Metformina, el fármaco paradigma del siglo XXI / Metformin, the paradigm medication of the XX1th century

Por muchos años, la metformina se ha consolidado como el principal pilar del tratamiento de la diabetes mellitus; sin embargo, los aspectos de su mecanismo de acción han permanecido mal definidos. Avances recientes han revelado que esta droga, además de su propiedad de reducir la glucemia, puede ser promisoria para identificar blancos metabólicos entre la señalización metabólica normal y anormal. El centro del mecanismo de acción de la metformina es la alteración del metabolismo energético de la célula, de tal forma que su efecto hipoglucemiante ocurre por inhibición de la gluconeogénesis hepática, opuesto a la acción del glucagón. La inhibición del complejo I mitocondrial resulta en defectos en AMPc y señalización de la protein cinasa A en respuesta al glucagón. La estimulación de la protein cinasa activada 5'AMP, aunque dispensable para el efecto hipoglucemiante de la metformina, confiere sensibilidad a la insulina, principalmente por modulación del metabolismo lipídico. Conjuntamente con su efecto hipoglucemiante se ha despertado interés en las potenciales acciones relevantes sobre las enfermedades cardiovasculares y cáncer. No obstante, tales mecanismos de acción permanecen esquivos. La data convincente coloca al metabolismo energético en el centro del mecanismo de acción de la metformina en la diabetes y también puede jugar un papel importante en las enfermedades cardiovasculares y cáncer. En esta revisión se discute el conocimiento actualizados de la acción antigluconeogénica de la metformina y sus implicaciones en el descubrimiento de nuevos objetivos(AU)

Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the aspects of its action remained ill defined. Recent advances revealed that this drug, in addition to its glucose-lowering action, might be promising for specifically targeting metabolic differences between normal and abnormal metabolic signaling. The knowledge gained from dissecting the principal mechanisms by which metformin works can help us develop novel treatments. The center of metformin's mechanism of action is the alteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulation of 5'-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Here, we discuss the updated understanding of the antigliconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer(AU)

Manual Venezolano de Diabetes Gestacional

La diabetes mellitus gestacional (DMG) es uno de los trastornos metabólicos más frecuentes que pueden afectar el embarazo. Su prevalencia aumenta en la misma proporción que la epidemia de obesidad y sobrepeso. Reconocer y tratar cualquier grado de alteración de la glucemia que afecte la gestación conduce a la disminución de complicaciones maternas y fetales, inmediatas y a largo plazo. A pesar de un cúmulo de investigación básica y clínica, aun no existe un enfoque único para diagnosticar y tratar la diabetes durante el embarazo. Lo deseable para nuestro país es buscar la uniformidad de criterios en la pesquisa y el diagnóstico de la DMG, y de esa manera, poder tener nuestra propia casuística. Es por ello que la Sociedad Venezolana de Endocrinología y Metabolismo ha concebido la idea de elaborar este Manual de Diabetes Gestacional, con la colaboración de la Sociedad de Obstetricia y Ginecología de Venezuela, la Sociedad Venezolana de Medicina Interna y Especialistas que integran el equipo multidisciplinario de atención a la embarazada de alto riesgo conformado por endocrinólogos, internistas, obstetras, nutricionistas, deportólogos y/o biólogos del ejercicio y neonatólogos, para que pueda ser utilizado tanto a nivel primario como en áreas de especialización. Este manual se enfocará en la prevención, la pesquisa, el diagnóstico, el tratamiento y seguimiento de la Diabetes Mellitus Gestacional, pudiendo servir de base para la integración del equipo de salud que se constituya para atender a nuestra paciente.

Gestational diabetes mellitus (GDM) is one of the most common metabolic disorders that can affect pregnancy. Its prevalence increases in the same proportion as the epidemic of obesity and overweight. Recognize and treat any degree of impaired glucose affecting pregnancy leads to decreased maternal and fetal, immediate and long-term complications. Despite a wealth of basic and clinical research, there is no single approach to diagnose and treat diabetes during pregnancy. Desirable for our country is to seek uniformity of criteria in the screening and diagnosis of GDM and thus able to have our own casuistry. That is why the Venezuelan Society of Endocrinology and Metabolism has conceived the idea of a Manual of Gestational Diabetes, in collaboration with the Society of Obstetrics and Gynecology of Venezuela, the Venezuelan Society of Internal Medicine and specialists who make up the multidisciplinary care team high-risk pregnant formed with endocrinologists, internists, obstetricians, nutritionists, exercise physiologists and/or biologists exercise and neonatologist so that it can be used both at the primary level and areas of expertise. This manual will focus on prevention, screening, diagnosis, treatment and monitoring of Gestational Diabetes Mellitus and can serve as a basis for integrating health team to serve our patient.

Assessing the validity of asthma associations for eight candidate genes and age at diagnosis effects.

BACKGROUND: Before the advent of genome-wide association studies (GWAS), ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B), IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis. METHODOLOGY/PRINCIPAL FINDINGS: We systematically evaluated 286 common single nucleotide polymorphisms (SNPs) of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls). We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R. CONCLUSIONS/SIGNIFICANCE: Our results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.

No association between genetic ancestry and susceptibility to asthma or atopy in Canary Islanders.

Asthma is a complex respiratory disease characterized by chronic inflammation of airways and frequently associated with atopic symptoms. The population from the Canary Islands, which has resulted from a recent admixture of North African and Iberian populations, shows the highest prevalence of asthma and atopic symptoms among the Spanish populations. Although environmental particularities would account for the majority of such disparity, genetic ancestry might play a role in increasing the susceptibility of asthma or atopy, as have been demonstrated in other recently African-admixed populations. Here, we aimed to explore whether genetic ancestry was associated with asthma or related traits in the Canary Islanders. For that, a total of 734 DNA samples from unrelated individuals of the GOA study, self-reporting at least two generations of ancestors from the Canary Islands (391 asthmatics and 343 controls), were successfully genotyped for 83 ancestry informative markers (AIMs), which allowed to precisely distinguishing between North African and Iberian ancestries. No association was found between genetic ancestry and asthma or related traits after adjusting by demographic variables differing among compared groups. Similarly, none of the individual AIMs was associated with asthma when results were considered in the context of the multiple comparisons performed (0.005 ≤ p value ≤ 0.042; 0.221 ≤ q value ≤ 0.443). Our results suggest that if genetic ancestry were involved in the susceptibility to asthma or related traits among Canary Islanders, its effects would be modest. Larger studies, examining more genetic variants, would be needed to explore such possibility.

Circulating levels of high-sensitivity C-reactive protein and soluble markers of vascular endothelial cell activation in growth hormone-deficient adolescents.

BACKGROUND/AIMS: Significant endothelial dysfunction as determined by lower flow-mediated vasodilation of the brachial artery was recently reported by us in growth hormone-deficient (GHD) adolescents. The circulating concentrations of markers of vascular endothelial cell and platelet activation and their relationship to inflammatory markers have not been previously evaluated in this group of patients. OBJECTIVE: To assess the relationship between circulating levels of high-sensitivity C-reactive protein (CRP) and soluble markers of vascular endothelial cell activation in GHD adolescents. DESIGN/METHODS: Twenty-eight GHD children on GH treatment with a chronological age of 15.7 +/- 2.6 years and 16 untreated GHD adolescents with a chronological age of 16.6 +/- 3.3 years were studied. Concentrations of CRP, as an inflammatory marker, were measured in all patients and the association between CRP and the fasting soluble markers of vascular endothelial cell activation intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin levels was evaluated. Sixteen healthy adolescents with a mean chronological age of 15.1 +/- 2.2 years served as controls. RESULTS: CRP and P-selectin levels were significantly higher in untreated GHD adolescents than in treated GHD subjects or in healthy controls (p < 0.02), while VCAM-1 concentrations were increased in both untreated and treated GHD adolescents when compared to controls (p < 0.007). E-selectin and ICAM-1 levels were similar in all three groups. CRP was found to be associated with BMI (r: 0.62; p < 0.001), P-selectin (r: 0.43; p < 0.01), E-selectin (r: 0.27; p < 0.03), ICAM-1 (r: 0.23; p < 0.05) and VCAM-1 (r: 0.40; p < 0.001) concentrations in untreated GHD adolescents and with P-selectin (r: 0.88; p < 0.001) and E-selectin (r: 0.29; p < 0.01) in treated GHD subjects. A weak inverse association was observed in a subgroup of patients between brachial artery endothelium-dependent dilation and P-selectin (r: -0.56; p < 0.07). CONCLUSIONS: Low-grade inflammation as manifested by increased circulating levels of CRP seems to be associated with the early activation of vascular endothelial cells in GHD adolescents.

Equivalencia terapéutica entre atorvastatina amorfa (Atovarol) y atorvastatina cristalina tipo I (Lipitor) en el tratamiento de pacientes con hipercolesterolemia / Therapeutic equivalence of amorphous atorvastatin (atovarol) and type I crystalline atorvastatin (lipitor) in the treatment of hypercholesterolemic patients

Determinar la equivalencia terapéutica y la seguridad de la atorvastatina amorfa y la atorvastatina cristalina, utilizadas en la fabricación de Atovarol® y Lipitor ®, a la dosis de 10 mg/día en pacientes con hipercolesterolemia. Estudio clínico multicéntrico, prospectivo, comparativo, simple-ciego, distribuido al azar, de grupos paralelos. A los pacientes que cumplieron los criterios de inclusión les fue administrada atorvastatina amorfa (Atovarol®) o atorvastatina cristalina (Lipitor®) durante un mes. Se realizó una evaluación de laboratorio previa y otra al mes de tratamiento. Se incluyeron 43 pacientes, de los cuales uno fue retirado del estudio por efectos adversos. Los 42 pacientes que completaron el tratamiento con atorvastatina (20 pacientes en el grupo atorvastatina amorfa y 22 pacientes en el grupo atorvastatina cristalina) durante un período de 4 semanas presentaron reducciones estadísticamente significativas en los valores séricos de colesterol total, colesterol LDL y triglicéridos comparados con los valores basales en cada grupo de tratamiento. No se observaron diferencias estadísticamente significativas entre los dos grupos de tratamiento, ni previo ni posterior al tratamiento. Atorvastatina amorfa fue terapéuticamente equivalente a atorvastatina cristalina en la disminución de los valores de colesterol total, colesterol LDL y triglicéridos. El porcentaje de reducción de estos valores está dentro de los rangos reportado por otros estudios clínicos realizados con atorvastatina.

To determine the therapeutic equivalence and the safety of amoãphous and crystalline atorvastatin, used in the manufacture of Atovarol® and Lipitor®, at a dose of 10 mg/day in patients with hypercholesterolemia. Multicenter, prospective, comparative, somple-blind, randomized, parallel group clínical study. Amorphous atorvastatin (Atovarol®) or crystalline atorvastatin (Lipitor®) were administered for one month to patients that met the inclusion criteria. Laboratory evaluations were performed previously and one month after treatment. 43 patients were included, of which one was withdrawn from the study due to adverse effects. The 42 patients that completed atorvastatin treatment for a period of 4 weeks (20 patients in the amorphous atorvastatin and 22 patients in the crystalline atorvastatin group), presented statistically significant reductions in serum values of total cholesterol, cholesterol-LDL and triglycerides, as compared with pretreatment values in each group. Statistically significant differences were not observed between the groups, either before or after treatment. Amorphous atorvastatin is therapeutically equivalent to crystalline atorvastatin in the reduction of total cholesterol, cholesteron-LDL and triglyceride values. The percentage of reduction of these values is withim the range reported by other atorvastatin clinical studies.

Growth hormone deficiency, low levels of adiponectin, and unfavorable plasma lipid and lipoproteins.

OBJECTIVE: To examine the impact of adolescent growth hormone deficiency (GHD) on circulating adiponectin levels and the relation between adiponectin, fasting insulin, plasma lipid, and lipoprotein levels. STUDY DESIGN: Twelve children with GHD on GH treatment with a chronological age (CA) of 14.4 +/- 2.0 years and 12 untreated adolescents with GHD with a CA of 14.9 +/- 2.3 years were studied. Adiponectin concentrations were measured in all patients, and the association of adiponectin with fasting insulin, total, LDL, and HDL cholesterol, triglycerides, apolipoprotein A-1, and apolipoprotein B was evaluated. Twelve healthy adolescents served as control subjects. RESULTS: Adiponectin levels were significantly lower in untreated GHD adolescents than in treated GHD subjects or in control subjects (P < .008). Total and LDL cholesterol, triglycerides, and Apo B concentrations were increased in untreated GHD adolescents, whereas HDL cholesterol levels were similar in all three groups. Insulin levels were significantly increased in treated GHD adolescents when compared with control subjects (P < .05) but similar to those with untreated GHD. Adiponectin was found to be negatively associated with body mass index, waist-to-hip ratio, and with Apo B, total cholesterol, triglycerides, and LDL cholesterol concentrations in untreated GHD adolescents, whereas a positive correlation between adiponectin and HDL cholesterol was noted in both untreated and treated GHD subjects. Adiponectin correlated inversely with fasting insulin levels in untreated and treated GHD adolescents. CONCLUSIONS: GHD in adolescence is associated with low levels of adiponectin and with an unfavorable plasma lipid and lipoprotein profile. Our data suggest that treatment with GH may improve the abnormalities seen.

Peripheral inflammatory and fibrinolytic markers in adolescents with growth hormone deficiency: relation to postprandial dyslipidemia.

OBJECTIVE: To determine whether peripheral inflammatory and fibrinolytic markers are elevated in growth hormone-deficient (GHD) adolescents and associated with increased postprandial lipoproteins. STUDY DESIGN: Fifteen GHD children on GH treatment with a chronologic age of 12.7 +/- 2.5 years and 10 untreated GHD adolescents with a chronologic age of 13.0 +/- 2.6 years were studied. Triglycerides (TG), C-reactive protein (CRP), fibrinogen, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured in the fasting state and 4 hours after ingesting a high-fat meal; 15 healthy adolescents served as controls. RESULTS: Fasting and postprandial TG of untreated GHD children were higher than those in treated subjects and healthy controls. Fasting TNF-alpha, CRP, and fibrinogen concentrations of untreated GHD adolescents were higher than those in healthy controls, but similar to those of GH-treated GHD adolescents. Although fibrinogen levels increased after a high-fat meal in GHD adolescents, CRP, TNF-alpha, and IL-6 concentrations did not increase further. Fasting and postprandial TG of untreated GHD adolescents were positively associated with fasting and postprandial CRP, and with postprandial TNF-alpha and IL-6 concentrations. Fasting TG also correlated positively with fasting fibrinogen concentrations in untreated and treated GHD adolescents. CONCLUSIONS: The pronounced inflammatory response seen in GHD adolescents seems to be associated with the presence of elevated levels of fasting and postprandial TG, which may result in an increased susceptibility for premature atherosclerosis.

Cardiovascular risk of young growth-hormone-deficient adolescents. Differences in growth-hormone-treated and untreated patients.

OBJECTIVE: To determine whether postprandial lipids, coagulation factors and homocysteine levels are abnormal in young growth hormone (GH)-deficient (GHD) adolescents. METHODS: Fifteen GHD adolescents on GH replacement were studied. Ten untreated GHD adolescents and 15 healthy subjects served as controls. Fasting lipids, lipoprotein(a), fibrinogen, plasminogen activator inhibitor-1, homocysteine, folate and vitamin B12 levels were measured. Cholesterol and triglycerides were measured 4 h after a high fat meal. RESULTS: Fasting and postprandial triglycerides and homocysteine levels of untreated GHD patients were increased compared to those of GH-treated GHD subjects and healthy controls; fibrinogen concentrations were elevated in both treated and untreated adolescents. CONCLUSIONS: GHD adolescents present an abnormal fasting and postprandial lipid profile. In addition, the increased fibrinogen and homocysteine levels are suggestive of the accumulation of cardiovascular risk factors early on in life.

Undecanoato de testosterona en el síndrome de deficiencia parcial de andrógenos en el hombre que envejece (PADAM) / Testosterone undecanoate to androgens deficiency partial syndrome in the man that ages (PADAM)

La andropausia implica grandes cambios hormonales y pérdida de la capacidad fértil, pero no existe evidencia de pausa verdadera de secreción hormonal masculina. Estudios recientes revelan que existen deficiencia andrógenica en hombres que envejecen comparándolos con jóvenes, denominándose esto como PADAM (Deficiencia Androgénica Parcial en hombres que envejecen, por sus siglas en inglés). Determinar la eficacia del undecanoato de testosterona (UT), en hombres que envejecen. Proyecto abierto multicéntrico, no comparativo. 32 pacientes (50-70 años) recibieron 120 mg de UT (andriol) diariamente por 8 semanas. Se evaluaron síntomas climatéricos del hombre que envejece de acuerdo a escala y niveles de FSH, LH, PRL, TL, TT y PSA. Se observó mejoría en síntomas PADAM (p< 0.0001), incremento en PRL (p= 0.022) y disminución en niveles de FSH (p= 0.013) postratamiento. La TL incrementó pero sin significancia estadística (p =0.097). 17 pacientes incrementaron sus niveles de TL y 9 no, no hubo diferencia significativa entre grupos en relación a mejoría de los síntomas PADAM (p=0.533). No hubo variación en niveles de LH y de PSA. El medicamento es efectivo para el tratamiento de hombres con PADAM. El mejoramiento de los síntomas PADAM sin incremento de TL, puede explicarse por un aumento en la testosterona posible

Acné vulgar: tratamiento con espironolactona / Acne vulgaris: treatment with spironulaclone

Cortez, G.; Pacheco, A.; Naranjo, H. y Palacios, A. Acné Vulgar. Tratamiento con Estironolactona. Salus Militiae. 1987; 12:. Las propiedades antiandrogénicas de la Espironolactona fueron evaluadas, clínicamente en 12 mujeres, con acné persistente después de los 18 años de edad, que no mejoraban con los tratamientos comunes. La droga se administró a razón de 100 mgs. diarios, desde el 5 día de la mestruación por períodos de 15 días. Los resultados beneficiosos se obtuvieron entre los 2 y 3 meses de tratamiento y estuvieron caracterizados por una reducción significativa del acné. Por consiguiente consideramos que la espironolactona puede ser de valor en el tratamiento de casos seleccionados en esta entidad

Inseminación artificial con donante experience de 182 casos / Artificial insemination by donor experience of 182 cases

Se analizaron los resultados de nuestra experiencia en 12 años de IAD, en 158 parejas que solicitaron el procedimiento 182 veces. Se analizaron los criterios de selección de donantes, tipo de semen utilizado y manejo clínico de las parejas que se someten a la IAD. Del total de 182 casos, en 139 se completó el procedimiento y 43 están actualmente en tratamiento. Se logró embarazo en 80 casos (57,5%), de los cuales el 18,7% terminó en aborto. Hubo un 12,2% de embarazos gemelares por el uso frecuente de inductores de ovulación. De los 55 niños en los cuales se conoce la evolución, el 52,8% fue de sexo masculino y el 47,2% femenino, el peso promedio fue de 3.024 grs. Se analizan las causas que explican la baja incidencia de embarazos, entre las que se cuentan problemas de fertilidad en la esposa, abandono del tratamiento antes de completar los 6 ciclos y uso de semen congelado

Espironolactona en el tratamiento del acné / Spironolactone in the treatment of acne

Las propiedades antiandrogénicas de la Espironolactona fueron evaluadas, clínicamente en 12 mujeres, con acné persistente después de los 18 años de edad, que no mejoraban con los tratamientos usuales. La droga se administró a razón de 100 mgs. diarios, desde el 5o. día de la menstruación por períodos de 15 días. Los resultados beneficiosos se obtuvieron entre los 2 y 3 meses de tratamiento y estuvieron caracterizados por una reducción significativa del acné. Por consiguiente consideramos que la Espironolactona puede ser de valor en el tratamiento de casos seleccionados de esta entidad