Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI)

ABSTRACT: BACKGROUND: Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2--3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment. METHODS: Term newborns (gestational age >= 36 weeks and birth weight >= 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests. DISCUSSION: This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns. Trial registration Current Controlled Trials ISRCTN62175998; ClinicalTrials.gov Identifier NCT01241019; EudraCT Number 2010-018627-25.     

Transient MRI abnormalities in a case of occipital lobe epilepsy with favorable outcome.

We describe the case of a 13-year-old boy, in good health, with transient occipital MRI abnormalities just after one generalized seizure and the appearance of macropsia. The EEG showed a 3-5 Hz sub-continuous left occipital activity, with sporadic sharp waves. Macropsia disappeared in 2 years. This case may suggest that the presence of transient MRI abnormalities does not exclude a favorable prognosis.     

Preliminary report on postmenopausal endometrial hyperplasia treatment with Danazol: histological and endocrinological aspects

The synthetic steroid Danazol is commonly used in the hormonal treatment of endometriosis; however, little is known about its effects on human endometrium. This study was performed to verify the efficacy of Danazol on the treatment of endometrial hyperplasia in postmenopausal patients. Ten patients with histologically proven endometrial hyperplasia were treated with Danazol at a dosage of 600 mg/day for 30 days. The E1S and E1 plasma levels were also determined before and at the end of therapy. In all patients the regression of endometrial hyperplasia was observed in the endometrial biopsy specimens obtained after the treatment. Furthermore, the increased E1S/E1 ratio as compared to the basal values suggests an impairment of the peripheral sulfatase activity. The inhibition of the conversion of E1S to active unconjugated estrogens appears to be one of the mechanisms by which Danazol may act on the endometrium.     

Combination of statins and hormone replacement therapy in postmenopausal women is associated with increased bone mineral density.

Recent studies have shown that statins might be potent inhibitors of bone resorption and osteoclast number, and there is evidence for their bone anabolic effects. Statin treatment seems to protect against non-pathological fractures in older women. However, contradictory findings have been obtained. In this retrospective study we found that postmenopausal women on statins and hormone replacement therapy (HRT) showed higher bone mineral density than women on HRT alone. This evidence provides further confirmation of the effect of statins on bone turnover and shows that the combination of HRT and statins reduces the risk of bone fracture by virtue of the antiresorptive effect of HRT and the anabolic and antiresorptive effects of statins.     

Delivery of doxorubicin across the blood–brain barrier by ondansetron pretreatment: a study in vitro and in vivo

Doxorubicin (Dox) has got a limited efficacy in the treatment of central nervous system tumors because of its poor penetration through blood–brain barrier mediated by MDR efflux transporters. We investigated the possibility that ondansetron (Ond) enhances Dox cytotoxicity in cell lines interfering with P-glycoprotein and increases Dox concentration in rat brain tissues.     

In silico mining of microsatellite markers for the Red Palm Weevil as contribution to its invasion management

The Red Palm Weevil is an invasive pest causing huge damages by attacking several palm species of the family Arecaeae. One of the most important challenges of conservation biology for the near future is the management of biological invasions and their effects. In this study we used 454 pyrosequencing and in silico mining to identify novel microsatellite markers for investigating the reproductive biology and the invasion dynamics, crucial to plan the control strategies against the pest. We report 14 variable microsatellites out of 37 screened for levels of polymorphism. Allele number per locus ranged between 2 and 15 and H_o from 0.04 to 0.86.