LY. Ammonium-dependent sodium uptake in mitochondrion-rich cells of medaka (Oryzias latipes) larvae. In this study, a scanning ion-selective electrode technique (SIET) was applied to measure H ϩ , Na ϩ , and NH 4 ϩ gradients and apparent fluxes at specific cells on the skin of medaka larvae. Na ϩ uptake and NH3/NH 4 ϩ excretion were detected at most mitochondrion-rich cells (MRCs). H ϩ probing at MRCs revealed two group of MRCs, i.e., acid-secreting and base-secreting MRCs. Treatment with EIPA (100 M) blocked 35% of the NH3/ NH 4 ϩ secretion and 54% of the Na ϩ uptake, suggesting that the Na ϩ /H ϩ exchanger (NHE) is involved in Na ϩ and NH3/NH 4 ϩ transport. Low-Na ϩ water (Ͻ0.001 mM) or high-NH 4 ϩ (5 mM) acclimation simultaneously increased Na ϩ uptake and NH3/NH 4 ϩ excretion but decreased or even reversed the H ϩ gradient at the skin and MRCs. The correlation between NH 4 ϩ production and H ϩ consumption at the skin surface suggests that MRCs excrete nonionic NH3 (base) by an acid-trapping mechanism. Raising the external NH 4 ϩ significantly blocked NH 3/NH4 ϩ excretion and Na ϩ uptake. In contrast, raising the acidity of the water (pH 7 to pH 6) enhanced NH3/NH 4 ϩ excretion and Na ϩ uptake by MRCs. In situ hybridization and real-time PCR showed that the mRNAs of the Na ϩ /H ϩ exchanger (slc9a3) and Rhesus glycoproteins (Rhcg1 and Rhbg) were colocalized in MRCs of medaka, and their expressions were induced by low-Na ϩ acclimation. This study suggests a novel Na ϩ /NH 4 ϩ exchange pathway in apical membranes of MRCs, in which a coupled NHE and Rh glycoprotein is involved and the Rh glycoprotein may drive the NHE by generating H ϩ gradients across apical membranes of MRCs.

Topiramate was safe and effective in the treatment of partial-onset seizures in children.

Summary:Purpose: Six double-blind, placebo-controlled trials were conducted with topiramate (TPM) initiated as adjunctive therapy in adults with treatment-resistant partial-onset seizures with or without secondary generalization.Methods: Because protocols and study populations were similar, data from the studies were pooled and analyzed for 527 patients treated with TPM and 216 treated with placebo.Results: Seizures were reduced 250% in 43% of TPM-treated patients and in 12% of placebo-treated patients (p < 0.001); 5% of TPM-treated patients, but no placebo-treated patients, were seizure free during 11-1 9 weeks of double-blind treatment (p c 0.001). The therapeutic effect was consistent regardless of seizure type, age, gender, baseline seizure rate, or conIn the modern era of antiepileptic drug (AED) development, new AEDs are typically evaluated as add-on therapy in double-blind, placebo-controlled trials. A statistically significant difference favoring the active agent's efficacy over that of placebo provides proof of the new AED's treatment effect. Characteristics common to the initial randomized controlled trials of AEDs include (a) relatively short duration, (b) relatively small sample size (typically <75 patients per treatment arm), (c) involvement of patients with medically refractory seizures for whom all previous therapies have failed, (d) homogeneous populations (e.g., seizure type), (e) protocol-defined escalation to fixed target dosages rather than maximal therapeutic effect, and (0 lack of flexibility in adjusting dosages of study drug or concomitant AEDs to alleviate treatment-emergent adverse events (TEAEs). comitant antiepileptic drug (AED). With 100 mg/day TPM as a starting dosage and weekly dosage increments of 100-200 mg/ day added to maximally tolerated dosages of AEDs, the most common treatment-emergent adverse events (TEAEs) were dizziness, somnolence, fatigue, psychomotor slowing, nervousness, paresthesia, ataxia, memory difficulty and speech problems. These central nervous system effects were generally mild to moderate in severity, usually occurred early in treatment, often during titration, and resolved with continued treatment. Other notable TEAEs were weight loss and, in a small percentage of patients, renal calculi. Key Words: TopiramateAntiepileptic-Adults-Partial epilepsy.reduction in seizure rate, and particularly percentage of patients seizure free during treatment, are often secondary end points.Topiramate (TPM) was evaluated as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization, in six double-blind, placebo-controlled trials (1-6). Because of the potency of the drug, large sample sizes were not required to demonstrate its efficacy. However, because of the small sample sizes, the individual trials could not reliably detect whether patient characteristics such as age, gender, seizure type, or AED co-therapy predict response to treatment. However, data from individual trials can be pooled for analysis if the protocols and patient p...

Although the primary efficacy analysis was negative, time-to-exit analyses that included time-to-first-seizure as a covariate, between-group differences in seizure-free rates, and longer time-to-first-seizure with higher serum concentration provide evidence that topiramate is effective as monotherapy in patients with localization-related epilepsy.

No abstract