The serotonin transporter promoter polymorphism (5-HTTLPR) affects the relation between antidepressant serum concentrations and effectiveness in major depression.

INTRODUCTION: Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations. METHODS: 49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly. RESULTS: Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L(A) allele carriers (r² = 34.3 %; p = 0.001), but not in S/L(G)-allele carriers (p = 0.31). DISCUSSION: In the group of L(A) allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials.

Immunomodulatory activity of IL-27 in human periapical lesions.

IL-27, a cytokine with pro-inflammatory and anti-inflammatory properties, is a new member of the IL-6/IL-12 family, whose function in periapical lesions is unknown. We hypothesized that the production of IL-27 and its effect depend upon the type of immune/inflammatory response and clinical presentation of periapical lesions. We tested this hypothesis by studying the expression and function of IL-27 in human periapical lesions, both in situ and in culture. Immunohistochemistry demonstrated the strongest expression of IL-27 by endothelial cells and mononuclear phagocytes. Its production by periapical lesion mononuclear cells (PL-MNC), especially in symptomatic lesions, was significantly higher compared with that in peripheral blood MNC and correlated with the frequency of CD14(+) and CD3(+) cells. Exogenous IL-27 stimulated Th1 and down-regulated Th17 cytokine production by PL-MNC from symptomatic lesions, but down-regulated Th1 and Th2 responses in asymptomatic lesions. These findings suggest that IL-27 is an immunomodulatory cytokine in periapical lesions, with complex biological effects.

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

BACKGROUND: Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O-desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N-desmethylvenlafaxine (NDV). OBJECTIVES: The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. METHOD: In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. RESULTS: There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1.8 and the 10th and 90th percentiles 0.3 and 5.2, respectively. Individuals with ODV/V ratios below 0.3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5.2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1.1 +/- 0.8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4.8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0.3 had more side effects (P < 0.005) and reduced serum concentrations of sodium (P < 0.05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. CONCLUSION: The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects.

Relationship between mirtazapine dose, plasma concentration, response, and side effects in clinical practice.

OBJECTIVE: The aim of this study was to evaluate the benefit of mirtazapine plasma concentration monitoring in a typical clinical setting. METHODS: The relationship between mirtazapine plasma concentration, dose, response, and side effects was studied in 65 inpatients presenting with a depressive episode according to ICD-10. Plasma concentrations, the 17-item Hamilton Depression Rating (HAMD), and the UKU side effect rating were performed weekly. A subgroup of 45 patients was evaluated for a concentration-response relationship. RESULTS: We found a low positive correlation between plasma concentration and dose. A low negative correlation between plasma concentration and increased duration of sleep was noted in the first week of mirtazapine treatment, but not during the entire observation time. Responders to mirtazapine treatment presented with higher plasma concentrations than non-responders, revealing a threshold concentration of 30 ng/mL. CONCLUSION: The mirtazapine dose is a weak predictor of mirtazapine plasma concentrations. Plasma concentration measurements may therefore be useful to adjust mirtazapine doses in non-responders with plasma concentrations below 30 ng/mL. Sedative effects appear temporary and require no plasma concentration control when standard doses are administered.

Therapeutic drug monitoring of tricyclic antidepressants: how does it work under clinical conditions?

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCA) is established in the treatment of depression to optimize outcome and safety. However, there are few reports on TDM under naturalistic clinical conditions. In the present study, we investigated a TDM group (TDM) and a randomly assigned parallel group without TDM (no-TDM) while on TCA treatment. Serum levels were analyzed in both cohorts, but feedback and dose recommendation were only provided for the TDM group. Serum levels of TCA were assessed by high-performance liquid chromatography (HPLC). The outcome was measured weekly using the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impressions Scale (CGI), and the UKU side-effect scale. 84 patients with depressive disorder according to DSM-IV were recruited in three centers (TDM, n = 43; no-TDM, n = 41; mean age 49.9 +/- 13.2 years, 63.1 % female). Patients were treated with either amitriptyline (n = 69) or doxepin (n = 15); the mean dosage at endpoint was 126 +/- 35 mg and 155 +/- 47 mg, respectively. The mean study duration was 21 +/- 8 days. Both groups improved according to HAMD (from 25.2 +/- 8.4 at baseline to 12.0 +/- 7.4 at endpoint) and CGI scores (68 % responders). Moderately severe or severe side effects occurred in 16 % of patients. Adequate dose adjustment was significantly higher in the TDM group (60 % vs. 46 %, p < 0.05); this led to a significantly higher rate of therapeutic serum levels in the TDM group (58 % vs. 44 %, p < 0.05). Direct effects of TDM were not found for effectiveness. Therapeutic TCA serum levels over weeks one to three, however, were associated with significantly better outcome at endpoint (p < 0.05) as measured with changes in the HAMD or CGI response rates from baseline to endpoint. Finally, considerable side effects occurred significantly more often when serum levels were above the therapeutic range (27 % vs. 11 %; p < 0.01). We conclude that treating depression with TCA can be optimized by early TDM, which is superior to clinical judgment on its own. Since the psychiatrists in charge were less than completely "compliant" to the recommendations provided together with serum levels, the effect could be more pronounced than this study shows. The results encourage further studies in order to optimize antidepressant pharmacotherapy when using TDM appropriately.

Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine.

INTRODUCTION: Melperone, a butyrophenone neuroleptic, is frequently used for its sleep-inducing properties. Despite its common use for more than 30 years, it is not yet characterized regarding its effects on cytochrome P450 s (CYPs). In an open pilot study, effects of melperone on the steady-state blood levels of venlafaxine, a recently introduced serotonin- and noradrenaline reuptake inhibiting antidepressant, were assessed. METHODS: The dose-corrected serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed retrospectively in a therapeutic drug-monitoring (TDM) database comprising 94 patients. In addition, three patients received venlafaxine and melperone concomitantly and the serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed before, during, and after melperone co-medication. The effect of melperone on CYP2D6 was further assessed in seven patients by means of the dextromethorphan O-demethylation, which serves as a CYP2D6 probe reaction. RESULTS: Patients treated concomitantly with venlafaxine and melperone had significantly higher (mean +/- SD) venlafaxine (3.27 +/- 2.9 vs. 0.97 +/- 0.99 ng/ml per mg/d; p < 0.05) and lower O-desmethylvenlafaxine serum concentrations (0.69 +/- 0.35 vs. 1.51 +/- 0.9 ng/ml per mg/d; p < 0.01) compared to patients without melperone comedication. In the three patients, venlafaxine serum concentrations increased, on average by 52 % during melperone co-medication, whereas O-desmethylvenlafaxine was decreased, on average by 29 %. Administration of melperone over three days elevated the ratio of dextromethorphan to dextrorphan from 0.044 +/- 0.04 to 0.09 +/- 0.083 (p < 0.05). DISCUSSION: This study pointed to an inhibitory effect of melperone on the O-demethylation of venlafaxine. Because the O-demethylation of venlafaxine is almost exclusively catalyzed by CYP2D6 it is concluded that melperone is an inhibitor of CYP2D6. The hypothesis was further corroborated by the inhibitory effect of melperone on the dextromethorphan O-demethylation.

Programa de atención de embarazadas adolescentes en el hospital de Peñaflor: informe preliminar / Program of medical attention for adolescent pregnant women at Peñaflor hospital: preliminary report

En el contexto de un programa diseñado a nivel local durante 1990, se efectuaron Talleres de Atención de Embarazadas Adolescentes, de las cuales, a fines de año, 53 habían tenido su parto. A través de diversas encuestas se midieron parámetros socio-culturales y de apoyo afectivo. Se observó que el grupo de estudio evidenció partos y pesos de nacimiento comparativamente mejores ue los observados en la población general de parturientas del Servicio de Salud Metropolitano Occidente y del propio Hospital de Peñaflor. La situación detectada coincide con importantes experiencias extranjeras en las que hay intervención activa en detectar los riesgos de parto prematuro y en dar apoyo a la embarazada en diversos aspectos que se analizan en detalle y que van desde el área afectiva hasta la ayuda material. En nuestras pacientes hemos observado una mejor conducta en el preparto, parto y puerperio, pues se relacionan mejor con el Equipo de Salud. Se notan menos ansiosas y toleran mejor los procedimientos. Este informe preliminar se proyectará a futuro, hacia la medición de otros factores como lactancia materna, evolución nutricional, desarrollo psicomotor, morbilidad, rendimiento escolar, etc. en los grupos de trabajo de madres adolescentes

Estudio de las vías aéreas y senos paranasales mediante telerradiografía de perfil en niños / Study of the paranasal sinuses and superior airways by teleradiography of the profile in children

El trabajo destaca la importancia de la telerradiografía lateral de cráneo y realiza un análisis de las vías aéreas superiores y de los senos paranasales mediante un sencillo trazado cefalométrico en papel de transparencia colocado sobre la radiografía. El estudio es aplicado en un grupo de 38 niños que se encontraban en tratamiento dental, los que, para realizar las comparaciones, fueron clasificados según el tipo de oclusión de Angle. Se observó que el grupo de niños que presentaba una maloclusión del tipo distoclusión tenían en promedio un mayor grado de obstrucción de las vías aéreas respecto del grupo con neutroclusión y también que en ellos el área del seno maxilar era levemente mayor. No se pudieron establecer otras diferencias entre los grupos estudiados

Ensayo terapeutico con levamisole en bronquitis obstructiva recidivante. / Therapeutic trial with levamisole in recurrent obstructive bronchitis

En este articulo informamos de los resultados obtenidos en el tratamiento de 48 ninos portadores de Bronquitis Obstructiva Recidivante en un ensayo efectuado con el producto Levamisole en la dosis recomendada en la literatura de 2,5mg x kg de peso por dia, dividido en dos tomas diarias, dos dias seguidos en la semana durante seis meses de tratamiento. Los buenos resultados obtenidos, similares a los conseguidos con otros procedimientos, se comparan con la situacion inversa ocurrida en ninos no tratados. Se mide el posible dano de frenacion hematologica a nivel medular que no fue detectado en la serie estudiada. Se analizan los diversos mecanismos de accion invocados en la literatura y se senalan otros efectos adversos descritos tambien en la literatura revisada