Influence of CYP2B6 Genotype on Methadone Dosage in Patients from the Methadone Maintenance Treatment (MMT) Program in Pereira, Colombia.

Methadone treatment reduces the use of heroin and withdrawal symptoms; however, methadone is an expensive medication with a narrow safety margin. We compared the retention rates, persistence of heroin use, and quality of life of a group of patients undergoing conventional Methadone Maintenance Treatment (MMT) with a group for whom the CYP2B6 516G>T polymorphism was used in addition to the MMT to calculate the required methadone dose. Over 12 weeks, the retention rate, heroin usage, and quality of life of patients under conventional treatment (n = 34) were compared with those of patients for whom we used genetic markers to calculate methadone dosage (n = 38). At the end of the study, 26.4% of patients abandoned the program, and neither demographic nor clinical variables were associated with treatment adherence. Of the remaining patients, 16% of the control group and 8% of patients in the pharmacogenetic group reported heroin use, while both groups showed a 64% reduction in the use of cocaine/crack (no significant differences between the groups were found). Starting in the second week, the methadone dosage was lower among the patients for whom methadone was prescribed based on genotype. Although there were six individuals in the control group and three in the pharmacogenetic group with QTc intervals > 450 ms (a threshold that is considered dangerous), we did not find a relationship between the QTc interval and methadone dosage. There were no differences in the perception of quality of life between the two groups. The results of this pilot study suggest that concerning methadone therapy, the CYP2B6 genotype contributes to reduced effective doses and treatment costs.

Medicamentos modificadores en esclerosis múltiple: esquemas terapéuticos actuales / Disease-Modifying drugs in multiple sclerosis: current therapeutic schemes

La esclerosis múltiple (EM) es una enfermedad crónica, autoinmune y neurodegenerativa; que tiene como principal característica la desmielinización de los axones en el sistema nervioso. Los medicamentos modificadores de la enfermedad (MME) logran retrasar la aparición de los síntomas y modificar parcialmente el progreso de la desmielinización y daño neuronal, resultando cada vez más complejo determinar un esquema terapéutico estandarizado según la condición particular de cada paciente. En este artículo se presenta una revisión actualizada de la evidencia clínica que ha llevado al uso de los esquemas terapéuticos en EM. La mayoría de los medicamentos aprobados actualmente son utilizados para la EM remitente-recurrente y se pueden dividir de acuerdo a la eficacia y seguridad. Los medicamentos de primera línea han mostrado una baja o moderada eficacia y alta seguridad; después de usar estos fármacos sin lograr una buena respuesta o ante una enfermedad avanzada se usan medicamentos de segunda y tercera línea que tienen una alta eficacia, pero son menos seguros, presentando mayores efectos secundarios y riesgos asociados para los pacientes. El ocrelizumab es el único fármaco aceptado para la EM primaria progresiva y el siponimod fue aprobado como una alternativa para la EM secundaria progresiva. El desarrollo de nuevos medicamentos y el seguimiento clínico de los ya aprobados permitirá establecer un mejor abordaje terapéutico logrando así mejorar la calidad de vida de cada paciente.

Multiple sclerosis (MS) is a chronic, autoimmune and neurodegenerative disease; whose main characteristic is the demyelination of axons in the nervous system. Disease-modifying drugs (DMD) can delay the onset of symptoms and partially modify the progression of demyelination and neuronal damage, making it increasingly complex to determine a standardized therapeutic scheme that is individualized to each patient. This article presents an updated review on the clinical evidence that has led to the use of current therapeutic schemes in MS with focus on DMD. Current medications in treating relapsing-remitting MS can be divided according to efficacy and safety. First-line drugs have shown low or moderate efficacy and high safety. Second- and third-line drugs are used after a poor response or in cases of advanced disease. These drugs are highly effective, but less safe, presenting greater side effects and associated risks for patients. Ocrelizumab is the only accepted drug for primary progressive MS and siponimod is accepted as an alternative for secondary progressive MS. The development of new medications and the clinical follow-up of those already approved will allow establishing a better therapeutic approach, thus improving the quality of life of each patient.

Dosis de células madre en el tratamiento de osteoartritis de rodilla / Stem cell doses in knee osteoarthritis

Resumen La osteoartritis (OA) es una enfermedad degenerativa, cuyo tratamiento convencional incluye medicamentos, fisioterapia o prótesis. Las células madre con Plasma Rico en Plaquetas y factores de crecimiento son una opción que promete controlar los síntomas, mejorar la función y regenerar el cartílago; sin embargo, no se han especificado muchos detalles del tratamiento, como el tipo y la cantidad de células madre que se deben aplicar para obtener mejores resultados. En este estudio buscamos comparar la efectividad, la seguridad y los costos de dos dosis (1X107vs 3X107) de células madre derivadas de tejido adiposo (ADSC), aplicadas por vía intraarticular. Diez pacientes, con OA de rodilla grados II y III, fueron aleatorizados para recibir 10 (n = 5) o 30 millones (n = 5) de ADSC autólogos. Al inicio y 6 a 10 meses después de la inyección, se evaluaron de acuerdo con los criterios clínicos (evaluación médica, escala WOMAC, calidad de vida) y paraclínicos (artroscopia, resonancia, biopsia). En términos de efectividad y seguridad no se observaron diferencias entre los dos grupos de dosificación, ya que todos los pacientes tuvieron una mejoría de acuerdo con los criterios médicos y la escala WOMAC (P = 0,001); en el control artroscópico, 7 pacientes tuvieron una respuesta "buena / muy buena", 1 "neutral" y 2 abandonaron el control; Las biopsias confirman la regeneración articular, aunque no hubo diferencias en las resonancias magnéticas anteriores y posteriores. En la osteoartritis de rodilla, la aplicación de 10 o 30 millones de ADSC fue igualmente efectiva y segura; sin embargo, el protocolo con 10 millones de células no requiere expansión in vitro, requiere menos tiempo, es más simple y tiene un costo menor. Este estudio muestra una buena razón para realizar ensayos clínicos aleatorios para obtener evidencia de mayor calidad.

Abstract Osteoarthritis (OA) is a degenerative disease where conventional treatment includes drugs, physiotherapy, or prostheses. Stem cells and growth factors are a promising option in controlling symptoms, functional improvement and cartilage regeneration; however, many treatment details have not been specified, such as type and number of stem cells that should be applied to obtain optimal results. In this study we sought to compare effectiveness, safety and costs of two doses (1X107vs 3X107) of adipose tissue derived stem cells (ADSC), applied intra-articularly. Ten patients, with knee OA grades II and III, were randomized to receive 10 (n=5) or 30 million (n=5) of autologous ADSCs. At baseline and 6 to 10 months after injection, they were evaluated according to clinical (medical evaluation, WOMAC scale, quality of life) and paraclinical criteria (arthroscopy, resonance, biopsy). 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, 7 patients had "good/very good" response, 1 "neutral" and 2 forwent control; biopsies confirm joint regeneration, although there were no differences in the before and after magnetic resonances. In knee osteoarthritis, the application of 10 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.

Evaluación del programa de mantenimiento con metadona del Hospital Mental de Risaralda / Evaluation of the Methadone Maintenance Program of the Risaralda Mental Hospital

Introducción: La atención psicosocial y el tratamiento de mantenimiento con metadona (TMM) son las estrategias preferidas para el manejo de adictos a heroína, pero los resultados siguen siendo insatisfactorios, lo que justifica la búsqueda e intervención sobre los factores que influyen en la respuesta al tratamiento. Métodos: Con el propósito de determinar la contribución de una serie de variables demográficas, clínicas y genéticas en las concentraciones séricas y la respuesta a la metadona, estudiamos a pacientes del TMM que estuvieran recibiendo metadona con supervisión y sin cambios en las dosis por lo menos durante las últimas 2 semanas. Se les registró edad, sexo, índice de masa corporal (IMC), tiempo de abuso de heroína, adicción a otras drogas, antecedentes delictivos, dosis diaria actual de metadona, tiempo de permanencia en el TMM, comorbilidad y comedicación. Se les tomaron muestras de sangre para determinar concentraciones séricas de metadona racémica y sus enantiómeros R-y S-, y para la tipificación de alelos candidatos de los genes POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DßH y ARRB2, todos ellos asociados con el metabolismo, la distribución tisular y el mecanismo de acción de la metadona. La cuantificación de metadona se hizo mediante HPLC-DAD y la detección de los marcadores genéticos por los métodos de PCR en tiempo real y VNTR. Resultados: Se incluyó a 80 personas de 23,5 ± 5a ˜nos (el 86% varones), todos policonsumidores de sustancias adictivas, el 60% con antecedentes delictivos, con 5,1 ± 2,9 años de consumo de heroína y 5,3 ± 4 meses de ingreso al TMM, con 41 ± 12 mg/día de meta-dona tomada con supervisión. 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 heroína en el 61,3% (49/80) de los voluntarios; el descenso en el consumo de cocaína/basuco fue del 83%; el de marihuana, del 30% y el de otros psicoactivos (inhalantes, benzodiacepinas, anfetaminas) bajó a cero, mientras el consumo de tabaco permaneció en el 93,5% (75/80). Las concentraciones de metadona racémica y sus enantiómeros se correlacionaron significativamente con las dosis diaria del fármaco, pero ninguna de las demás variables demográficas, clínicas o genéticas incidió en la concentración sérica de metadona. En cuanto a los resultados del TMM, los no consumidores y los consumidores ocasionales de heroína, así como los que abandonaron el consumo de otros psicoactivos y los que no, tuvieron características similares con respecto a las variables demográficas, genéticas y clínicas, incluidas las concentraciones sanguíneas de metadona, con excepción de los individuos que no disminuyeron el consumo de otros psicoactivos distintos de heroína, quienes tuvieron significativamente (p = 0,03) mayores concentraciones sanguíneas de S-metadona que quienes sí abandonaron el consumo. Conclusiones: Hubo importante reducción en los consumos de heroína y otros psicoactivos y reinserción social de los pacientes; sin embargo, la amplia superposición entre las dosis efectivas e inefectivas de metadona apunta a la presencia de variables personales y sociales que trascienden el simple manejo farmacológico y probablemente deban ser abordadas con más éxito desde lo psicosocial, particularmente en lo que tiene que ver con la identificación y superación de las experiencias detonantes de recaídas y con ciertos rasgos del paciente, tales como su nivel de estrés psicológico o sus trastornos psiquiátricos.

Background: Psychosocial care and methadone maintenance treatment (MMT) are the preferred strategies for the management of heroin addicts, but the results are still unsa-tisfactory, justifying the search and intervention of the factors influencing the response to treatment. Methodology: 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. Results: 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. Conclusions: 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.

[Evaluation of the Methadone Maintenance Program of the Risaralda Mental Hospital]. / Evaluación del programa de mantenimiento con metadona del Hospital Mental de Risaralda.

BACKGROUND: 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. METHODOLOGY: 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. RESULTS: 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. CONCLUSIONS: 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.

Genetic variants associated with addictive behavior in Colombianaddicted and non-addicted to heroin or cocaine / Variantes genéticas asociadas con conducta adictiva en colombianos adictos y no adictos a heroína o cocaína

Objective:Determine the prevalence and compare somegenetic markers involved in addictive behavior in a groupof addicts to derivative of coca (cocaine/crack) or heroinand a control group of non-addicted people matched forgender, age and ethnicity.Methods:A 120 addicts and 120 non-addicts Colombianmale were surveyed and genotyped for 18 polymorphismof the OPRM1, DRD2, DRD4, SLC6A3, SLC6A4, ABCB1,DβH and CYP2B6 genes. For the identification of allelesmarkers were used mini-sequencing and fragment multi-plex PCR techniques; ethnicity of cases and controls wasanalyzed with 61 AIMs.Results:The age of onset use of heroin or coca derivati-ves (cocaine/crack) was 16,5±6 years and 99,2 percent of themconsume several illicit drugs. It showed that controlsand addicts belong to the same ethnic group. Significantdifferences between addicts and controls in relation toschooling, marital status, social security family historyof substance abuse (p<0,001), Int8-VNTR SLC6A3 gene(p=0,015) and SNP 3435C>T ABCB1 gene (p=0,001) werefound.Conclusion:The present results indicate that the VNTR-6R polymorphism of the gene SLC6A3 and the genoty-pe 3435CC in the ABCB1 gene, are both associated withaddictive behavior to heroin or cocaine.

Genetic variants associated with addictive behavior in Colombian addicted and non-addicted to heroin or cocaine.

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, DßH 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 <0.001), Int8-VNTR SLC6A3 gene (p= 0.015) and SNP 3435C>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 g énero, edad y etnicidad. METODOLOGÍA: 120 varones adictos y 120 no adictos fueron encuestados y genotipificados para 18 alelos de los genes OPRM1, DßH, DRD2, DRD4, SLC6A3, SLC6A4, ABCB1 y CYP2B6. Para la identificación de los diferentes alelos se utilizaron las técnicas de minisecuenciaci ón 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 <0.001), estado civil (p <0.001), seguridad social (p <0.001) e historia familiar de drogadicción (p <0.001), genotipo int8-VNTR del gen SLC6A3 (p= 0.015) y al SNP 3435C>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.

ß(2) -adrenoreceptor polymorphisms in asthmatic and non-asthmatic schoolchildren from Colombia and their relationship to treatment response.

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 ß(2) -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 ß-(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.

Características demográficas y de consumo en pacientes adictos a heroína o derivados de la coca / Demographic characte ristics and consumption in patients addicted to heroin or coca derivatives / Características demográficas e de consumo em pacientes viciados em heroína ou derivados da cocaína

Introducción: el problema de psicoactivos en Colombia es crítico, porque padecemos la triple condición de productores, exportadores y consumidores de sustancias ilícitas.Métodos: en esta serie de casos exploramos características del consumo de heroína y derivados de la coca (basuco, cocaína) en 120 varones mayores de 16 años, sometidos a tratamiento de abstinencia en 13 comunidades terapéuticas del municipio de Pereira. Resultados: la edad promedio fue de 31±10 años (rango: 16-59 años); el 89% tenía nivel de educación entre primaria y bachillerato; sólo el 20% estaba casado o en unión libre y el 30% carecía de seguridad social. La edad de inicio en el consumo fue de 16.5±6 años, el 81% de ellos reportó la existencia de al menos un familiar drogadicto; prevalece el consumo de derivados de la coca (115/120) sobre la heroína (31/120) y 119 de los 120 pacientes eran policonsumidores. Conclusión: el perfil demográfico y de consumo que se encontró, coincide con los reportes de numerosos estudios epidemiológicos. El consumo de heroína tiende a concentrarse en las personas de menor edad, mientras las tasas de consumo debasuco y cocaína se reparten a lo largo de todas las edades.

Introduction: the problem of psychoactive substances in Colombia is especially critical, because we suffer the triple condition of producer, exporter, and consumer country of illicit drugs. Methods: in this study we explored the characteristics of heroin and coca derivatives (crack, cocaine) intake in 120 men older than 16 years under treatment for drug abuse withdrawal in 13 therapeutic communities in the municipality of Pereira. Results: the average age of volunters was 31±10 years (range: 16-59 years), 89% had levels between primary and secondary school education, only 20% were married or cohabiting and 30% had no social security. The age of first heroin or coca derivatives use was 16.5±6 years, 81% of them reported the existence of at least one family drug addict, coca derivatives consumption predominates over heroin (115/120 and 31/120, respectively), and 119 of 120 patients were multiple consumers. Conclusion: the demographic profile and consumption habits matches with reports of numerous epidemiological studies. Heroin use tends to focus on younger people, while rates of crack and cocaine use are spread across all ages.

Introdução: o Problema dos psicoativos na Colômbia é crítico porque padecemos a tríplice condição de produtores, exportadores e consumidores de substâncias ilícitas. Métodos: nesta série de casos exploramos características do consumo de heroína e derivados da coca (basuco, cocaína) em 120 homens, maiores de 15 anos, submetidos a tratamento de abstinência em 13 comunidades terapêuticas do município de Pereira. Resultados: a idade média foi de 31±10 anos (universo: 16-59 anos); 89% tinham nível de educação entre básico e médio. Só 20% estavam casados ou em união livre e 30% não tinham previdência social. A idade no início do consumo foi de 16,5 anos mais ou menos, 8,1% deles reportou a existência de pelo menos um familiar viciado, prevalece o consumo de derivados da coca (115/120) sobre a heroína (31/120) e 119 dos 120 pacientes eram poli-consumidores. Conclusão: o perfil demográfico e de consumo que se encontrou, coincide com os de numerosos estudos epidemiológicos. O consumo de heroína tende a se concentrar nas pessoas de menos idade, enquanto as de basuco e cocaína se repartem ao longo de todas as idades.

Factores genéticos y ambientales asociados con la respuestaa warfarina en pacientes colombianos / Genetic and bioenvironmental factors associated with warfarin response in Colombian patients

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.

Introduction. Warfarin is an anticoagulant that is difficult to administer because of its narrow therapeutic margin and the numerous factors that influence patient response.Objective. Demographic, clinical and genetic variables were characterized to establish the appropriate maintenance dosages of warfarin. Materials and methods. 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. Results. 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. Conclusion: 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.

Resistencia y sensibilidad a Warfarina / Resistance and sensibility to Warfarina

La warfarina, el anticoagulante oral de mayor prescripci¨®n en el mundo, es unf¨¢rmaco dif¨ªcil de manejar por su estrecho margen terap¨¦utico, amplia gama de interacciones y gran variabilidad inter-individual en la respuesta. De una cohorte de 145 pacientes en anticoagulaci¨®n cr¨®nica con warfarina reportamos una serie de casos de sensibilidad (dosis ¡Ü 15 mg/semana) y de resistencia (dosis ¡Ý 70 mg/semana) al f¨¢rmaco y, tras una breve revisi¨®n de sus aspectos farmacol¨®gicos relevantes, discutimos los posibles factores causantes de estas respuestas exageradas al medicamento.

[Genetic and bioenvironmental factors associated with warfarin response in Colombian patients]. / Factores genéticos y ambientales asociados con la respuesta a warfarina en pacientes colombianos.

INTRODUCTION: Warfarin is an anticoagulant that is difficult to administer because of its narrow therapeutic margin and the numerous factors that influence patient response. OBJECTIVE: Demographic, clinical and genetic variables were characterized to establish the appropriate maintenance dosages of warfarin. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

La farmacogenómica en medicina / Pharmacogenomics in medicine

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.

Tratamiento de las úlceras crónicas en los miembros inferiores con un equivalente cutáneo autólogo y desbridación con larvas de Lucilia sp. (Diptera: Calliphoridae). Reporte de un caso / Chronic lower limb ulcers treatment with autologous skin equivalent and larvae debriding (Diptera Calliphoridae)

Introducción: las úlceras en los miembros inferiores constituyen una causa importante de hospitalización y deterioro en la calidad de vida de los pacientes, al interferir con sus actividades laborales y sociales. Estas lesiones obedecen a diferentes enfermedades, la más frecuente de las cuales en Medellín es la insuficiencia venosa; una vez diagnosticadas, existen muchas alternativas de tratamiento, que buscan crear un lecho apropiado para el cierre de la herida. El uso de larvas para el desbridamiento es una alternativa rápida y de bajo costo, con la cual se logra un tejido de granulación adecuado para la aplicación de equivalentes cutáneos autólogos, que constituyen una opción para pacientes refractarios a otros tratamientos. Materiales y métodos: se seleccionó y evaluó a una paciente de acuerdo con los criterios de inclusión establecidos para el estudio. Para desbridar la úlcera se recurrió a la aplicación de larvas de Lucilia sp. (Diptera: Calliphoridae), btenidas a partir de huevos previamente desinfectados con hipoclorito de sodio y sembrados en un medio de cultivo con antibióticos. Se aplicaron las larvas directamente en la lesión y posteriormente se procedió a tapar esta con muselina, permitiendo la obtención de oxígeno y facilitando el drenaje del tejido necrótico. Las larvas se dejaron por 48 horas, al cabo de las cuales se retiraron con una pinza estéril y se descartaron en alcohol al 70%; luego se procedió a evaluar la limpieza de la lesión. Este procedimiento se llevó a cabo en el Laboratorio de Entomología (GIEM) de la Universidad Antioquia. Se procesó una biopsia de piel de la paciente, obtenida siguiendo un protocolo previamente establecido, para obtener queratinocitos y fibroblastos. Para el cultivo primario de queratinocitos el 90% de las células obtenidas de la biopsia se sembró en cajas de cultivo de 75 cm2, en presencia de 7 x 106 células de la línea 3T3-Swiss tratadas con mitomicina C (10 μg/mL) como capa alimentadora; para el cultivo primario de fibroblastos, se sembró el 10% de las células en cajas de cultivo de 75 cm2 con el medio DMEM suplementado. En la producción del equivalente cutáneo se utilizó un gel obtenido con una mezcla de plasma humano de sangre AB de banco de sangre, 6-7,5 x 104 fibroblastos, CaCl2 y ácido tranexámico. Sobre dicho gel se sembraron luego los queratinocitos provenientes del cultivo primario y se hizo seguimiento del cultivo en microscopio invertido. Cuando se obtuvo una confluencia celular cercana al 100%, se desprendió el equivalente cutáneo con pinzas estériles para aplicarlo inmediatamente sobre la úlcera. Se reportan los resultados del tratamiento de una úlcera en el miembro inferior izquierdo de una paciente de 66 años con la terapia combinada de desbridamiento con larvas y cultivo de equivalentes cutáneos autólogos. Después de 15 meses de iniciado el tratamiento, la úlcera continúa cerrada y la paciente no tiene dolor ni impedimentos funcionales en la extremidad.

Human splenic macrophages as a model for in vitro infection with Mycobacterium tuberculosis.

Macrophages play an important role during Mycobacterium tuberculosis (MTB) infection. In humans most of the studies on MTB-macrophage interactions have been performed using circulating monocytes and monocyte-derived macrophages. However, little research has been performed on this interaction using tissue macrophages. Herein, we used human splenic macrophages to characterize particular responses to MTB infection. Based on morphological, biochemical, and immunological markers, splenic adherent cells exhibit characteristics of tissue macrophages. They were able to efficiently phagocytose both live and heat-killed (h-k) MTB H37Rv. Upon infection with live, but not h-k MTB, an increase in secreted TNF-alpha was elicited. Splenic macrophages produced high basal levels of IL-10; however, infection with live or h-k MTB resulted in decrease IL-10 secretion. Both IL-12p40 and IL-12p70 basal levels were also decreased upon infection with live or h-k MTB; however, while the reduction for IL-12p40 levels was observed at earlier time points (4h) for both live and h-k MTB, infection with live MTB, but not h-k MTB, resulted in a time-dependent secretion of IL-12p40 at 24 and 48h after infection. IL-12p70 levels were completely reduced upon infection by either live or h-k MTB. These results support that human splenic macrophages may represent a potential useful model to study MTB-macrophage interactions in vitro.

Beta-2-adrenergic receptor polymorphisms and changes in lipids induced by metoprolol.

Polymorphisms Arg(16)Gly and Gln(27)Glu of the gene of adrenoreceptor beta(2)(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: Arg(16) (49.5%); Gly(16) (50.5%); Gln(27) (89%); Glu(27) (11%); Arg(16)Arg (28.6%); Arg(16)Gly (41.9%); Gly(16)Gly (29.5%); Gln(27)Gln (81%); Gln(27)Glu (16.1%), and Glu(27)Glu (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 Gln(27)Gln genotype, whereas in the Gln(27)Glu heterozygous triglycerides increased (p = 0.025). We only found 3 patients homozygous for Glu(27)Glu 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 beta-adrenergic receptor antagonists.

Phenotype-genotype analysis of CYP2C19 in Colombian mestizo individuals.

BACKGROUND: Omeprazole is metabolized by the hepatic cytochrome P450 (CYP) 2C19 enzyme to 5-hydroxyomeprazole. CYP2C19 exhibits genetic polymorphisms responsible for the presence of poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers (EMs). The defective mutations of the enzyme and their frequencies change between different ethnic groups; however, the polymorphism of the CYP2C19 gene has not been studied in Colombian mestizos. The aim of this study was to evaluate the genotype and phenotype status of CYP2C19 in Colombian mestizos, in order to contribute to the use of appropriate strategies of drug therapy for this population. METHODS: 189 subjects were genotyped using the multiplex SNaPshot technique and a subgroup of 44 individuals received 20 mg of omeprazole followed by blood collection at 3 hours to determine the omeprazole hydroxylation index by HPLC. RESULTS: 83.6%, 15.3% and 1.1% of the subjects were genotyped as EMs, IMs and PMs, respectively. The frequencies of the CYP2C29*1 and CYP2C19*2 alleles were 91.3% and 8.7% respectively whereas the *3, *4, *5, *6 and *8 alleles were not found. No discrepancies were found between the genotype and phenotype of CYP2C19. CONCLUSION: The frequency of poor metabolizers (1.1%) in the Colombian mestizos included in this study is similar to that in Bolivian mestizos (1%) but lower than in Mexican-Americans (3.2%), West Mexicans (6%), Caucasians (5%) and African Americans (5.4%). The results of this study will be useful for drug dosage recommendations in Colombian mestizos.

Epidemiologia de la infeccion recurrente en pacientes pediatricos hospitalizados / Epidemiology of recurrent infection in pediatric pacients hospitalized

Introducción: las infecciones recurrentes constituyen una causa frecuente de consulta y hospitalización en todo el mundo; algunas de ellas pueden ser la expresión de enfermedades de base de origen inmunológico y no inmunológico. Objetivo y tipo de estudio: con el propósito de establecer las características epidemiológicas de la infección recurrente que demanda hospitalización, se realizó un estudio descriptivo retrospectivo del total de casos atendidos por enfermedad infecciosa en un servicio especializado de infectología pediátrica durante el año 1998. Métodos: se revisaron las 240 historias clínicas que tenían como diagnóstico principal una enfermedad infecciosa y los correspondientes recibos de facturación. Los datos sobre las variables de interés fueron registrados en un formato y una base de datos diseñados previamente. Resultados: todos los pacientes fueron menores de 15 años, con una media de edad de 3.7 ± 3.8 años; el 57.9 por ciento de los infectados eran varones. La hospitalización obedeció a los siguientes grupos de infecciones: aparato respiratorio inferior (30.4 por ciento), sistema nervioso central (12.9 por ciento), piel y tejidos blandos (12.5 por ciento), artritis séptica y osteomielitis (11.7 por ciento), infecciones vírales específicas (9.2 por ciento), aparato respiratorio superior (7.1 por ciento), tuberculosis extrapulmonar (3.3 por ciento), otras infecciones y parasitosis (12.9 por ciento)...

[Phenotypic diagnosis of primary immunodeficiencies in Antioquia, Colombia, 1994-2002]. / Diagnóstico fenotípico de las inmunodeficiencias primarias en Antioquia, Colombia, 1994-2002.

Recurrent infections are a frequent cause of medical visits. They can be due to a heterogeneous group of dysfunctions that increase the susceptibility to pathogenic and opportunistic microorganisms, such as immunological deficiencies. To define an opportune rational treatment and to guide the molecular diagnosis of primary immunodeficiency diseases, we establish a program for the phenotypic diagnosis of these illnesses in Antioquia, Colombia, including clinical and laboratory evaluations of patients who present recurrent infections with abnormal evolution. Between August 1, 1994 and July 31, 2002, phenotypic diagnosis of primary immunodeficiency was made in 98 patients. Similar to data reported in the literature, antibody deficiencies were the most frequent (40.8%), followed by combined deficiencies (21.4%). This phenotypic characterization has allowed for appropriate treatments for each patient and, in some cases, functional and molecular studies that can lead to a definite molecular diagnosis.