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The CYP4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at individual patients' level to capture the possible effect of ethnicity, gene-gene interaction or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95%CI 7-10%), with a higher effect in females, in patients taking acenocoumarol and in Whites. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. This article is protected by copyright. All rights reserved.

In Latin America, the cultivation of Arabica coffee (Coffea arabica) plays a critical role in rural livelihoods, biodiversity conservation, and sustainable development. Over the last 20 years, coffee farms and landscapes across the region have undergone rapid and profound biophysical changes in response to low coffee prices, changing climatic conditions, severe plant pathogen outbreaks, and other drivers. Although these biophysical transformations are pervasive and affect millions of rural livelihoods, there is limited information on the types, location, and extent of landscape changes and their socioeconomic and ecological consequences. Here we review the state of knowledge on the ongoing biophysical changes in coffee-growing regions, explore the potential socioeconomic and ecological impacts of these changes, and highlight key research gaps. We identify seven major land-use trends which are affecting the sustainability of coffee-growing regions across Latin America in different ways. These trends include (1) the widespread shift to disease-resistant cultivars, (2) the conventional intensification of coffee management with greater planting densities, greater use of agrochemicals and less shade, (3) the conversion of coffee to other agricultural land uses, (4) the introduction of Robusta coffee (Coffea canephora) into areas not previously cultivated with coffee, (5) the expansion of coffee into forested areas, (6) the urbanization of coffee landscapes, and (7) the increase in the area of coffee produced under voluntary sustainability standards. Our review highlights the incomplete and scattered information on the drivers, patterns, and outcomes of biophysical changes in coffee landscapes, and lays out a detailed research agenda to address these research gaps and elucidate the effects of different landscape trajectories on rural livelihoods, biodiversity conservation, and other aspects of sustainable development. A better understanding of the drivers, patterns, and consequences of changes in coffee landscapes is vital for informing the design of policies, programs, and incentives for sustainable coffee production. Supplementary Information The online version contains supplementary material available at 10.1007/s13593-021-00712-0.

We describe an ancestry-informative autosomal SNP multiplex designed to be a small-scale, flexible panel that can complement uniparental markers in assessing the American variability (i.e. pre-Colombian) found in contemporary indigenous American populations. This study centered on choosing SNPs with the specific characteristics of: 1) extreme allele frequency differences between indigenous Americans and the African, European and East Asian population groups that contribute to present-day population variation in the Americas; 2) high informativeness-for-assignment In values; and 3) well-spaced genomic distribution and chromosomal separation from existing small-scale forensic ancestry marker sets. The resulting capillary electrophoresis SNaPshot single base extension test was named: PIMA (Population Informative Multiplex for the Americas), comprising 26 autosomal SNPs, a single X-chromosome SNP plus the amelogenin sex marker adapted for SNaPshot. PIMA complements the established 34plex forensic ancestry panel to provide a powerful and simple tool for the analysis of American populations, including those with admixed histories, commonly encountered in America. Comparing the results obtained with the combined marker panels of PIMA and 34plex to SNP data from a much larger ancestry panel allowed us to gauge their relative efficiency. PIMA+34plex gives equivalent power to the 314-SNP 'LACE' genomic ancestry control panel, while requiring a much smaller genotyping effort. The ancestry profiles and genetic structure of 22 populations spread across the American continent were estimated using PIMA+34plex data, and those estimates were contrasted with information provided by uniparental markers (mtDNA and Y-chromosome loci) for a small set of admixed individuals from Venezuela. Our results indicate that an American genetic component is efficiently detected in contemporary American populations using a small set of ancestry informative SNPs, and these co-ancestry estimates are consistent with the known history and demography of the Americas. The small scale and high population differentiation power of PIMA, particularly when combined with 34plex, provides a practical and powerful tool for genetic studies of American populations as well as forensic DNA analyses.

The authors regret that the institutional affiliation of Dr. Fernando Rondon Gonzalez was incorrect in the original publication. The correct affiliation of School of Biology, Industrial University of Santander (UIS), Colombia is inserted above. The authors would like to apologise for any inconvenience caused.

Background & Aim Osteoarthritis (OA) is a degenerative disease in which conventional treatment includes drugs for pain and inflammation, physiotherapy, or implanting prostheses in advanced stages. Stem cells and growth factors are a promising option in the control of symptoms, functional improvement and regeneration of cartilage, however many details of the treatment have not been specified, such as the type and number of stem cells that should be applied to obtain optimal results. We proposed to evaluate the effectiveness, safety, and costs of two ADSC dose regimens administered intra-articularly in patients with knee OA. Methods, Results & Conclusion Ten patients of both genders, with knee OA grades II and IV, were randomized to receive ten million (n=5) or 30 million (n=5) of autologous ADSCs. To the patients whom 10 million ADSCs were applied, the pellet of the stromal vascular fraction containing the concentrated stem cells was reconstituted in a volume of 6 ml of plasma rich in growth factors, while the patients who were applied 30 million ADSC, these cells were first cultivated until achieving the required concentration, at approximately two weeks. At baseline and 6 to 10 months after the injection of the cells, the patients were evaluated according to clinical criteria (medical evaluation, WOMAC scale and quality of life) and paraclinical (arthroscopy, magnetic resonance and biopsy); adverse events were recorded during the procedure and the follow-up period. In terms of effectiveness and safety there were no differences observed among the two dosage groups since all patients had improvement according to medical criteria and the WOMAC scale (P=0,001); in the arthroscopic control (figure 1 and 2), 7 patients had "good/very good" response, 1 "neutral" and 2 did not undergo control arthroscopy; Biopsies confirm joint regeneration, although there were no differences between the magnetic resonances performed before and after the administration of the cells. All patients reported pain and mild to moderate edema during the first days of the intervention, but there were no serious adverse reactions. In osteoarthritis of the knee, the application of 10 million or 30 million ADSCs was equally effective and safe; however, the protocol with 10 million cells does not require in vitro expansion, requires less time, is simpler and has a lower cost. This study shows good reason to undertake randomized clinical trials to gain higher quality evidence.

Objective: Determine the prevalence and compare some genetic markers involved in addictive behavior in a group of addicts to derivative of coca (cocaine/crack) or heroin and a control group of non-addicted people matched for gender, age and ethnicity.Methods: A 120 addicts and 120 non-addicts Colombian male were surveyed and genotyped for 18 polymorphism of the OPRM1, DRD2, DRD4, SLC6A3, SLC6A4, ABCB1, DβH and CYP2B6 genes. For the identification of alleles markers were used mini-sequencing and fragment multiplex PCR techniques; ethnicity of cases and controls was analyzed with 61 AIMs. Results: The age of onset use of heroin or coca derivatives (cocaine/crack) was 16.5±6 years and 99.2% of them consume several illicit drugs. It showed that controls and addicts belong to the same ethnic group. Significant differences between addicts and controls in relation to schooling, marital status, social security family history of substance abuse (p T ABCB1 gene (p= 0.001) were found. Conclusion: The present results indicate that the VNTR-6R polymorphism of the gene SLC6A3 and the genotype 3435CC in the ABCB1 gene, are both associated with addictive behavior to heroin or cocaine. Objetivo: Determinar la prevalencia y comparar marcadores genéticos involucrados en conducta adictiva en un grupo de adictos a cocaína/crack o heroína y en un grupo control de no adictos apareados por género, edad y etnicidad.Métodos: 120 varones adictos y 120 no adictos fueron encuestados y genotipificados para 18 alelos de los genes OPRM1, DβH, DRD2, DRD4, SLC6A3, SLC6A4, ABCB1 y CYP2B6. Para la identificación de los diferentes alelos se utilizaron las técnicas de minisecuenciación y multiplex PCR. La etnicidad de casos y controles fue analizada con 61 marcadores ancestro-informativos.Resultados: La edad de inicio en el consumo de heroína o derivados de la coca fue de 16.5±6 años y el 99.2% de ellos eran policonsumidores. Los controles y los adictos pertenecen al mismo grupo étnico. Diferencias significativas entre adictos y controles fueron encontradas en relación con escolaridad (p T (rs1045642) del gen ABCB1(p= 0.001).Conclusión: Los resultados indican que el polimorfismo VNTR-6R del gen SLC6A3 y el genotipo 3435CC en el gen ABCB1, están asociados con conducta adictiva a heroína o cocaína. Funding for this study was provided by Vicerrectoría de Investigaciones, Innovación y Extensión of the Universidad Tecnológica de Pereira, Pereira (Colombia) SI

La hipertension representa alta carga de salud por su prevalencia, por su bajo nivel de diagnostico y control y por ser factor de riesgo primario de otras enfermedades cardiovasculares. Segun el JNC 7 report son hipertensas las personas con cifras de 140/90 mm Hg o mayores y deben tratarse con esquemas que disminuyan las cifras por debajo de 120/80 mm Hg y tengan en cuenta la morbilidad asociada y la presencia de otros factores de riesgo. En este estudio se evaluo la efectividad, la tolerabilidad y la adherencia al tratamiento en una muestra aleatoria de 458 hipertensos en tratamiento por no menos de un ano en seis ciudades colombianas. Un grupo de enfermeras entrenadas contacto a los pacientes cuando asistian a su control de rutina de presion arterial y, tras obtener su consentimiento, procedieron a la medicion de la presion arterial y de otros datos antropometricos, y a consignar en el formulario los datos relacionados con morbilidad asociada, factores de riesgo, medicacion antihipertensiva prescrita y usada, y otros medicamentos empleados. Algunos de estos datos se recabaron de las historias clinicas. La edad promedio de los pacientes fue de 57,6±13 anos, con 67,5% de mujeres; 92% tenia adherencia total al tratamiento y 59% no reporto eventos adversos asociados con la medicacion. El 44% era tratado con monoterapia antihipertensiva y los agentes mas empleados fueron, en su orden: hidroclorotiazida, verapamilo, enalapril, captopril, metoprolol y propranolol. El 45,2% (n=207) de los pacientes del estudio esta controlado, 35,1% tiene hipertension estado 1 y 19,7%, estado 2. Mediante el analisis multivariable se encontro que la hipertension no controlada se asocia significativamente con el adulto mayor, con quienes reciben combinaciones de antihipertensivos y con pacientes que residen en Ibague, Barranquilla o Manizales donde se emplean las menores dosis diarias definidas totales de agentes antihipertensivos. Se recomienda al equipo de salud ajustar los esquemas posologicos con base en objetivos terapeuticos bien definidos.

In Colombian populations older than 15 years, 12.6% suffer from hypertensive disease. Pharmacological therapies for hypertension and associated diseases were compared for 11,947 adult hypertensive patients of both sexes. All had been in treatment for more than 3 months (November/01-January/02), and were distributed among six Colombian cities. The data were retrieved from medication consumption registers that were maintained by the institutions that distribute medications to patients selected for the study. The average age of patients was 55.8 +/- 13.8, and 67.7% were women. Men were older (p < 0.05) and consumed other drugs more than women (67.7% vs. 62.4%, p < 0.05); 53.2% of patients received only one drug and 46.8% received between 2 to 5 drugs for hypertension disease. Medications most commonly prescribed were hydrchlorothiazide (31.8%), captopril (27.9%), verapamil (27.6%), enalapril (25%), metoprolol (15.1%) and propranolol (14.9%). The most common combinations were hydrochlorothiazide + ACE inhibitors (n = 2,001), hydrochlorothiazide + calcium channel antagonists (n = 1,367), verapamil + ACE inhibitors (n = 1,153) and hydrochlorothiazide + beta blocker (n = 1,021). Other prescribed medications included ASA as antiplatelet (38.2% of patients), nonsteroidal anti-inflammatory drugs (NSAID, 16.2%), lipid-lowering drugs (11.8%), hypoglycemic agents (10.9%) and antiulcerous drugs (9.6%). Some agents are probably underemployed (ACE inhibitors, ASA) and others overused (antiulcerous). Potentially dangerous pharmacological interactions were discovered in 410 cases (3.43%). Significant differences occurred in physicians' formulations among the six cities, but rational prescription patterns prevailed. Newly designed educational strategies are recommended to prevent administration of potential harmful combinations. Further exploration of clinical results in these formulations is indicated.

Psychosocial care and methadone maintenance treatment (MMT) are the preferred strategies for the management of heroin addicts, but the results are still unsatisfactory, justifying the search and intervention of the factors influencing the response to treatment.In order to determine the contribution of demographic, clinical and genetic variables on serum concentrations and response to methadone, we investigated patients on MMT, who were receiving methadone in supervised and unchanged doses at least during the previous two weeks. The age, gender, body mass index (BMI), duration of heroin abuse, addiction to other drugs, criminal background, current daily methadone doses, time spent in the TMM, comorbidity and concomitant medication were recorded. Blood samples were taken for the determination of serum levels of racemic methadone and its R and S-enantiomers, and for typing of candidate alleles of POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DßH and ARRB2 genes, all associated with the metabolism, tissue distribution and mechanism of action of methadone. Methadone quantification was by HPLC-DAD, and the detection of genetic markers by Real Time PCR and VNTR methods.A total of 80 subject volunteers were enrolled, with a mean age of 23.5 (5) years (86% male), all of them were addicts of multiple drugs, 60% with a criminal background, 5.1 (2.9) years taking heroin, and 5.3 (4) months on MMT, and taking a supervised dose of 41 (12) mg/day methadone. The (R), (S) and (R, S) methadone enantiomer trough plasma levels were, 84 (40), 84 (42), and 168 (77) ng/mL, respectively. All genotypes were in Hardy-Weinberg equilibrium. The two urine tests were negative for heroin in 61.3% (49/80) of the volunteers, the decline in cocaine/crack use was 83%, 30% of marijuana, and other psychoactives (inhalants, benzodiazepines, amphetamines) decreased to zero, while the consumption of snuff remained at 93.5% (75/80). Blood concentrations of racemic methadone and its enantiomers were significantly associated with the dose/day of the medication, but none of the other demographic, clinical or genetic variables impacted on serum levels of methadone. As for the results of the MMT, non-users and occasional users of heroin, as well as those who stopped taking other psychoactive drugs, and the ones who did not, were similar as regards the demographic, genetic and clinical variables. This included the blood metahdone concentrations, except for individuals who did not reduce their consumption of other psychoactives other than heroin, who had significantly (P=.03) higher blood levels of S-methadone, compared with those who did stop taking them.There was a significant reduction in the consumption of heroin and other psychoactives, and social rehabilitation of patients. However, the extensive overlap between effective and ineffective doses of methadone suggests the presence of personal and social variables that transcend the simple pharmacological management. These probably need to be addressed more successfully from the psychosocial features, particularly as regards to identifying and overcoming relapse-trigger experiences, as well as certain features of the patient, such as their psychological distress level or their psychiatric disorders.

Asthma is a chronic and recurrent disease. Its high prevalence around the world is the result of a complex interaction between genetic and environmental factors. The genetic aspects of susceptibility, severity, and response to treatment in asthma are of great scientific interest. The purpose of the study was to establish the relationship between the Gln27Glu and Arg16Gly alleles of the β2-adrenergic receptor (ADRB2) gene with respect to the susceptibility to and severity of asthma, as well as the response to treatment in mestizo schoolchildren. 109 schoolchildren with asthma diagnosis and 137 asymptomatic controls were genotyped for the Arg16Gly and Gln27Glu alleles of the ADRB2 gene by minisequencing. Allele, genotype, and haplotype frequencies of the ADRB2 gene between asthmatic and non-asthmatic as well as demographic, clinical, and spirometric variables among asthmatic patients according to their genotype were compared. ADRB2 gene expression was determined by real-time quantitative PCR. No statistical differences were found in allele, genotype, and haplotype frequencies of the ADRB2 gene between cases and controls. We did not find differences between asthmatic patients classified according to their ADRB2 genotypes and haplotypes when evaluating demographic, clinical, and spirometric variables. The ADRB2 genotype and haplotype are not associated with spirometric responses or ADRB2 gene expression after administration of a β-2 agonist plus a glucocorticoid. These results suggest that in the group of mestizo schoolchildren studied, the Arg16Gly and Gln27Glu polymorphisms are not markers of susceptibility or severity of asthma and do not affect ADRB2 gene expression during the rescue therapy. Pediatr Pulmonol. 2012. 47:848–855. © 2012 Wiley Periodicals, Inc.

Warfarin is an anticoagulant that is difficult to administer because of its narrow therapeutic margin and the numerous factors that influence patient response.Demographic, clinical and genetic variables were characterized to establish the appropriate maintenance dosages of warfarin.The Colombian patients consisted of 145 adults of both sexes. They were in stable anticoagulation status with international normalized ratio between 2 and 3 for at least two months, and without changes in the warfarin commercial preparation or in the dosage. After signing the informed consent, the following data was recorded for each volunteer: age, gender, weight, height, smoker status, co-morbidity, co-medication, International Normalized Ratio (INR), warfarin dose, and commercial brand. Each patient was typed for genes CYP2C9, VKORC1, CYP4F2 and PROC; for 59 patients, the serum levels of warfarin were quantified. The genotyping and the blood quantification were performed by mini-sequencing and HPLC methods, respectively.Age, co-medication with enzymatic inhibitors (amiodarone, sertraline, fluoxetine) or inducers (phenytoin, carbamazepine), and the alleles rs1799853 (*2) and rs1057910 (*3) of the CYP2C9 gene, as well as rs9923231 of the VKORC1 gene were associated with warfarin dose required to achieve anticoagulation with INR of 2-3. These variables were included in a multiple linear regression model for predicting the optimum dose/week of warfarin. This resulted in an algorithm that explained 47.4% of the variability in the dose responses.Clinical and pharmacogenetic variables provided a basis for improving the safety and effective dosage of warfarin; however, the use of a pharmacogenetic algorithm will require patient data obtained during clinical trials.

Introducción: La farmacogenómica estudia la forma como las variaciones del genoma influyen en la respuesta a medicamentos. Su principal valor médico consiste en: i) la identificación de individuos en quienes se puede predecir si un fármaco será eficaz y a qué dosis o, por el contrario, si el fármaco se debe evitar por alto riesgo de toxicidad o porque el paciente nunca responderá a él; ii) identificar blancos moleculares susceptibles de ser intervenidos por fármacos. Objetivo: Revisar y sistematizar información farmacogenómica relacionada con la utilización y el impacto clínico de medicamentos. Metodología: Se consultó la literatura biomédica pertinente en las bases de datos Medline, Proquest, Science Direct, Ovid y Cochrane, así como la información disponible en sitios web de organismos sanitarios internacionales. Introduction: Pharmacogenomics studies how changes in the genome influence the response to drugs. Its main medical value consists in: i) the identification of individuals in which it is possible to predict if certain drug and dose will be effective or on the contrary, if the drug must be avoided due to its high toxicity risk or because the patient will never respond to it; ii) to identify molecular targets able to be intervened by drugs. Objective: To carry out a systematic review about pharmacogenomic oriented to the use and clinical impact of drugs. Methodology: The pertinent biomedical literature was searched in several databases such as Medline, Proquest, Science Direct, Ovid and Cochrane, as well as the available information in web sites of international sanitary organizations.

Polymorphisms Arg16Gly and Gln27Glu of the gene of adrenoreceptor β2(ADRB2) are associated with altered sympathetic responses. This study evaluated the relationship between these polymorphisms and changes in lipids induced by metoprolol in hypertensive patients. 105 adults were enrolled. After serum lipid levels and genotype had been determined, metoprolol was administered orally. Genotyping was performed using a mini-sequencing technique. Allelic and genotypic frequencies were: Arg16 (49.5%); Gly16 (50.5%); Gln27 (89%); Glu27 (11%); Arg16Arg (28.6%); Arg16Gly (41.9%); Gly16Gly (29.5%); Gln27Gln (81%); Gln27Glu (16.1%), and Glu27Glu (2.9%). Ninety patients concluded the study. There were no significant differences between the demographic, pharmacological and biochemical variables evaluated, grouped by their genotype in positions 16 and 27 of the ADRB2 gene. We did not find differences in lipid profiles in the whole group, but when we compared these profiles within each genotypic subgroup, we found that total cholesterol diminished (p = 0.03) in the patients with the native Gln27Gln genotype, whereas in the Gln27Glu heterozygous triglycerides increased (p = 0.025). We only found 3 patients homozygous for Glu27Glu and 2 of them were treated with diet and antidyslipidemic drugs. These results suggest that the polymorphism of codon 27 constitutes the target of the changes in lipids induced by β-adrenergic receptor antagonists.

Different polymorphisms of the ADRB2 gene encoding the β2-adrenergic receptor (ADRB2) are associated with changes in a variety of responses of the sympathetic nervous system (SNS). In this study, we have investigated the distribution of frequencies of ADRB2-relaled allelic variants (Arg 16 Gly, Gln 27 Glu, Thr 164 Ile) in the Colombian population, as well as the influence of the Gln 27 Glu polymorphism as a risk factor for the development of dyslipidemia following propranolol administration. Genotyping was performed in unrelated Colombian volunteers, using PCR-RFLP methods. To examine the association between the Gln 27 Glu polymorphism of the ADRB2 gene and dyslipidemia induced by propranolol, we recruited 19 healthy individuals who were homozygous for either the Gln 27 (wild-type, N = 11) or the Glu 27 (homozygous mutant, N = 8) genotype. Electrocardiography (ECG), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), serum lipid levels (T-CHO, HDL-CHO, TG), and fibrinogen were determined before and after propranolol administration. The distribution of genotypes was as follows: Arg 16 Arg 46%, Arg 16 Gly 47.4%, Cly 16 Gly 6.6%, Gln 27 Gln 44.7%, Gln 27 Glu 48.2%, and Glu 27 Glu 7.1%, with allelic frequencies of 69.7% for Arg 16 , 30.3% for Gly 16 , 68.8% for Gln 27 , and 31.2% for Glu 27 . The Thr 164 Ile polymorphism was found only in one subject, who was heterozygous for the isoleucine variant. Significant changes in physiological parameters (HR, SBP, DBP) have been found in association with ADRB2 variants in both native and mutant subgroups after propranolol intake. HDL-CHO levels diminished (p = 0.005) in native homozygous individuals (Gln 27 Gln). whereas TG levels were found increased (p = 0.012) in the mutant homozygous individuals (Glu 27 Glu). T-CHO levels and serum fibrinogen levels remained unaltered in both subgroups. The evidence that subjects homozygous for Gln 27 in the ADRB2 gene show a significant reduction of HDL-CHO levels, as well as the increased TG levels in subjects homozygous for Glu 27 after propranolol administration, suggest that the Gln 27 Glu polymorphism represents a risk factor for dyslipidemia induced by propranolol. These results may contribute to a better understanding of the mechanisms underlying dyslipidemia induced by ADRB2 antagonists.

Thiopurine methyltransferase (TPMT) catalyzes the inactivation of thiopurine drugs (merecaptopurine, thioguanine and azathioprine) used to treat acute lymphoblastic leukemia, autoimmune diseases and recipients of transplanted organs. No endogenous substrates for this enzyme are known. The TPMT polymorphism is a major determinant of individual differences in the toxicity or therapeutic efficacy of these drugs. The molecular basis of this polymorphism has been established in Caucasians. Africans, African-Americans and Asians, but not yet in the heterogeneous Latin American groups, including the Colombian population. The frequency of the four allelic variants of the TPMT gene, TPMT*2 (G 238 C), TPMT*3A (G 460 A and A 719 G), TPMT*3B (G 460 A) and TPMT*3C (A719G) were determined in 140 Colombian volunteers of Mestizo origin, using allele-specific PCR and PCR-RFLP assays. The *3A allele was found in 10 samples and the *2 allete in one, all heterozygotes; neither homozygous mutant genotypes nor the *3B and *3C alleles were detected. In agreement with these results, 92.1% and 7.9% of the Colombian population correspond to the phenotypes high and intermediate methylators, respectively. These results show that the frequency of mulations and the allelic distribution of the TPMT gene in the Colombian population are similar to the genetic profile found among US and Europcan Cancasian populations, where the *3A allele is prevalent and the *2 allele is currently present.

Cytochrome P450 2D6 monooxygenase metabolizes several commonly used drugs, particularly psychotropics and cardiovascular agents. The gene that encodes this isoenzyme is highly polymorphic, with 1-10% of the population carrying mutations that produce an inactive enzyme, and 1-29% of individuals who possess additional copies of functional CYP2D6 genes. The genotypic features of the CYP2D6 gene have already been studied in many ethnic groups: however, the genetic characteristics of this enzyme are unknown in the Colombian population. The allelic variants and mutations of this polymorphic isoenzyme are the main cause of interindividual and interethnic differences in the therapeutic efficacy and adverse effects at standard doses of drugs metabolized by the products of the CYP2D6 gene. In the present study we have isolated, sequenced and genotyped the CYP2D6 gene in the Colombian population. The distribution of allelic frequencies of 10 alleles associated with normal, diminished or increased CYP2D6 activity has been studied in 121 healthy volunteers. The commonest alleles detected in the Colombian people were the functional alleles *1 (38.8%) and *2 (37%). Among the seven nonfunctional alleles studied in our sample, we found frequencies of 19.4%. 1.6%, 1.2% and 0.8%, for the *4, *17, *3 and *5 alleles, respecitively. The alleles *6, *7 and *8 could not be identified in any of the subjects studied. The frequency of the duplicate allele was 1.2%. In this Colombian sample, 91.7% of the individuals were normal metabolizers (EM), 6.6% were poor metabolizers (PM), and 1.7% were ultra-rapid metabolizers (UM). These results show that the allelic distribution of the CYP2D6 gene in the Colombian population of mestizo-prevalent subjects is compatible with the genomic assembly of the constitutive tri-ethnic origin of this Latin American country.

Resumen Introduccion La atencion psicosocial y el tratamiento de mantenimiento con metadona (TMM) son las estrategias preferidas para el manejo de adictos a heroina, pero los resultados siguen siendo insatisfactorios, lo que justifica la busqueda e intervencion sobre los factores que influyen en la respuesta al tratamiento. Metodos Con el proposito de determinar la contribucion de una serie de variables demograficas, clinicas y geneticas en las concentraciones sericas y la respuesta a la metadona, estudiamos a pacientes del TMM que estuvieran recibiendo metadona con supervision y sin cambios en las dosis por lo menos durante las ultimas 2 semanas. Se les registro edad, sexo, indice de masa corporal (IMC), tiempo de abuso de heroina, adiccion a otras drogas, antecedentes delictivos, dosis diaria actual de metadona, tiempo de permanencia en el TMM, comorbilidad y comedicacion. Se les tomaron muestras de sangre para determinar concentraciones sericas de metadona racemica y sus enantiomeros R- y S-, y para la tipificacion de alelos candidatos de los genes POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DsH y ARRB2 , todos ellos asociados con el metabolismo, la distribucion tisular y el mecanismo de accion de la metadona. La cuantificacion de metadona se hizo mediante HPLC-DAD y la deteccion de los marcadores geneticos por los metodos de PCR en tiempo real y VNTR. Resultados Se incluyo a 80 personas de 23,5 ± 5 anos (el 86% varones), todos policonsumidores de sustancias adictivas, el 60% con antecedentes delictivos, con 5,1 ± 2,9 anos de consumo de heroina y 5,3 ± 4 meses de ingreso al TMM, con 41 ± 12 mg/dia de metadona tomada con supervision. Las concentraciones valle de RS-, R- y S-metadona fueron, respectivamente, 168 ± 77, 84 ± 40 y 84 ± 42 ng/ml. Todos los genotipos estuvieron en equilibrio de Hardy-Weinberg. Las dos pruebas de orina fueron negativas para heroina en el 61,3% (49/80) de los voluntarios; el descenso en el consumo de cocaina/basuco fue del 83%; el de marihuana, del 30% y el de otros psicoactivos (inhalantes, benzodiacepinas, anfetaminas) bajo a cero, mientras el consumo de tabaco permanecio en el 93,5% (75/80). Las concentraciones de metadona racemica y sus enantiomeros se correlacionaron significativamente con las dosis diaria del farmaco, pero ninguna de las demas variables demograficas, clinicas o geneticas incidio en la concentracion serica de metadona. En cuanto a los resultados del TMM, los no consumidores y los consumidores ocasionales de heroina, asi como los que abandonaron el consumo de otros psicoactivos y los que no, tuvieron caracteristicas similares con respecto a las variables demograficas, geneticas y clinicas, incluidas las concentraciones sanguineas de metadona, con excepcion de los individuos que no disminuyeron el consumo de otros psicoactivos distintos de heroina, quienes tuvieron significativamente (p = 0,03) mayores concentraciones sanguineas de S-metadona que quienes si abandonaron el consumo. Conclusiones Hubo importante reduccion en los consumos de heroina y otros psicoactivos y reinsercion social de los pacientes; sin embargo, la amplia superposicion entre las dosis efectivas e inefectivas de metadona apunta a la presencia de variables personales y sociales que trascienden el simple manejo farmacologico y probablemente deban ser abordadas con mas exito desde lo psicosocial, particularmente en lo que tiene que ver con la identificacion y superacion de las experiencias detonantes de recaidas y con ciertos rasgos del paciente, tales como su nivel de estres psicologico o sus trastornos psiquiatricos.

Introducción. La warfarina es un anticoagulante de difícil manejo por su estrecho margen terapéutico y los numerosos factores que influyen en la respuesta. Objetivo. Determinar la contribución de variables demográficas, clínicas y genéticas sobre las dosis de mantenimiento de warfarina en pacientes colombianos. Materiales y métodos. Se incluyeron 145 adultos de ambos sexos, en anticoagulación estable con International Normalized Ratio (INR) entre 2 y 3, al menos, durante dos meses, sin cambio en las dosis de warfarina ni en el preparado comercial. Previa firma del consentimiento informado de cada voluntario, se registró su edad, sexo, peso, talla, tabaquismo, enfermedades concomitantes, medicación simultánea, INR, dosis de warfarina, su indicación y nombre comercial. Cada paciente se tipificó para los genes CYP2C9, VKORC1, CYP4F2 y PROC, y en 59 de ellos, se cuantificaron las concentraciones séricas de warfarina. La genotipificación y la cuantificación sanguínea se hicieron mediante minisecuenciación y HPLC, respectivamente. Resultados. Los factores de edad, medicación simultánea con inhibidores (amiodarona, sertralina, fluoxetina) o inductores enzimáticos (fenitoína, carbamacepina), los alelos rs1799853 (*2) y rs1057910 (*3) del gen CYP2C9, así como rs9923231 del gen VKORC1, se asociaron con las dosis de warfarina requeridas para conseguir anticoagulación con INR de 2 a 3. Dichas variables se incluyeron en un modelo de regresión lineal múltiple que permitiera predecir la dosis semanal de warfarina, y se obtuvo un algoritmo que explica el 47,4% de la variabilidad en las dosis. Conclusión. La consideración de las variables clínicas y las farmacogenéticas puede mejorar la relación entre seguridad y eficacia de la warfarina, aunque la adopción de un algoritmo de dosificación farmacogenético requiere información obtenida con ensayos clínicos.

La warfarina, el anticoagulante oral de mayor prescripción en el mundo, es un fármaco difícil de manejar por su estrecho margen terapéutico, amplia gama de interacciones y gran variabilidad inter-individual en la respuesta. De una cohorte de 145 pacientes en anticoagulación crónica con warfarina reportamos una serie de casos de sensibilidad (dosis ≤ 15 mg/semana) y de resistencia (dosis ≥ 70 mg/ semana) al fármaco y, tras una breve revisión de sus aspectos farmacológicos relevantes, discutimos los posibles factores causantes de estas respuestas exageradas al medicamento.