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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.

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

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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.

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.

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.

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.