Effectiveness of risk minimisation measures for valproate: a drug utilisation study in Europe, analysis of data from Spain. / Eficacia de las medidas de minimización de riesgos del ácido valproico: estudio de utilización del fármaco en Europa, análisis de datos de España.

INTRODUCTION: Risk minimisation measures for valproate were implemented in Spain in 2015. OBJECTIVE: The objective of this study is to assess the effectiveness of valproate risk minimisation measures in Spain intended to decrease the use of valproate as a first-line therapy, and to evaluate the prescribing patterns of valproate in women, including women of childbearing potential, in the pre- and post-implementation risk minimisation measures periods. MATERIALS AND METHODS: The prescribing patterns of valproate in females and women of childbearing potential before and after risk minimisation measures implementation were examined using the longitudinal patient data database, which includes patient information from two panels: primary care physicians and neurologists/psychiatrists. Primary endpoint was the proportion of initial valproate prescriptions with at least one medication related to the valproate indications before the valproate initiation date. RESULTS: The proportion of incident valproate prescriptions with previous use of medication related to valproate indications was 78.0% (95% CI, 73.9%; 81.5%), and 78.2% (74.5%; 81.4%) in the main pre-and post-implementation periods in the primary care physician panel. The corresponding figures for women of childbearing potential were 79.6% (73.6%; 84.5%) and 75.5% (69.7%; 80.6%), respectively. The incidence rate of pregnancies exposed to valproate (per 1,000 person-years) in women of childbearing potential decreased from 17.4 the entire pre-implementation to 8.5 in the entire post-implementation periods. CONCLUSION: After the implementation of risk minimisation measures for valproate in Spain, no meaningful change in prescribing was observed regarding the proportion of valproate initiations preceded by prior medication related to valproate indications. The preventative measures recommended for use of valproate in women of childbearing potential should be considered.

TITLE: Eficacia de las medidas de minimización de riesgos del ácido valproico: estudio de utilización del fármaco en Europa, análisis de datos de España.Introducción. En 2015 se aplicaron en España distintas medidas para la minimización de los riesgos (MMR) del ácido valproico. Objetivo. El objetivo de este estudio es evaluar la eficacia de las MMR del ácido valproico en España, con el fin de reducir el uso de ácido valproico como terapia de primera línea y evaluar los patrones de prescripción de ácido valproico en las mujeres, incluidas las mujeres en edad fértil (MEF), en los períodos previos y posteriores a la implementación de las MMR. Materiales y métodos. Los patrones de prescripción del ácido valproico en mujeres y MEF antes y después de la implementación de las MMR se examinaron utilizando la base de datos longitudinales de pacientes (longitudinal patient data, LPD por sus siglas en inglés), que incluye información de pacientes de dos paneles: médicos de atención primaria (MAP) y neurólogos/psiquiatras. El criterio principal de valoración fue la proporción de prescripciones iniciales de ácido valproico con al menos un medicamento relacionado con indicaciones de ácido valproico antes de la fecha de inicio del ácido valproico. Resultados. La proporción de prescripciones de ácido valproico secundarias con uso previo de medicamentos relacionados con indicaciones de ácido valproico fue del 78% ­intervalo de confianza (IC) al 95%: 73,9-81,5%­ y del 78,2% (IC al 95%: 74,5-81,4%) en los períodos principales previo y posterior a la implementación en el panel de MAP. Las cifras correspondientes a MEF fueron del 79,6% (IC al 95%: 73,6-84,5%) y del 75,5% (IC al 95%: 69,7-80,6%), respectivamente. La tasa de incidencia de embarazos expuestos al ácido valproico (por 1.000 personas-años) en MEF disminuyó de 17,4 en el período completo previo a la implementación a 8,5 en el período completo posterior a la implementación. Conclusión. Tras la implementación de las MMR del ácido valproico en España no se observó ningún cambio significativo en las prescripciones respecto a la proporción de iniciaciones de ácido valproico precedidas por medicación previa relacionada con indicaciones de ácido valproico. Se deben tener en cuenta las medidas preventivas recomendadas para el uso de ácido valproico en MEF.

The reduced glutathione and S-nitrosothiols levels in acute phase of experimental demyelination--pathophysiological approach and possible clinical relevancy.

UNLABELLED: Multiple sclerosis (MS) is characterized by inflammatory process associated with nitric oxide (NO) and the related species production in CNS, which can nitrosylate protein thiols and modulate their structure and functions, also reducing the CNS content of redox active compounds, such as glutathione (GSH). We have evaluated the relationships between S-nitrosothiols (RSNO) and GSH in the experimental model of MS - experimental autoimmune encephalomyelitis (EAE), during the treatment with inducible NO synthase inhibitor - aminoguanidine (AG) and thiol donor molecule - N-acetyl-L-cysteine (NAC). MATERIAL AND METHODS: EAE was induced by myelin basic protein, dissolved in phosphate-buffered saline (PBS), emulsified in the complete Freund's adjuvant (CFA) followed by injections of Pertussis toxin. Animals assigned to the control (PBS), EAE, CFA, EAE+AG, AG, EAE+NAC and NAC groups were scored daily for the clinical signs of EAE. RSNO and GSH were evaluated in whole encephalitic mass and cerebellum. RESULTS: RSNO concentration was increased in EAE-untreated animals compared to the AG and NAC-treated EAE animals (p<0.05). Also, during the treatment with AG and NAC, GSH concentration was increased compared to the untreated animals (p<0.05). The EAE clinical signs were reduced in EAE-treated animals compared to the other groups (p<0.05). CONCLUSION: The findings of our work suggest a potential role of RSNO and GSH in early clinical presentation of experimental MS, that might be also useful as predictive parameters for MS treatment directed to increased GSH and thiol pool in CNS.

Rare metastases of pancreatic tail carcinoma in female genital organs.

A case is presented of pancreatic tail carcinoma metastasizing to the uterus, right ovary and right sacrouterine ligament 2.5 years after the primary tumor had been detected and treated. During explorative laparotomy, performed after 3D color Doppler ultrasonographic visualization of a suspected finding in the right adnexal region, metastatic deposits in the uterus, right ovary, right sacrouterine ligament and right ureter originating from the primary adenocarcinoma of the tail of the pancreas were detected and surgically removed.

Rare metastases of carcinoma of uterine cervix.

This paper describes a case of cancer of the uterine cervix metastasizing in the spleen two years after the primary carcinoma was diagnosed and treated. After detailed diagnostics, the patient was subjected to surgery. Histopathological examination after splenectomy confirmed a very rare case - presence of metastases of planocellular carcinoma of the uterine cervix. Over the last ten years, references cite isolated cases of metastases of adenocarcinoma of the colon, stomach and breast in the spleen as well as lung carcinoma and malignant skin melanoma. Until now cases of uterine cervix carcinoma metastasizing to the spleen have been published as micrometastases detected in autopsy material.

Spermidine influence on the nitric oxide synthase and arginase activity relationship during experimentally induced seizures.

Nitric oxide (NO), a potential candidate for a modulator of convulsive activity, is a mediator in several pathological events in the central nervous system. The polyamines, spermidine (Spd) and spermine, are neuromodulators influencing the metabolism of L-arginine and NO production. Here we examined the effects of Spd on NO production and arginase activity during convulsions induced by pentylenetetrazol (PTZ). Male Wistar rats were allocated into four experimental groups of 8 animals each and received the following treatments: I (control)--saline, intraperitoneally (i.p.); II (PTZ)--seizures induced by pentylenetetrazol (100mg/kg bw i.p); III (Spd)--Spd (1 mg/kg bw i.p.) 50 min before PTZ application; IV (Mid)--antiepileptic Midazolam (100 mg/kg bw) 45 min before PTZ. In brain cortex, striatum, hippocampus, cerebellum, and brainstem homogenates, nitrite + nitrate levels and arginase activity were determined. Spermidine showed proepileptic effects. shortening seizure latency and inducing a more profound increase of NO production than PTZ in all brain structures. PTZ reduced arginase activity, whereas Spd pretreatment increased enzyme activity, with the most profound effects in cerebellum and brainstem. The results point out the importance of polyamine and arginine metabolism in the brain during seizures, suggesting a regulatory role for polyamines and arginase in NO production.