Is the step-wise tiered approach for ERA of pharmaceuticals useful for the assessment of cancer therapeutic drugs present in marine environment?

Methotrexate (MTX) and tamoxifen (TMX) cancer therapeutic drugs have been detected within the aquatic environment. Nevertheless, MTX and TMX research is essentially bio-medically orientated, with few studies addressing the question of its toxicity in fresh water organisms, and none to its' effect in the marine environment. To the authors' knowledge, Environmental Risk Assessments (ERA) for pharmaceuticals has mainly been designed for freshwater and terrestrial environments (European Medicines Agency-EMEA guideline, 2006). Therefore, the purpose of this research was (1) to assess effect of MTX and TMX in marine organism using the EMEA guideline, (2) to develop an ERA methodology for marine environment, and (3) to evaluate the suitability of including a biomarker approach in Phase III. To reach these aims, a risk assessment of MTX and TMX was performed following EMEA guideline, including a 2-tier approach during Phase III, applying lysosomal membrane stability (LMS) as a screening biomarker in tier-1 and a battery of biochemical biomarkers in tier-2. Results from Phase II indicated that MTX was not toxic for bacteria, microalgae and sea urchin at the concentrations tested, thus no further assessment was required, while TMX indicated a possible risk. Therefore, Phase III was performed for only TMX. Ruditapes philippinarum were exposed during 14 days to TMX (0.1, 1, 10, 50 µg L(-1)). At the end of the experiment, clams exposed to environmental concentration indicated significant changes in LMS compared to the control (p<0.01); thus a second tier was applied. A significant induction of biomarkers (activity of Ethoxyresorufin O-deethylase [EROD], glutathione S-transferase [GST], glutathione peroxidase [GPX], and lipid peroxidation [LPO] levels) was observed in digestive gland tissues of clams compared with control (p<0.01). Finally, this study indicated that MTX was not toxic at an environmental concentration, whilst TMX was potentially toxic for marine biota. This study has shown the necessity to create specific guidelines in order to evaluate effects of pharmaceuticals in marine environment which includes sensitive endpoints. The inadequacy of current EMEA guideline to predict chemotherapy agents toxicity in Phase II was displayed whilst the usefulness of other tests were demonstrated. The 2-tier approach, applied in Phase III, appears to be suitable for an ERA of cancer therapeutic drugs in the marine environment.

Are standard tests sensitive enough to evaluate effects of human pharmaceuticals in aquatic biota? Facing changes in research approaches when performing risk assessment of drugs.

Nowadays, the presence of pharmaceutical products in aquatic environments is not only common, but is also of significant concern regarding the adverse effect they may produce to aquatic biota. In order to determine the adverse effects of caffeine (CAF), ibuprofen (IBU), carbamazepine (CBZ) and novobiocin (NOV), at environmental occurring concentrations, standardized endpoints applied in current guidelines were evaluated in four organisms including bioluminescence response in Vibrio fischeri, growth inhibition in Isochrysis galbana (marine water) and Pseudokirchneriella subcapitata (fresh water) and fertilization and embryo-larval development in Paracentrotus lividus. To reach this aim bioassays were implemented by exposing organisms to water spiked with drugs dissolved in DMSO (0.001% v/v). Risk characterization was performed, calculating the environmental impact of drugs by calculating environmental concentration and predicted no effect concentration ratio (MEC/PNEC). Results indicate that acute toxicity was found above environmental concentrations in the order of mg L(-1) for bacteria bioluminescence, microalgae growth inhibition and sea urchin fertilization. However, teratogenicity was observed on sea urchin after exposure to environmental concentrations of drugs at 0.00001 mg L(-1); at this concentration CBZ and IBU were found to reduce significantly the embryo-larval development compared to controls (p<0.01). The risk calculated for selected drugs suggested they are harmless for aquatic environment except when applying the embryo-larval development endpoint. Endpoints applied in this study showed the necessity of using more sensitive responses, when assessing risk of pharmaceuticals in aquatic environments, since endpoints applied in current guidelines may not be suitable.

Comparative performances of eggs and embryos of sea urchin (Paracentrotus lividus) in toxicity bioassays used for assessment of marine sediment quality.

The potential toxicity of sediments from various ports was assessed by means of two different liquid-phase toxicity bioassays (acute and chronic) with embryos and eggs of sea urchin Paracentrotus lividus. Performances of embryos and eggs of P. lividus in these bioassays were compared for their interchangeable applicability in integrated sediment quality assessment. The obtained endpoints (percentages of normally developed plutei and fertilized eggs) were linked to physical and chemical properties of sediments and demonstrated dependence on sediment contamination. The endpoints in the two bioassays were strongly correlated and generally exhibited similar tendency throughout the samples. Therein, embryos demonstrated higher sensitivity to elutriate exposure, compared to eggs. It was concluded that these tests could be used interchangeably for testing toxicity of marine sediments. Preferential use of any of the bioassays can be determined by the discriminatory capacity of the test or vulnerability consideration of the test subject to the surrounding conditions.

Improved sea-urchin embryo bioassay for in situ evaluation of dredged material.

Sediments usually contain many contaminants derived from human activities. In case of dredging activities, these sediment-bound contaminants arise following the excavation and remobilization of sediments. Previous studies have used different species of clam, crabs, lugworms, etc. for the evaluation of dredged material in situ, but there are not studies that use acute bioassays for these purposes. The sea-urchin embryo bioassay has been chosen to characterize biological effects in situ in two ports of the southwest of Spain, the Port of Huelva and the Port of Cadiz. The sea-urchin embryo bioassay has been adapted for in situ evaluation of seawater quality in coastal areas, however, they are necessary for further improvements to take into account differences of temperature between sites. This temperature variation is one of the principal reasons (other than pollution) of larval mortality and the slow down in the growth rate of the urchin. In the present study a bioassay was conducted in both field and laboratory conditions, in order to compare the effects in situ with the effects under controlled conditions of temperature, salinity and oxygen dissolved. Results showed a good correlation between samples obtained in situ and in the laboratory, but in the field the percentage of normal pluteus larvae is less than under laboratory conditions.

Anticoncepción de emergencia: perfil de las usuarias y características de la demanda / Emergency contraceptive: profile of the users and demand characteristics

OBJETIVOS. Describir el perfil de las usuarias de la anticoncepción de emergencia así como las características de la demanda de dicho medicamento. MATERIAL Y MÉTODOS. Estudio descriptivo, transversal, realizado en el ámbito de las urgencias de Atención Primaria en un medio urbano. Las participantes fueron las pacientes que solicitaron la píldora del día después en dichas urgencias. RESULTADOS. Características generales: 132 mujeres, cuya media de edad fue 22,9 años (rango 14-46 años); referido a sus características sociales, un 85,6% estaban solteras, un 12,1% casadas y el 2,3% separadas. En cuanto a su nivel de estudios, un 45,8% eran estudiantes, tenían estudios primarios un 18,2%, secundarios un 66,7% y superiores un 15,2%. Las razones de la demanda en un 75,8% se debió a un fallo en el método de barrera o preservativo, el 17,7% no usó ningún método anticonceptivo y un 6,5% lo atribuyó a otras razones. Los meses de mayor demanda fueron agosto, septiembre y diciembre; los sábados y domingos los días en que más se solicitó. La media de horas transcurridas desde el coito sin protección hasta la solicitud de este medicamento fueron 14,5. Hasta un 24,4% de las mujeres ya habían utilizado previamente la anticoncepción de emergencia. CONCLUSIÓN. El perfil de las usuarias de la anticoncepción de emergencia se ajusta al descrito en otros estudios. Existe un uso abusivo o mal uso de la píldora del día después y un bajo uso de los métodos de barrera

OBJECTIVE. Describe user profile of emergency contraceptions and the characteristics of demand for this drug. MATERIAL AND METHODS. Descriptive, cross-sectional study conducted in primary care emergency setting in urban area. Participants were patients who requested the day after pill in such emergencies. RESULTS. General characteristics: 132 women, whose mean age was 22.9 years (range 14-46 years). Social characteristics: 85.6% were single, 12.1% married and 2.3% separated. Regarding study level, 45.8% were students, 18.2% had primary studies, 66.7% secondary and 15.2% upper education. Reasons for the demand were due to failure of barrier method or condom in 75.8%, 17.7% did not use any contraceptive method and 6.5% attributed it to other reasons. The months of greatest demand were August, September and December. Saturday and Sunday were the days on which it was requested most. Mean hours since the intercourse without protection until request of the medication was 14.5. Up to 24.4% of the women had already previously used the emergency contraception. CONCLUSION. The user profile of emergency contraceptives adjusts to its description in other studies. There is an abusive or bad use of the day after pill and low use of barrier methods

Efectividad del consejo antitabaco en fumadores con espirometría normal y con espirometría obstructiva (EPOC) / Effectiveness of antitobacco advise in smokers with normal spirometry and obstructive spirometry (COPD)

Objetivos: El objetivo de este estudio es valorar la efectividad delconsejo médico antitabaco (CMA) en dos poblaciones de fumadores,una con espirometría normal (EN) y otra con espirometría obstructiva(EPOC).Pacientes y métodos: Estudio descriptivo transversal en el ámbitode Atención Primaria. Se realizó espirometría a fumadores mayoresde 40 años. A los que tenían EN se les daba consejo antitabaco durante3-5 minutos, mientras que a los del grupo EPOC se les dedicaban 8-10minutos. Al año se contactó telefónicamente y se les interrogó sobresu hábito tabáquico en ese momento, intentos de abandono y utilizaciónde otros métodos para intentar la abstinencia.Resultados: La muestra la formaban 217 sujetos (176 EN y 41EPOC) con edad media de 50,5 años. El 57,1% eran varones. Hubo 70intentos de abandono (53,7% del grupo EPOC vs 27,3% del grupo EN;χ2 = 10,59; p < 0,001), consiguiendo abandonarlo 19 del grupo EN y 13del grupo EPOC (10,8 vs 31,7%; OR 3,86; IC95% 1,7-8,6). En el análisismultivariante, el sexo masculino, el índice tabáquico, la realización deintentos de deshabituación previa y la alteración en la espirometría fueronlas variables asociadas a mayor frecuencia de abandono.Conclusiones: Los fumadores a los que se diagnostica de EPOCy se les da CMA durante 8-10 minutos abandonan significativamentemás el tabaco que aquellos otros con espirometría normal y un consejode menor duración. Creemos que, en Atención Primaria, debe potenciarsela realización de CMA

Foundation: Fighting against nicotine poisoning is a fundamentalobjective for a Sanitary System. The target of this survey is to assess theeffectiveness of smoking cessation counseling over two samples of smokers,one of them with a normal spirometry (NS) and the other, with apathologic spirometry (COPD).Patients and methodology: Transversal descriptive survey, carriedout within the primary attention area. Smoking patients over their 40’shad a spirometry made. Those patients who smoked and had a normalspirometry (NS group) were given anti-smoking counsel for 3-5 minutes,while those patients with an obstructive spirometry (COPD group),received counsel for 8-10 minutes. One year later, all of them were contactedon the phone and were asked about: their smoking habit in thatmoment, attempts to quit smoking and use of other resources or methodsto reach abstinence.Results: The sample was finally composed of 217 patients (176 NSand 41 COPD) with an average age of 50.5 years; 57.1% of them weremales. There were 70 attempts to quit smoking (53.7% within the COPDgroup vs. 27.3% within the NS group; χ2 = 10.59; p < 0.001); 19 patientsin the NS group and 13 in the COPD group succeeded in giving up smoking(10.8% vs. 31.7%; OR 3.86; IC95% 1.7–8.6 ). In the multi-variantanalysis, the variables which associate with a higher frequency in givingup smoking are: the masculine gender, the tobacco habit indicator, theprevious attempting to break oneself of the habit of smoking and the alterationin the spirometry.Conclussions: Smokers with a COPD diagnosis who receive medicalanti-smoking counsel for 8-10 minutes, give up smoking more significantlythan patients with a normal spirometry and a shorter medicalcounsel. We believe that within the primary attention frame,anti-smoking counsel should be promoted

Prevalencia y factores de riesgo de EPOCen fumadores y ex fumadores / Prevalence of Chronic Obstructive Pulmonary Disease and Risk Factors in Smokers and Ex-smokers

OBJETIVO: Estimar la prevalencia de enfermedad pulmonar obstructiva crónica (EPOC) en fumadores y ex fumadores mayores de 40 años y describir los factores asociados. MATERIAL Y MÉTODOS: Se realizó un estudio descriptivo transversal en el ámbito de la atención primaria. En él se incluyo a 444 personas de 40 años de edad o mayores que fumaban o habían fumado. A todos se les realizó una espirometría. Si la relación volumen espiratorio forzado en el primer segundo/porcentaje de la capacidad vital forzada era menor del 70 por ciento, se realizaba una prueba de broncodilatación y se repetía la espirometría a los 15-20 min tras dos inhalaciones de terbutalina (500 µg/dosis). Si la relación volumen espiratorio forzado en el primer segundo/porcentaje de la capacidad vital forzada seguía siendo inferior al 70 por ciento y el volumen espiratorio forzado en el primer segundo menor del 80 por ciento del teórico, se diagnosticaba EPOC. También se recogieron edad, sexo, consumo de tabaco, edad de inicio, índice tabáquico (paquetes/día × años de consumo) e intentos de abandono. RESULTADOS: La edad media de los pacientes era de 53,5 años, y un 65,8 por ciento eran varones. En el momento del realizar el estudio fumaban 248 sujetos (55,9 por ciento). La mediana de inicio del consumo resultó de 16,5 años, y la del índice tabáquido fue de 26,7. El 72,1 por ciento había realizado al menos un intento de abandono. Se diagnosticó de EPOC a 70 personas (24 ya conocidas), lo que supone una prevalencia del 16,4 por ciento (intervalo de confianza del 95 por ciento, 12,9-19,9). Un 10 por ciento eran casos graves. Tras el análisis multifactorial resultaron significativamente asociadas a EPOC la edad y el índice tabáquico. CONCLUSIONES: La prevalencia de EPOC hallada es ligeramente superior a la de otros estudios, si bien puede existir un sesgo en los resultados obtenidos al no haber podido establecer contacto con el 11,9 por ciento de la población objeto del estudio. Casi dos tercios de los casos eran desconocidos. Son claros factores de riesgo la edad y el consumo acumulado de tabaco (AU)

[Prevalence of chronic obstructive pulmonary disease and risk factors in smokers and ex-smokers]. / Prevalencia y factores de riesgo de EPOC en fumadores y ex fumadores.

OBJECTIVE: To estimate the prevalence of chronic obstructive pulmonary disease (COPD) in smokers and ex-smokers over 40 years of age and describe the associated risk factors. MATERIAL AND METHODS: A cross-sectional descriptive study at primary care level in which 444 current or ex-smokers 40 years of age or older were enrolled. Spirometry was performed with all subjects. If the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) was less than 70%, a bronchodilator test was performed and spirometry was repeated after 2 inhalations of terbutaline (500 g/dose). If the FEV1/FVC ratio continued to be less than 70% and FEV1 less than 80% of predicted, COPD was diagnosed. Age, sex, smoking, age smoking began, index of smoking history (packs per day x year) and attempts to quit smoking were also recorded. RESULTS: The patients' mean age was 53.5 years and 65.8% were men. At the time of the study, 248 subjects (55.9%) were current smokers. The median age smoking began was 16.5 years and the median pack-years index was 26.7. At least 1 attempt to quit had been made by 72.1% of the patients. COPD was diagnosed in 70 subjects (24 with the diagnosis previously established), representing a prevalence of 16.4% (95% confidence interval, 12.9-19.9). COPD was serious in 10%. A multifactorial analysis indicated that age and smoking history in pack-years were significantly associated with COPD. CONCLUSIONS: The prevalence of COPD in our study is slightly higher than in other studies, although selection bias may have affected our results given that we were unable to contact 11.9% of the population sample. Almost two thirds of cases had not been previously diagnosed. Two major risk factors are age and cumulative tobacco consumption.