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.

COMPLEMENTARY TECHNIQUES OF PERCUTANEOUS CLOSURE OF DUCTUS ARTERIOSUS USING DETACHABLE COOK COILS AND AMPLATZER DEVICES.

BACKGROUND: Patent Ductus Arteriosus (PDA) is a commoncardiac malformation whose treatment locally has been surgical ligation via a lateral thoracotomy. Device closure of the ductus was first performed at the Mater hospital in 1999 in a ten year old male using a five millilitre detachable cook coil. In 2000 the Amplatzer device was introduced to close larger ducts. Subsequently these devices have been used interchangeably to close both small and large ducts. We report this single centre experience of percutaneous PDA closure in a resource-limited setting; utilising the two techniques. OBJECTIVE: To describe our experience of trans-catheter closure of small and large ducts using either the detachable Cook coils or the Amplatzer occluders at the Mater Hospital Nairobi. DESIGN: A descriptive retrospective cohort study. Setting: The Mater Hospital, Nairobi, Kenya. SUBJECTS: Patients with clinical and echo-cardiographic features of patent ductus arteriosus who underwent cardiac catheterisation and angiography followed by device embolisation of the ductus. RESULTS: From April 1999 to October 2009 a total of ninety eight subjects were recruited. into the study. Sixty nine (70%) of these subjects had the ducts closed using the Amplatzer devices, while twenty nine (30%) were embolised using the cook detachable coils. Three of the subjects in the coil group had the ducts embolised using the double technique while the rest were embolised using single coils. Various coil sizes four to eight millimetres were used in patients with small to medium ducts (two to seven millimetres) whereas the Amplatzer duct occluder was successfully used in all the duct sizes. The Amplatzer atrial septal occluder device was used to close very large ducts in two of the patients. The overall success rate was 93.1%, but the coil group had higher failure rate of 6.9% compared to the Amplatzer group of 3%. One patient in the Amplatzer group had a late embolisation requiring surgical retrieval at one month post occlusion. There were no mortalities. CONCLUSION: Transcatheter device occlusion of PDA is a safe and alternative to

LEFT VENTRICULAR INFLOW OBSTRUCTION BY GIANT ATRIAL SEPTAL ANEURYSM IN A NEONATE WITH HYPOPLASTIC RIGHT HEART SYNDROME: CASE REPORT.

Atrial septal aneurysm remains a rare congenital cardiac malformation. In the neonatal age group it can occur as an isolated cardiac malformation or in association with complex hypoplastic cardiac malformations of the right and left heart. In the adult population most aneurysms have been described in association with stroke. Baby H.N delivered on 10/05/2008 by C/S, was cyanosed at birth with systemic desaturation. Chest X-ray showed oligaemic lung fields while two dimensional echocardiograms showed tricuspid atresia with hypoplastic right ventricle, large secundum atrial septal defect, and highly mobile gigantic aneurysms of the atrial septum obstructing the inflow of the mitral valve and entering the left ventricle in diastole. Surgical intervention was not possible and child died on second day.

Suicide in cancer patients in South East England from 1996 to 2005: a population-based study.

BACKGROUND: Studies from around the world have shown that suicide risk is increased in cancer patients, but no previous detailed analysis has been carried out in England. METHODS: We calculated standardised mortality ratios (SMRs) for suicide in 206,129 men and 211,443 women diagnosed with cancer in South East England between 1996 and 2005, relative to suicide rates in the general population. RESULTS: We found a significantly increased risk of suicide in men (SMR 1.45, 95% confidence interval (CI) 1.20-1.73) and a moderately increased risk in women (SMR 1.19, 95% CI 0.88-1.57). In both sexes, relative risk of suicide was greatest in the first year after cancer diagnosis (SMR for men 2.42, 95% CI 1.84-3.13; SMR for women 1.44, 95% CI 0.82-2.33), and was also greater in individuals diagnosed with types of cancer with high fatality (SMR for men 2.67, 95% CI 1.71-3.97; SMR for women 2.17, 95% CI 0.80-4.73). CONCLUSION: There is a critical period immediately after the diagnosis of cancer during which the excess risk of suicide is particularly high. Carers need to be aware of the importance of attending to both the physical and emotional needs of cancer patients and cancer survivors.

The future burden of cancer in England: incidence and numbers of new patients in 2020.

We estimated the future cancer incidence rates and the future numbers of cancer cases in England up to 2020 using cancer registration data for 1974-2003, and the official population projections from ONS up to 2023. Data were analysed using an age-period-cohort model as developed for the Nordic countries. We predict that for all cancers combined there will be relatively little change in age-standardised incidence rates in 2020. The number of new cancer cases per year in England is, however, predicted to increase by 33%, from 224,000 in 2001 to 299,000 cases in 2020. This increase is mainly due to the anticipated effects of population growth and ageing; cancer patients in 2020 will be older than today's cancer population.

Sildenafil in management of persistent pulmonary hypertension of the newborn: report of two cases.

Persistent pulmonary hypertension of the newborn (PPHN) was described in 1969 by Gersomy and co-workers as persistent foetal circulation. Supra - systemic pulmonary artery pressures result in right to left shunting of blood through the ductus arteriosus and/or foramen ovale. This results from failure of the normal adaptation to extra uterine life of the foetal heart/lung system. The incidence is estimated at about 0.1-0.2% of live born infants, majority being term or post term. There is no race or gender related predisposition. Management was always difficult before the advent of nitric oxide (and now sildenafil). We report two newborn infants born at The Mater Hospital with perinatal asphyxia resulting inpersistent pulmonary hypertension that were successfully managed with sildenafil.