Biomedical subjects

Julio Benitez

Publications and source records attributed to Julio Benitez.

7 recordsLinked to original sources

PubMed2006

Adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) G2677T/A gene polymorphism is associated with high risk of lung cancer.

BACKGROUND: P-glycoprotein (P-gp) is a transmembrane transporter that is encoded by the adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) gene, which plays a role in cell defense against environmental attacks, like those generated by xenobiotics. P-gp is expressed in the lung, where it has been suggested to transport these compounds from the interstitium into the lumen. METHODS: Two functional ABCB1 polymorphisms were examined, G2677T/A (in exon 21) and C3435T (in exon 26), in a group of lung cancer patients and in a control group. RESULTS: Whereas 3435T allelic and genotype frequencies were unchanged between both study groups, lung cancer patients showed higher frequency of the 2677T variant allele compared with the control group (0.67 vs. 0.43; P < .001; odds ratio, [OR], 2.6; 95% confidence interval [95% CI], 1.7-4.0). Among the histologic tumor types that were included in the study, squamous cell carcinoma was associated most strongly with the presence of the 2677T allele (OR, 3.92; 95% CI, 2.2-6.9) and especially was associated with the 2677 TT genotype (OR, 6.75; 95% CI, 3.0-15.2). In a haplotype analysis, homozygous wild-type alleles were classified as genotype A, heterozygous alleles were classified as genotype B, and homozygous mutant allele were classified as genotype C both in exon 21 (first letter) and in exon 26 (second letter) loci. The haplotype CB displayed the highest association with lung cancer (OR, 18.09; 95% CI, 2.4-139.2). CONCLUSIONS: The current results taken together suggest that, aside from other known causes of lung cancer, such as tobacco smoke, the existence of polymorphisms in the ABCB1 gene and, specifically, the presence of the G2677T mutation can be crucial in conferring susceptibility to lung cancer. Further studies comprising larger populations are needed to confirm these preliminary findings.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

The effect of CYP2J2, CYP3A4, CYP3A5 and the MDR1 polymorphisms and gender on the urinary excretion of the metabolites of the H-receptor antihistamine ebastine: a pilot study.

AIMS: To determine the effect of gender and the genetic polymorphisms of CYP2J2, CYP3A4, CYP3A5 and MDR1 on the urinary excretion of the H(1) antihistamine ebastine in healthy subjects. METHODS: Eighty-nine Caucasians were studied. The presence of polymorphisms in genes known to be involved in ebastine metabolism and transport (CYP2J2*2,*3,*4,*6,*7, CYP3A4*1B, CYP3A5*3, *6 and MDR1(ABCB1)(C3435T)) was assessed by means of PCR-restriction fragment length polymorphism and sequencing methods. Genotype was correlated with the urinary excretion of the main ebastine metabolites (desalkylebastine and carebastine) under basal conditions and after administration of grapefruit juice. RESULTS: Women excreted statistically greater amounts of desalkylebastine in urine (mean +/- SD (95% confidence intervals, 95% CI), 23.0 +/- 19.5 (18.1, 27.9) micromol) than men (12.4 +/- 11.0 (7.9, 16.9)), (mean difference: 10.6 (2.4, 18.7), P < 0.005). The CYP2J2, CYP3A4 and CYP3A5 analysed polymorphisms did not greatly affect ebastine metabolite excretion. The MDR1(C3435T) polymorphism was found to affect both the urinary excretion of the active metabolite carebastine (32.3 +/- 18.3 (23.1, 41.4), 22.8 +/- 14.7 (18.6, 27.0) and 21.5 +/- 15.3 (14.7, 28.3) for CC, CT and TT carriers, respectively; P < 0.05) and the grapefruit juice-induced inhibition of its transport/formation (mean fold-decrease +/- SD (95% CI), 1.5 +/- 0.8 (1.0, 2.0), 1.1 +/- 0.9 (0.7, 1.4) and 0.9 +/- 0.4 (0.6, 1.2) for CC, CT and TT carriers, respectively; P = 0.01). CONCLUSIONS: Gender and the presence of the MDR1(C3435T) polymorphism both influence the excretion of ebastine metabolites in urine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Differences in CYP3A5*3 genotype distribution and combinations with other polymorphisms between Spaniards and Other Caucasian populations.

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.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2005

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.

Aged↗

PubMed2004

Using a computerized drug prescription screening system to trace drug interactions in an outpatient setting.

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 8342711 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.

Antifungal Agents↗

PubMed2004

Early detection of drug interactions utilizing a computerized drug prescription handling system-focus on cerivastatin-gemfibrozil.

OBJECTIVES: Based on the recent cerivastatin experience, we retrospectively evaluated the effect of notifying a drug alert utilizing a computerized drug-handling system. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Drug Interactions↗

PubMed2004

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.

Animals↗