Long-term efficacy and safety of adjunctive extended-release oxcarbazepine (Oxtellar XR® ) in adults with partial-onset seizures.

OBJECTIVE: To evaluate long-term outcomes of adjunctive therapy with SPN-804 (Oxtellar XR® , Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), in adults with refractory partial-onset seizures. METHODS: After completing a 16-week double-blind, placebo-controlled trial of SPN-804 at fixed dosages (1200 or 2400 mg QD), patients entering this open-label extension study were converted in blinded fashion to 1200 mg QD SPN-804 as a target starting dose for long-term treatment. Patients were followed for 1 year, during which SPN-804 dosages could be adjusted up to 2400 mg/day according to clinical response. RESULTS: Of 214 patients, 84% completed 1-year open-label treatment. Median maintenance SPN-804 dosage was 1200 mg; <10% of patients required 2400 mg. Median 28-day seizure frequency reduction from baseline was 59%; seizure frequency was reduced ≥50% in 58% of patients; 11% were seizure free ≥6 months; and 5% were seizure free ≥1 year. SPN-804 was discontinued due to adverse events in 5% (n = 10). Incidences of each of the most common adverse events (dizziness, headache, diplopia, nausea, vomiting, balance disorder, blurred vision) were ≤15% during 1-year follow-up and occurred most frequently in patients previously naïve to SPN-804. No new safety signals, no clinically significant changes in health status, and no deaths attributable to SPN-804 were observed. CONCLUSION: SPN-804 administered once daily for 1 year was effective as adjunctive therapy in improving seizure control and maintaining therapeutic response in adults with refractory partial-onset seizures. With dosage flexibility, SPN-804 was well tolerated.

Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR™) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of once-daily 1200 mg and 2400 mg SPN-804 (Oxtellar XR™, Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization. METHODS: The Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double-blind, parallel-group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week double-blind treatment period in the intent-to-treat (ITT) population with analyzable seizure data. Other efficacy analyses included proportion of patients with ≥ 50% seizure reduction, proportion of patients seizure free, and the relationship between clinical response and plasma concentration. RESULTS: Median percent reduction was -28.7% for placebo, -38.2% (P = 0.08 vs placebo) for once-daily SPN-804 1200 mg, and -42.9% (P = 0.003) for SPN-804 2400 mg. Responder rates were 28.1%, 36.1% (P = 0.08), and 40.7% (P = 0.02); 16-week seizure-free rates in a pragmatic ITT analysis were 3.3%, 4.9% (P = 0.59), and 11.4% (P = 0.008), respectively. When data were analyzed separately for study site clusters, a post hoc analysis demonstrated that both SPN-804 dosages were significantly superior to placebo in median percent seizure reduction (placebo: -13.3%; 1200 mg: -34.5%, P = 0.02; 2400 mg: -52.7%, P = 0.006) in the North American study site cluster. A concentration-response analysis also supported a clinically meaningful effect for 1200 mg. Adverse event types reflected the drug's established profile. Adverse event frequency was consistent with a pharmacokinetic profile in which SPN-804 produces lower peak plasma concentrations vs immediate-release OXC. Once-daily dosing was not associated with any new safety signals. CONCLUSIONS: Adjunctive once-daily SPN-804 improved seizure control in patients with inadequately controlled partial-onset seizures. Adverse event occurrence and discontinuations due to adverse events suggest improved tolerability vs previously published data with immediate-release OXC.

Chemical speciation studies on DU contaminated soils using flow field flow fractionation linked to inductively coupled plasma mass spectrometry (FlFFF-ICP-MS).

Flow field flow fractionation (FlFFF) in combination with inductively coupled plasma mass spectrometry (ICP-MS) was used to study the chemical speciation of U and trace metals in depleted uranium (DU) contaminated soils. A chemical extraction procedure using sodium pyrophosphate, followed by isolation of humic and fulvic substances was applied to two dissimilar DU contaminated sample types (a sandy soil and a clay-rich soil), in addition to a control soil. The sodium pyrophosphate fractions of the firing range soils (Eskmeals and Kirkcudbright) were found to contain over 50% of the total U (measured after aqua regia digestion), compared to approximately 10% for the control soil. This implies that the soils from the contaminated sites contained a large proportion of the U within more easily mobile soil fractions. Humic and fulvic acid fractions each gave characteristic peak maxima for analytes of interest (Mn, Fe, Cu, Zn, Pb and U), with the fulvic acid fraction eluting at a smaller diameter (approximately 2.1 nm on average) than the humic fraction (approximately 2.4 nm on average). DU in the fulvic acid fraction gave a bimodal peak, not apparent for other trace elements investigated, including natural U. This implies that DU interacts with the fulvic acid fraction in a different way to all other elements studied.

Complex hydrological controls on wet dune slacks: the importance of local variability.

Dune slacks are a species-rich habitat controlled largely by water chemistry and fluctuations in groundwater. Changes in water chemistry and water table level were analysed in 8 piezometers and 15 ephemeral surface water locations at a large UK dune system over a 12-month period. Total nitrogen concentrations in groundwater varied from 0.27-8.21 mg N L(-1), where dissolved organic nitrogen was dominant at the low nitrogen locations and nitrate was dominant at the high nitrogen locations. Principal components analysis of the water chemistry suggests at least four chemically distinct groundwater signatures. Water levels showed strong temporal heterogeneity. Comparisons of water levels with antecedent rainfall identified a component of year-round groundwater feed and differing seasonal responses overlain by a complex series of lags. In summer, there were lags of four, six and seven months with an additional rapid peaky response to daily rainfall with a one-day lag. In winter, water levels were strongly influenced by exogenous groundwater supply, but again exhibited multiple lags. This study shows that local variations in water chemistry and in hydrological regime can be more complicated than previously thought, with clear implications for optimum management of these high priority habitats for conservation.

Effects of increased deposition of atmospheric nitrogen on an upland moor: leaching of N species and soil solution chemistry.

This study was designed to investigate the leaching response of an upland moorland to long-term (10 yr) ammonium nitrate additions of 40, 80 and 120 kg N ha(-1) yr(-1) and to relate this response to other indications of potential system damage, such as acidification and cation displacement. Results showed increases in nitrate leaching only in response to high rates of N input, in excess of 96 and 136 kg total N input ha(-1) yr(-1) for the organic Oh horizon and mineral Eag horizon, respectively. Individual N additions did not alter ammonium leaching from either horizon and ammonium was completely retained by the mineral horizon. Leaching of dissolved organic nitrogen (DON) from the Oh horizon was increased by the addition of 40 kg N ha(-1) yr(-1), but in spite of increases, retention of total dissolved nitrogen reached a maximum of 92% and 95% of 80 kg added N ha(-1) yr(-1) in the Oh and Eag horizons, respectively. Calcium concentrations and calcium/aluminium ratios were decreased in the Eag horizon solution with significant acidification mainly in the Oh horizon leachate. Nitrate leaching is currently regarded as an early indication of N saturation in forest systems. Litter C:N ratios were significantly lowered but values remained above a threshold predicted to increase leaching of N in forests.

Changes in vegetation and soil characteristics in coastal sand dunes along a gradient of atmospheric nitrogen deposition.

A field survey was conducted to detect signals of atmospheric nitrogen (N) in 11 dune systems along a nitrogen deposition gradient in the United Kingdom. In the mobile and semi-fixed dunes, above-ground biomass was positively related to N inputs. This increase was largely due to increased height and cover of Ammophila arenaria. In the long term, this increased biomass may lead to increased organic matter accumulation and consequently accelerated soil development. In the fixed dunes, above ground biomass also showed a positive relationship with N inputs as did soil C : N ratio while soil available N was negatively related to N inputs. Plant species richness was negatively related to N inputs. In the dune slacks, while soil and bulk vegetation parameters showed no relationship with N inputs, cover of Carex arenaria and Hypochaeris radicata increased. Site mean Ellenberg N numbers showed no relationship with N deposition either within habitats or across the whole dataset. Neither abundance-weighting nor inclusion of the Siebel numbers for bryophytes improved the relationship. The survey reveals that the relationships of soil and vegetation with atmospheric N deposition vary between sand dune habitats but, despite this variability, clear correlations with N inputs exist. While this survey cannot establish causality, on the basis of the relationships observed we suggest a critical load range of 10 - 20 kg N ha(-1) yr(-1) for coastal sand dunes in the UK.

Organic composition of C/1999 S4 (LINEAR): a comet formed near Jupiter?

In the current paradigm, Oort cloud comets formed in the giant planets' region of the solar nebula, where temperatures and other conditions varied greatly. The measured compositions of four such comets (Halley, Hyakutake, Hale-Bopp, and Lee) are consistent with formation from interstellar ices in the cold nebular region beyond Uranus. The composition of comet C/1999 S4 (LINEAR) differs greatly, which suggests that its ices condensed from processed nebular gas, probably in the Jupiter-Saturn region. Its unusual organic composition may require reevaluation of the prebiotic organic material delivered to the young Earth by comets.

Isolation and identification of the cyanotoxin cylindrospermopsin and deoxy-cylindrospermopsin from a Thailand strain of Cylindrospermopsis raciborskii (Cyanobacteria).

A strain of Cylindrospermopsis (Cyanobacteria) isolated from a fishpond in Thailand was examined for its taxonomy based upon morphology and 16S rRNA gene sequence. It was also examined for production of the hepatotoxic cyanotoxin called cylindrospermopsin (CYN) and deoxycylindrospermopsin (deoxy-CYN). The strain (CY-Thai) was identified as C. raciborskii (Woloszynska) Seenaya and Subba Raju based upon morphological examination which was confirmed by 16S rRNA gene sequences and phylogenetic comparisons based upon its 16S rRNA gene. The alkaloid heptatotoxin CYN was confirmed using mouse bioassay, HPLC and HPLC-MS/MS while deoxy-CYN was confirmed using HPLC-MS/MS. The mouse bioassay gave a minimum lethal dose at 250mg dry weight cells/kg body weight within 24h and 125mg/kg at 72h, with signs of poisoning the same as in literature reports for CYN. HPLC chromatographic comparison of the CY-Thai toxin with standard CYN gave the same retention time and an absorbance maximum at 262nm. HPLC-MS/MS confirmed the presence of CYN (M+H 416) and deoxy-CYN (M+H 400). The CYN content in strain CY-Thai was estimated at 1.02mg/g and approximately 1/10 of this amount for deoxy-CYN. This is the first report from Asia of a CYN, deoxy-CYN producing Cylindrospermopsis raciborskii.

[D-Leu(1)] microcystin-LR, a new microcystin isoplated from waterbloom in a Canadian prairie lake.

A previously undescribed cyclic heptapeptide hepatotoxin was isolated from a cyanobacteria waterbloom collected in Pakowki Lake, Alberta, Canada (49 degrees 20'N and 110 degrees 55'W). The compound was characterized by amino acid analysis, ESIMS/CID/MS, (1)H and (13)C NMR, and UV spectroscopy. Structure of the new microcystin was assigned as [D-Leu(1)]microcystin-LR (1). The amino acid composition is the same as microcystin-LR (2) except for D-Leu and L-Leu in 1 instead of D-Ala and L-Leu in 2. This is the first microcystin identified, among the 64 known microcystins, that has both a D- and L-Leu amino acid. Toxicity as measured by the protein phosphatase inhibition activity of 1 is similar to microcystin-LR. The presence of microcystins in waterblooms from this lake is discussed in relation to the almost yearly bird mortalities that have occurred there since 1995.

Isolation and characterization of microcystins from a river nile strain of Oscillatoria tenuis Agardh ex Gomont.

The River Nile is the major source of drinking water in Egypt, however, increased eutrophication due to agricultural, municipal and industrial runoff has contributed to the growth of toxin producing cyanobacteria. This study describes the isolation and characterization of microcystins (MCYSTs), cyclic heptapeptide hepatotoxins, from a rare strain of Oscillatoria tenuis, isolated from the River Nile at Sohag province in July 1995. The MCYST concentration of laboratory-cultured O. tenuis strain E6 was found to be 0.3 mg/g freeze-dried weight determined by enzyme-linked immunosorbent assay (ELISA). Two microcystins, 1 and 2, were isolated from lyophilized cells using solid phase extraction and reversed-phase high performance liquid chromatography (HPLC). Structures were assigned based upon their amino acid analyses, electrospray ionization mass spectrometry (ESIMS, ESIMS-CID-MS), high resolution fast atom bombardment mass spectrometry, and nuclear magnetic resonance data ((1)H and (1)H COSY NMR). Toxin 1 was identified as MCYST-LR, and toxin 2, a new MCYST, as MCYST-LHArg ([L-homoarginine(4)]). Previous studies indicate that Oscillatoria agardhii strains produce demethylated MCYSTs (containing D-Asp and/or dehydroalanine). This is the first report of a toxic O. tenuis, strain E6, one which produces a fully methylated MCYST, MCYST-LR and a new L-homoarginine containing MCYST, MCYST-LHArg.

Modeling the kinetics of acylation of insulin using a recursive method for solving the systems of coupled differential equations.

This paper describes a theoretical method for solving systems of coupled differential equations that describe the kinetics of complicated reaction networks in which a molecule having multiple reaction sites reacts irreversibly with multiple equivalents of a ligand (reagent). The members of the network differ in the number of equivalents of reagent that have reacted, and in the patterns of sites of reaction. A recursive algorithm generates series, asymptotic, and average solutions describing this kinetic scheme. This method was validated by successfully simulating the experimental data for the kinetics of acylation of insulin.

Seven new microcystins possessing two L-glutamic acid units, isolated from Anabaena sp. strain 186.

Electrospray ionization mass spectrometry has been applied to the structure assignment of seven new microcystins (1-7), obtained from cultured Anabaena sp. strain 186. The seven new microcystins contain the dehydroalanine (Dha) or L-Ser unit instead of the N-methyldehydroalanine unit and the L-Glu and/or its delta-methyl ester [E(OMe)] units at the two variable L-amino acid units, and the structures were assigned as [Dha7]microcystin-E(OMe)E(OMe) (1), [D-Asp3,Dha7]microcystin-E(OMe)E(OMe) (2), [L-Ser7]microcystin-E(OMe)E(OMe) (3), [D-Asp3,L-Ser7]microcystin-E(OMe)E(OMe) (4), [Dha7]microcystin-EE(OMe) (5), [D-Asp3,Dha7]microcystin-EE(OMe) (6), and [L-Ser7]microcystin-EE(OMe) (7). These microcystins are the first examples containing dicarboxylic amino acids at the two variable L-amino acid units in microcystins.

Energy intakes and rotavirus diarrhoea: a prospective study - abstract

Dietary information and anthropometric measurements were obtained on 6 seperate occasions during one month for each of 68 children under 5 years of age during and after recovery from rotavirus diarrhoea. The period of exclusive breastfeeding was under 3 months for 89 percent of children, 36 percent had received solids before 4 months, and 24 percent were currently receiving some breastmilk. Eighty-two per cent of mothers had observed weight loss and reduced appetitie since the onset of diarrhoea. Dietary recalls (24-hour) showed that 94 percent of children were receiving less than two-thirds of the recommended allowance for energy during the acute phase of diarrhoea, 60 percent during early convalescence and 40 percent during late convalescence (4 and 14 days after cessation of diarrhoea respectively. Intakes per kilogramme body weight were also low: PHASE - Acute diarrhoea, Early convalescence, Late convalescence; JAMAICA 43 ñ 19, 68 ñ 23, 78 ñ 22 respectively KCALS/KG/DAY, BANGLADESH (Rotavirus patients) 63, 84, 100 respectively. Bangladesh studies report higher intakes among children with non-rotavirus diarrhoeas. Healthy Jamaican children are reported to have a mean intake of 80 Kcals/kg. The average weight gain of the children was twice the expected gain. However, children with lower energy intakes during early convalescence, when 85 percent had recovered appetities, gained less than the expected weight. Breastmilk can make an important contribution to energy intake during infection. This study found that most children receiving breastmilk had better weight gains. The study underlines the need for adequate diets during and following recovery from acute diarrhoea to counteract the negative nutritional impact of the episode. Breastfeeding can help to maintain a minimum intake in the face of appetite loss (AU)