptomycin or doxycycline and rifampin. The doxycycline levels in the plasma of patients in the group treated with rifampin were significantly lower than those in the plasma of patients treated with doxycycline and streptomycin. Furthermore, clearance in patients treated with rifampin was significantly higher than that in patients treated with doxycycline and streptomycin, and consequently, the elimination half-life and the area under the concentration-time curve were significantly lower. There was no therapeutic failure or relapse in the group treated with doxycycline and streptomycin, whereas 2 of 10 patients in the group treated with doxycycline and rifampin had a therapeutic failure or relapse. The plasma doxycycline levels had an inverse correlation with plasma rifampin levels. In the group treated with rifampin, those who were rapid acetylators had lower levels of doxycycline. In conclusion, combined treatment with rifampin reduces the levels of doxycycline in plasma. These data suggest that therapeutic failures or relapses may result from this interaction.

The arylamine N-acetyltransferase (NAT-2) polymorphism causes impaired drug metabolism in about half of the white population. By the combined use of polymerase chain reaction (PCR) and restriction mapping with the endonucleases Fok I and Dde I, we have studied the genetic basis underlying NAT-2 polymorphism in genomic deoxyribonucleic acid from 245 healthy Spaniards. The study of three mutations at the NAT-2 gene locus by PCR analysis (namely, 481T, 590A, and 857A) revealed that all these mutations were present in Spaniards at similar frequencies as described in other white populations, strongly contrasting with genetic differences in the CYP2D6 polymorphism between Spaniards and other white subjects. The frequencies for NAT-2 mutations were different in Spaniards compared with Hispanics. About 12% of the subjects studied were incorrectly genotyped by the PCR test. Further studies involving restriction mapping of PCR products revealed the occurrence of at least five NAT-2 mutations that, alone or combined, were present in eight allelic variants of the NAT-2 gene. The allele frequencies were as follows: wild type, 25.3%; 341C + 481T + 803G, 32.9%; 341C + 481T, 6.3%; 282T + 590A, 24.9%; 282T, 3.5%; 590A, 1.6%; 803G, 4.1%; and 857A, 1.4%. The prevalence of the poor acetylator genotype among Spaniards is 53%. Clinical Pharmacology and Therapeutics (1994) 56, 202–209; doi:10.1038/clpt.1994.124

We studied the oxidative and N-acetylator caffeine metabolic profile in 107 healthy Spanish volunteers. Smokers had significantly higher N-1- and N-3-demethylations activities than nonsmokers (p = 0.03 and p = 0.02, respectively), and the three caffeine demethylations indexes were strongly correlated with each other (r > 0.7; p < 0.001). Our in vivo studies suggest that CYP1A2 is involved, at least in part, in the primary N-demethylations of caffeine. A non-normal and possibly bimodal distribution was detected in the xanthine oxidase activity (p = 0.04), with about 4% of subjects deficient of this metabolic activity. The population exhibited a trimodal distribution of acetylator phenotype determined by use of the 5-acetylamino-6-amino-3-methyluracil/1-methylxanthine ratio (normality test; p = 0.004). Seventy subjects (65.4%) were phenotyped as slow acetylators. The mutated gene frequency was 0.81, which is similar to other white populations. Clinical Pharmacology and Therapeutics (1994) 55, 293–304; doi:10.1038/clpt.1994.30

The association between the polymorphism of the cytochrome P450 debrisoquin hydroxylase (CYP2D6) and lung cancer is controversial. Previous reports suggested a link between CYP2D6 phenotype and lung cancer, with poor metabolizers having reduced susceptibility. Nevertheless, negative findings have also been published. By using allele-specific amplification, we have studied the frequency of four CYP2D6 (wild type and mutant) alleles in 89 patients with histologically proved bronchogenic carcinoma and in 98 healthy volunteers. Our findings confirm that poor metabolizers are underpresented among patients with lung cancer because of a different genetic background. Our findings also reveal that the rare CYP2D6(C) mutant allele is sixfold more frequent among patients with lung cancer (p < 0.0005). This suggests that the CYP2D6(C) allele could be considered as an additional risk factor because carriers could have higher susceptibility to the development of lung cancer. Clinical Pharmacology and Therapeutics (1994) 55, 10–14; doi:10.1038/clpt.1994.3

[EN] In this paper, some formulas are found for the group inverse of aP | bQ, where P and Q are two nonzero group invertible complex matrices satisfying certain conditions and a, b nonzero complex numbers., College of Mathematics and Computer Science, Guangxi University for Nationalities, Nanning 530006, P.R. China (xiaojiliu72@yahoo.com.cn). Supported by the Guangxi Science Foundation (No. 0832084) and the Guangxi University Innovation Plan (No. gxun-chx2009092). ‡College of Mathematics and Computer Science, Guangxi University for Nationalities, Nanning 530006, P.R. China (wulingling-1982@163.com). §Departamento de Matem´atica Aplicada, Instituto de Matem´atica Multidisciplinar, Universidad Polit´ecnica de Valencia, Valencia, Spain (jbenitez@mat.upv.es). Supported by Spanish Project MTM2010-18539

We derive a very short expression for the group inverse of a(1) + ... + a(n) when a(1), ... , a(n) are elements in an algebra having group inverse and satisfying a(i)a(j) = 0 for i < j. We apply this formula in order to find the group inverse of 2 x 2 block operators under some conditions. (C) 2011 Taylor & Francis, X. Liu and T. Zhu are supported by Guangxi Science Foundation (0640016, 0832084).

Let T(1) and T(2) be two n x n tripotent matrices and c(1), c(2) two nonzero complex numbers. We mainly study the nonsingularity of combinations T = c(1)T(1) + c(2)T(2) - c(3)T(1)T(2) of two tripotent matrices T(1) and T(2), and give some formulae for the inverse of c(1)T(1) + c(2)T(2) - c(3)T(1)T(2) under some conditions. Some of these results are given in terms of group invertible matrices. (C) 2011 Taylor & Francis, X. Liu was supported by the National Natural Science Foundation of China (11061005) and the Ministry of Education Science and Technology Key Project (210164). J. Benitez was supported by Spanish Project MTM2010-18539. The authors wish to thank the referee for his/her careful review and comments which improved the quality of this article.

Matrices used in the analytic hierarchy process (AHP) compile expert knowledge as pair-wise comparisons among various criteria and alternatives in decision-making problems. Many items are usually considered in the same comparison process and so judgment is not completely consistent - and sometimes the level of consistency may be unacceptable. Different methods have been used in the literature to achieve consistency for an inconsistent matrix. In this paper we use a linearization technique that provides the closest consistent matrix to a given inconsistent matrix using orthogonal projection in a linear space. As a result, consistency can be achieved in a closed form. This is simpler and cheaper than for methods relying on optimisation, which are iterative by nature. We apply the process to a real-world decision-making problem in an important industrial context, namely, management of water supply systems regarding leakage policies - an aspect of water management to which great sums of money are devoted every year worldwide. (C) 2011 Elsevier Inc. All rights reserved., This work has been performed under the support of the project IDAWAS, DPI2009-11591 of the Direccion General de Investigacion del Ministerio de Ciencia e Innovacion (Spain), with the supplementary support of ACOMP/2010/146 of the Conselleria d'Educacio of the Generalitat Valenciana, and the support given to the first author by the Spanish project MTM2010-18539. The use of English in this paper was revised by John Rawlins; and the revision was funded by the Universitat Politecnica de Valencia, Spain.

A projective invariant generalization of the de Casteljau algorithm is described by using the cross ratio and an auxiliary line. We describe the implicit form of the section conics obtained by the algorithm proposed in this paper. Finally, we show how to construct specific conic sections using this approach. © 2010 Elsevier Ltd. All rights reserved.

Let X(dagger) denotes the Moore-Penrose pseudoinverse of a matrix X. We study a number of situations when (aA + bB)(dagger) = aA + bB provided a, b is an element of C\{0} and A, B are n x n complex matrices such that A(dagger) = A and B(dagger) = B. (C) 2011 Taylor & Francis

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 p 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.

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.

The debrisoquine oxidation phenotype was assessed in 137 healthy Italian volunteers and in 41 drug-free schizophrenic patients. A bimodal distribution of the urinary debrisoquine/4-hydroxydebrisoquine metabolic ratio was observed in healthy volunteers. Ten subjects were identified as poor metabolizers, yielding a frequency of 7.3% which is similar to that reported in other European countries. The prevalence of the poor metabolizer phenotype was 9.8% among schizophrenic patients. This indicates that there is no association between polymorphic drug oxidation and schizophrenic disorder. Treatment with chlorpromazine (100 or 150 mg daily) significantly increased the debrisoquine metabolic ratio in nine patients (P less than 0.01). These results confirm that neuroleptics of the phenothiazine class inhibit the oxidative metabolism of debrisoquine.

Fundamento y objetivo La ecuacion Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) ha sido propuesta para sustituir a la actualmente recomendada Modification of Diet in Renal Disease (MDRD) para el calculo de la tasa de filtrado glomerular (TFG), si bien no ha sido aun evaluada en la poblacion general. Pacientes y Metodo Estudio transversal de una muestra aleatoria de 858 individuos de la poblacion general con edades entre 50�75 anos sin enfermedad renal conocida. Comparacion de la prevalencia de una TFG

Three neurotransmitters, namely adrenaline, serotonin and tryptamine inhibit the in vitro activity of several cytochrome P450 (CYP) isozymes (CYP1A2, CYP2C9, CYP2D6 and CYP3A). In order to test whether this effect is related to inhibition of the CYP-coupled NADPH reductase activity, we assayed the potential inhibitory effect of these neurotransmitters and their main metabolites on the NADPH reductase activity. Of the five compounds analyzed: tryptamine, tryptophol, serotonin, 5-hydroxytryptamine and adrenaline, only adrenaline significantly decreased NADPH reductase activity at the fixed concentration of 500 microM. However, the effect became negligible when adrenaline concentration was decreased to 100 microM: whereas a high inhibitory effect was observed in CYP2D6, CYP2C9 and CYP3A4 enzyme activities, the NADPH reductase activity remains unchanged. This study indicates that the effect of these endogenous neurotransmitters on CYP enzymes is not related to changes in the reductase activity. In the light of these findings further studies on the inhibitory effect of these neurotransmitters on CYP enzymes can be designed ruling out the modulation of the coupled NADPH reductase activity as a confounding factor.

Oxidative phenotype and metabolic ratio (MR) of debrisoquine (DBQ) have been determined in 87 patients with Parkinson's disease and in 556 healthy control subjects. Three patients (3.45%) and 34 control subjects (6.12%), having an MR greater than 12.6, were classified as poor metabolisers (PM) of DBQ (ns). The distribution of MR values in the 84 Parkinsonian patients classified as extensive metabolisers (EM) showed a less efficient oxidative rate when compared with controls of the same phenotype (p less than 0.001). This difference may be due to enzymatic inhibition caused by drug treatment in 40 of these patients. As in patients not taking any drug known to inhibit the oxidation of DBQ, distribution of MR values was not different from that in controls. A negative correlation (r = -0.36, p less than 0.02) was found between MR of DBQ and age at onset of disease in patients free of drugs known to interact with DBQ metabolism. A higher rate of DBQ oxidation could be a genetic factor that delays the clinical onset of Parkinson's disease in predisposed people.

Background Extracorporeal photochemotherapy (ECP), also known as photopheresis, is a generally well-tolerated therapeutic, immunomodulatory approach successfully used in cutaneous T-cell lymphoma and other diseases produced by T-lymphocytes such as graft vs host disease. Observations On 2 separate occasions, a 54-year-old white man with Sezary syndrome developed cutaneous phototoxic reactions and chorioretinitis after being treated with ECP. A pharmacokinetic study showed therapeutic blood levels of 8-methoxypsoralen as long as 18 weeks after therapy had been terminated. However, the analysis of mutations in genes involved in the drug's disposition could not explain these abnormal levels. Conclusions To our knowledge, there has been no previous description of ECP-related retinal toxic effects. This adverse effect was probably linked to impaired drug elimination. Further studies would be needed to determine the underlying mechanism.

The goal of this study was to detect genotypic differences between Spaniards and other related populations regarding CYP3A4*1B, CYP3A5*3, and ABCB1 (MDR1) C3435T polymorphisms. DNA from 177 Spanish patients were analyzed for the presence of these mutations using PCR-restriction fragment length polymorphism or direct sequencing. The observed frequencies for CYP3A4*1B, CYP3A5*3, and C3435T alleles were within normal values in Caucasians (0.04, 0.91, and 0.5, respectively). However, 2.8% of the patients were homozygous for the wild-type CYP3A5*1 allele, an extremely uncommon genotype in other Caucasians. In addition, analysis of CYP3A4-3A5 haplotypes revealed the existence of 2 unusual subgroups: patients who were homozygous wild-type for both polymorphisms, and patients showing a CYP3A4*1A/*1B-CYP3A5*3/*3 genotype combination. The incidence of CYP3A5*1/*1 carriers and the occurrence of subjects combining the 2 above-mentioned unusual genotype combinations were more frequent in Spanish-Caucasians compared with American- or European-Caucasians. ABCB1 C3435T genotype frequencies were equally distributed between both single and combined CYP3A4 and 3A5 genotypes. These findings suggest that dose requirements for drugs metabolized by CYP3A and certain allele-disease association studies in white populations could show discrepancies in Spaniards.

To perform a historical introduction and a review of the mathematical model, emphasizing that our mathematical model may be the solution to the viscoelastic model. It is evident that the same experiment has been repeated over half a century, with similar results in all cases. We also show one of the projects we are working on: the electro-vesicogram for the evaluation of the filling phase, and Doppler uroflowmetry for the study of the voiding phase.We have chosen and studied in depth the results Dr. Virseda presents in his thesis of one of the experiments performed in relation to the viscoelastic model. After applying analytical methods we reach a differential equation we suppose defines detrusor behaviour, as it has been explained by the viscoelastic model. The solution of this equation by means of the Laplace's transform enables to obtain the values of the incognitas set by urodynamics. Besides, we analyzed the behaviour of solutions' stability using a matricial method following the Lyapunov theory. The former may solve the incognitas for the voiding phase. We used urethral Doppler with simultaneous uroflowmetry to obtain the data equations demanded; this is what we named "Doppler uroflowmetry". The filling phase was studied by superficial electromiography. We named it "electrovesicogram". We attach images for both Doppler wave and electrovesicogram. They both are the projects we are working on.Currently we can only explain the methodology we are following. Indeed, this article is the first of a series in which we aim to explain the methodology we are following in detail: Doppler wave capture; mounting process photogram by photogram, and vectorization and cleaning of the wave, either Doppler or flow waves; treatment in autocad to obtain the vector; and management of the vector with the matalab software, which gives us the results we are looking for.It is intuitive to deduct the usefulness of these methods as not invasive techniques in the urodynamic diagnosis. We have our illusions in these projects which open a window to the future.

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.

BACKGROUND: Drug—drug interactions are one of the main causes of adverse effects. These events have been studied most often in hospital settings; however, investigations on prescribing based on community practice have shown a high prevalence rate of potential drug interactions. OBJECTIVE: To develop a computerized system able to trace drug interactions quickly through the identification of clinicians issuing potentially unsafe prescriptions. METHODS: We retrospectively evaluated hazardous concomitant prescriptions of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) and azole antifungals, which were invoiced through 9 months of 2001 within an outpatient setting. The study was conducted in Badajoz, a southern Spanish province, and was divided in three 3–month periods according to the release of 2 warning notes on this drug combination by the Spanish Drug Agency. Prescriptions written during this period were optically scanned each month, and the resulting information, including data from patients, physicians, and drugs involved, was converted to a database and searched for potentially unsafe coprescriptions. RESULTS: A total of 8 342 711 prescriptions were invoiced in the period of study, 174 of which were for a statin—azole combination. The number of these prescriptions remained fairly constant during periods I and II (63 and 71, respectively), decreasing to 40 in period III. Some clinicians (12.6%) repeatedly prescribed a hazardous drug combination at some point in this study, whereas 18 of 171 patients who received the hazardous coprescription at any time did so repeatedly within a given period. The impact of drug alerts was remarkably deeper in urban rather than rural care centers. CONCLUSIONS: The computerized drug prescription handling system described here is able to readily identify physicians and patients who issue/consume hazardous drug combinations, thus allowing both the possibility of individually informing the healthcare professionals involved and early detection of adverse effects.

In this article we develop the analysis of stability of the solution(s) of the differential equation describing detrusor behaviour as a forced and overcushioned tensor. We followed the theories of Lyapunov about stability. Therefore, we used a matricial method which is more didactical and also analytically more graphic. Solutions are placed in the Trace-Determinant (T-D) plane. This work represents a previous study to the one about detrusor as a dispersing system. And about which we would have to perform an analysis, first from the point of view of the Hamiltonian systems, then from the point of view of chaos.We worked on the equation which has been widely described in previous articles in the series of publications titled "the bases of urodynamics". In previous articles, we gave results after applying other methods different from the ones that are usually employed to solve differential equations. We used the matricial method for the analysis of stability of solutions because of its greater didactical clarity.We conclude that we are in an unstable balance until the moment right before to start voiding. Once voiding is initiated, we are in front of a system with a drain, which at the same time is a fountain. Then we pass from a Hamiltonian dispersing system to a chaotic one. But this is another question...

To make an analysis of the usefulness of urodynamic tests and what can be obtained from them.We also perform and analytical deduction of those parameters that define detrusor behavior, such as the constant defining bladder compliance, the bladder elastic constant, in its tensile properties, and we found the expression of resistances and calculate the abdominal pressure formula; therefore we don't need to introduce a rectal catheter to know the value of those parameters that define bladder dynamics.Although they are provisional, they allow foreseeing a promising future for this application of a well-known device.Currently, we can only define the bladder behaviour, its resistances, the detrusor drive and compliance with the only discomfort of a perineal Doppler ultrasound. Time will open new possibilities.

We present the calculation of two parameters of practical interest for the urologists, which help to understand bladder phenomena. They are the real (total) power developed during micturition, and the spectral power of the flow curve, considered this as a finite time discrete signal.We use Doppler ultrasound to calculate the propelling power of the urine towards the exterior. The calculation of the spectral power is included among the auxiliary calculus methods employed for the calculation of the contractile power in those cases in which the flow curve has several humps; we could only calculate the real power in one of them because the Doppler only measured the speed in one curl.We report one case with several curls in the flow curve, in which we could only test speed in one of the curls. The calculation of the spectral power allows us to compare curls and to calculate the total power just by addition.These two power measures are the expression of the same phenomenon, but they are different, showing one the micturition process from the flow curve and the other one from bladder contraction. We believe it is interesting to know them as a useful work tool. In the same way, the usefulness of Doppler ultrasound to obtain the values of urine speed through the urethra is demonstrated, a necessary data for the calculation of the bladder contractile power.

Based on the recent cerivastatin experience, we retrospectively evaluated the effect of notifying a drug alert utilizing a computerized drug-handling system. The evaluation was carried out during three periods: period I corresponded to all prescriptions issued during April, 2001 (“baseline period”), before the Spanish Drug Agency issued alerts on the concomitant therapy with cerivastatin and gemfibrozil; period II (June) corresponded to a time in which a first informative note had been released; and period III (July) after the second warning alert was issued. Data collected included the reading of 2,693,656 drug prescriptions, 1,937,083 (71.9%) of which contained patient information. Forty-four patients received combined therapy with cerivastatin and gemfibrozil over the three periods, yielding 55 exposures: 27 during the baseline period, and 28 between periods II and III, when the alert bulletins had already been released. Moreover, 41.6% of doctors included in the follow-up repeated the hazardous prescription during those two periods. The effect of the informative notes about the risk of prescribing cerivastatin and gemfibrozil concomitantly on doctors’ prescribing habits was limited. The system for screening information from drug prescriptions presented herein allows the early detection of drug interactions by identifying the doctors who issue hazardous prescriptions as well as patients at the highest risk of adverse drug reactions, thus allowing a personal feedback with both of them.

To calculate the bladder softening factor, elastic constant and contractile potency.For the analysis we considered bladder behavior like that of a spring. See articles 1 and 2 published in this issue. Using flowmetry, Doppler ultrasound and abdominal pressure (Transrectal pressure register catheter) an analytical solution that permits calculation of factors defining bladder behavior was looked for. Doppler ultrasound allows us to know urine velocity through the prostatic urethra and, therefore, to calculate bladder contractile potency.Equations are solved reaching an analytical solution that allows calculating those factors that define bladder behavior: Bladder contractile potency, detrusor elastic constant, considering it behaves like a spring, and calculation of muscle resistance to movement. All thanks to Doppler ultrasound that allows to know urine speed.The bladder voiding phase is defined with the aforementioned factors; storage phase behavior can be indirectly inferred. Only uroflowmetry curves, Doppler ultrasound and abdominal pressure value are used. We comply with the so called non invasive urodynamics although for us it is just another phase in the biomechanical study of the detrusor muscle. Main conclusion is the addition of Doppler ultrasound to the urodynamist armamentarium as an essential instrument for the comprehension of bladder dynamics and calculation of bladder behavior defining factors. It is not a change in the focus but in the methods, gaining knowledge and diminishing invasion.

Background Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor that is approved for the treatment of renal cell carcinoma (RCC). However, several patients either do not respond to treatment or they experience significant toxicity. Our study aims to find genetic markers of toxicity and efficacy using a commercially available DNA microarray genotyping system. Methods 30 patients with newly diagnosed metastatic RCC, from January 2010 to May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain). Pts received SU in repeated 6-wk cycles of 50 mg/day (4 wks on followed by 2 wks off treatment). A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic pathways of drugs were analyzed using Drug inCode ® pharmacogenetic service. SNPs in candidate genes, together with clinical characteristics were tested univariately for association with the number of days of SU treatment until the first reduction of dose, PFS and OS. Results Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1. a low metabolizing genotype, had an increased risk of dose reductions due to toxicity compare to allele *1F (Median time to dose reduction: 2.33 months Vs NR; p Conclusions This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs may be associated with toxicity in patients with RCC treated with SU. As CYP1A2 and CYP2C19 activity could be affected by a variety of non-genetic factors, if confirmed, these results could lead to the necessity of controlling toxic and dietary habits of pts treated with SU. SNPs associated with toxicity and survival in this preliminary analysis are being validated in an independent cohort of RCC treated with SU (Garcia-Donas J, et al. Lancet Oncol 2011) and will be presented. Disclosure All authors have declared no conflicts of interest.

In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S-mephenytoin hydroxylation polymorphism. The same 14 healthy subjects studied in that investigation were given 150 mg of caffeine. The reciprocal of plasma clozapine AUC (0,24), was correlated with an index of the N3-demethylation of caffeine (rs = 0.84; P = 0.0024), used as a measure of cytochrome P4501A2 (CYP1A2) activity. N1- and N7-demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (rs = 0.89 and 0.85; P = 0.0013 and 0.0023; respectively). No significant relationships with xanthine oxidase and N-acetyl transferase activity, also assessed by a caffeine test, were found. This study suggests that clozapine is metabolised by CYP1A2 to a major extent.

Acetylator phenotype has been determined with sulphamethazine (sulphadimidine) in 69 Spanish patients with rheumatoid arthritis (48 females), all of whom were on second line therapy, and in 96 age-matched normal controls (54 females). Thirty-two patients (46.4%) and 56 controls (58.3%) were classified as slow acetylators. On analysing separately the females in both groups, 37.5% of patients and 63% of controls were found to be slow acetylators. No difference was found in the males (patients 66.3% and controls 52.4% slow acetylators). Rapid acetylator phenotype may be a risk factor for the development of severe rheumatoid arthritis in women.

Dietary heterocyclic aromatic amines (HAAs) are members of a family of chemicals that comprise highly mutagenic compounds related to colon cancer. The polymorphic N-acetyltransferase 2 enzyme (NAT2, E.C. 2.3.1.5) plays a key role in the transformation of HAAs to ultimate carcinogens. NAT2 enzyme activity is expressed in a genotype-dependent manner in colon epithelium. Therefore local activation of HAAs in colon, and hence increased risk to develop colon cancer, is likely to be related to high NAT2 enzyme activity. This study is aimed at analysing the association between genotypes leading to high NAT2 activity and colorectal cancer risk.Genomic DNA from 120 colorectal cancer patients and 258 healthy individuals were analysed for enzyme-inactivating mutations at the coding region of the NAT2 gene by means of a mutation-specific polymerase chain reaction.Among patients with sigmoid colon cancer, a significant excess of individuals with genotypes leading to high NAT2 activity was observed as compared both to controls and to the rest of patients with colorectal cancer (P0.05).Our findings, which require independent confirmation, suggest that the NAT2 genotype constitutes a secondary risk factor to develop sigmoid colon cancer.

Twenty-five healthy volunteers were given 100 mg caffeine orally and several estimates of cytochrome P450 1A2 (CYP1A2) activity were evaluated. The validation was performed by correlation of different parameters in plasma, saliva, and urine to two measures of caffeine clearance, CL on and CL 137X→17X that served as standards of reference. Two subjects were excluded because of noncompliance with a caffeine-free diet. In the remaining 23 subjects, both plasma and saliva total clearances of caffeine were highly correlated with each other (r s = 0.97, p < 0.0001). The ratio 17X/137X restricted to one sampling point taken 4 hours after dose, showed a high correlation (r s ) with CL oral and CL 137X→17X in plasma (0.84/0.83) and saliva (0.82 / 0.77) (p < 0.0001 for all the correlation values) where 17X is 1,7--dimethylxanthine (paraxanthine) and 137X is 1,3,7-trimethylxanthine (caffeine). Additionally, the ratio (AFMU + IU + IX + 17U + 17X)/137X in a 0-24 hours urine sampling showed the highest correlation with CL 137X→17X (r s = 0.85, p < 0.001) where AFMU is 5-acetylamino-6-formylamino-3-methyluracil, 1U is 1-methyluracil, 1X is 1-methylxanthine, and 17U is 1,7-dimethyluric acid. The major estimates of CYP1A2 activity were significantly less in nonsmoking females, and this probably was related to the use of oral contraceptives in this subpopulation. In summary, among caffeine-based approaches for CYPI A2, the authors recommend either plasma or saliva 17X/137X ratio and the urinary (AFMU + IU + IX + 17U + 17X)/137X ratio during a sampling interval of at least 8 hours, starting at time zero since caffeine intake. These indices are simple, reliable, and relatively inexpensive estimates of CYP1A2 activity to be used in the study of human populations.

The aim of this study was to find whether endogenous substances could modulate CYP3A activity. There is evidence that CYP3A, a major phase-I xenobiotic metabolizing enzyme, is present in human brain but, at the present time, endogenous substrates for such an enzyme remain to be identified. A possible linkage between the CYP2D6 enzyme and serotonergic transmission has been recently reported by our group. In the same manner, structurally related enzymes such as CYP3A could also be related to endogenous compounds.CYP3A activity was measured using the enzyme-specific substrate midazolam in human liver microsomes. Several neurotransmitters, precursors, and their metabolites, corresponding to three different metabolic routes, were assayed as putative modulators of CYP3A enzyme activity. These comprised serotonergic, catecolaminergic, and GABAergic transmitters and precursors. The inhibitory capacity of ketoconazole, a competitive inhibitor of CYP3A, was also analyzed for comparison.The kinetic analysis of the midazolam 1-hydroxylase activity measured in microsomes from five human liver samples indicated Km values (mean +/- SD) of 5.8 +/- 4.9 microM, and Vmax values of 1.7 +/- 1.4 nmol min(-1) per mg microsomal protein in all the samples used in the study. Of the 14 substances analyzed, adrenaline, serotonin, and 5-hydroxytriptofol were full inhibitors of CYP3A enzyme activity (Ki values of 42.3, 26.4, and 43 microM, respectively). The remaining substances were weak inhibitors or had no inhibitory effect.Brain CYP3A activity could be modulated by some neurotransmitters and precursors.

OBJECTIVE: To analyse the population pharmacokinetic-pharmacodynamic relationships of racemic ibuprofen administered in suspension or as effervescent granules with the aim of exploring the effect of formulation on the relevant pharmacodynamic parameters. DESIGN: The pharmacokinetic model was developed from a randomised, cross-over bioequivalence study of the 2 formulations in healthy adults. The pharmacodynamic model was developed from a randomised, multicentre, single dose efficacy and safety study of the 2 formulations in febrile children. PATIENTS AND PARTICIPANTS: Pharmacokinetics were studied in 18 healthy volunteers aged 18 to 45 years, and pharmacodynamics were studied in 103 febrile children aged between 4 and 16 years with bodyweight 225kg. METHODS: The pharmacokinetic study consisted of two 1-day study occasions, each separated by a 1-week washout period. On each occasion ibuprofen 400mg was administered orally as suspension or granules. The time course of the antipyretic effect was evaluated in febrile children receiving a single oral dose of 7 mg/kg in suspension or 200 or 400mg as effervescent granules. During the pharmacodynamic analysis, the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used. RESULTS: The disposition of ibuprofen was described by a 2-compartment model. No statistical differences (p > 0.05) were found between the 2 formulations in the distribution and elimination parameters. Absorption of ibuprofen from suspension was adequately described by a first-order process; however, a model with 2 parallel first-order input sites was used for the drug given as effervescent granules, leading to time to reach maximum drug concentration (tmax) values of 0.9 and 1.9 hours for suspension and granules, respectively. The time course of the antipyretic effect was best described using an indirect response model. The estimates (with percentage coefficients of variation in parentheses) of Emax (maximum inhibition of the zero-order synthesis rate of the factor causing fever), EC50 (plasma concentration eliciting half of Emax), n (slope parameter) and k(out) (first order rate constant of degradation) were 0.055 (10), 6.16 (14) mg/L, 2.71 (18) and 1.17 (23) h(-1), respectively, where To is the estimate of the basal temperature, 38.8 (1) degrees C. No significant (p > 0.05) covariate effects (including pharmaceutical formulation) were detected in any of the pharmacodynamic parameters. CONCLUSIONS: Because of the indirect nature of the effect exerted by ibuprofen, the implications of differences found in the plasma drug concentration profiles between suspension and effervescent granules are less apparent in the therapeutic response.

The oxidative polymorphism of debrisoquine (DBQ) has been determined in 89 patients with colo-rectal cancer and in 556 normal control subjects. Four patients and 34 controls, with a metabolic ratio greater than 12.6, were classified as poor metabolisers of DBQ (n.s.). No difference was found in the distribution of the frequencies of the MR of DBQ between patients and controls. It is concluded that polymorphic oxidation of DBQ is not related to the risk of developing colo-rectal cancer in human beings.

The polymorphic human cytochrome P450 2A6 (CYP2A6) metabolises a number of drugs, activates a variety of precarcinogens and constitutes the major nicotine C-oxidase. A relationship between CYP2A6 genotype and smoking habits, as well as incidence of lung cancer, has been proposed. Two defective alleles have hitherto been identified, one of which is very common in Asian populations. Among Caucasians, an additional defective and frequently distributed allele (CYP2A6*3) has been suggested to play a protective role against nicotine addiction and cigarette consumption. Here, we have re-evaluated the genotyping method used for the CYP2A6*3 allele and found that a gene conversion in the 3′ flanking region of 30–40% of CYP2A6*1 alleles results in genotype misclassification. In fact, no true CYP2A6*3 alleles were found among 100 Spaniards and 96 Chinese subjects. In one Spanish poor metaboliser of the CYP2A6 probe drug coumarin, we found two novel defective alleles. One, CYP2A6*5, encoded an unstable enzyme having a G479L substitution and the other was found to carry a novel type of CYP2A6 gene deletion (CYP2A6*4D). The results imply the presence of numerous defective as well as active CYP2A6 alleles as a consequence of CYP2A6/CYP2A7 gene conversion events. We conclude that molecular epidemiological studies concerning CYP2A6 require validated genotyping methods for accurate detection of all known defective CYP2A6 alleles.

Objectives and study design The genetic basis of two polymorphisms of drug- and carcinogen-metabolizing enzymes, NAT2 (arylamine N-acetyltransferase-2) and CYP2E1 (cytochrome P450 2E1), was studied in genomic deoxyribonucleic acid from 137 healthy, unrelated subjects from a mixed Nicaraguan population. Results Six point mutations were identified at the coding region of the NAT2 gene, including the most common alleles NAT2*4 (41.6%), NAT2*5B (31.4%), and NAT2*6A (16.8%). The percentage of carriers of two defective genes was 49.6%. The Nicaraguan population studied was in Hardy-Weinberg's disequilibrium for the NAT2 genotype (p < 0.01) and the allele frequencies were significantly different from those of other populations, being intermediate between those of pure Central American Indians and Spanish persons. The frequency of CYP2E1 allels mutated at the RsaI site (c2 allele; 16.5%) was intermediate between that of Spanish white and Asian subjects. About 5% of the subjects were homozygous for the c2 allele. Conclusions These findings indicate a high impact of genetic admixture of populations of Asian origin (Central American Indians) and white persons (Spaniards) on the genetic polymorphisms studied here and suggest that among mixed Hispanics a high heterogeneity of genotypes and phenotypes can be expected depending on the degree of genetic admixture of every subgroup. Therefore different subgroups of mixed Hispanic subjects can exhibit different results when treated with drugs that are inactivated through polymorphic enzymes. Clinical Pharmacology & Therapeutics (1998) 63, 623–628; doi