Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate.

OBJECTIVES: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. METHODS: Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual eslicarbazepine exposures to safety outcomes and efficacy responses. RESULTS: Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. CONCLUSIONS: Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions.

Structural model and functional significance of pH-dependent talin-actin binding for focal adhesion remodeling.

Actin filament binding by the focal adhesion (FA)-associated protein talin stabilizes cell-substrate adhesions and is thought to be rate-limiting in cell migration. Although F-actin binding by talin is known to be pH-sensitive in vitro, with lower affinity at higher pH, the functional significance of this pH dependence is unknown. Because increased intracellular pH (pH(i)) promotes cell migration and is a hallmark of metastatic carcinomas, we asked whether it increases FA remodeling through lower-affinity talin-actin binding. Talin contains several actin binding sites, but we found that only the COOH-terminal USH-I/LWEQ module showed pH-dependent actin binding, with lower affinity and decreased maximal binding at higher pH. Molecular dynamics simulations and NMR of this module revealed a structural mechanism for pH-dependent actin binding. A cluster of titratable amino acids with upshifted pK(a) values, including His-2418, was identified at one end of the five-helix bundle distal from the actin binding site. Protonation of His-2418 induces changes in the conformation and dynamics of the remote actin binding site. Structural analyses of a mutant talin-H2418F at pH 6.0 and 8.0 suggested changes different from the WT protein, and we confirmed that actin binding by talin-H2418F was relatively pH-insensitive. In motile fibroblasts, increasing pH(i) decreased FA lifetime and increased the migratory rate. However, expression of talin-H2418F increased lifetime 2-fold and decreased the migratory rate. These data identify a molecular mechanism for pH-sensitive actin binding by talin and suggest that FA turnover is pH-dependent and in part mediated by pH-dependent affinity of talin for binding actin.

Non-convulsive status epilepticus: usefulness of clinical features in selecting patients for urgent EEG.

BACKGROUND: Non-convulsive status epilepticus (NCSE) is status epilepticus without obvious tonic-clonic activity. Patients with NCSE have altered mental state. An EEG is needed to confirm the diagnosis, but obtaining an EEG on every patient with altered mental state is not practical. OBJECTIVE: To determine whether clinical features could be used to predict which patients were more likely to be in NCSE and thus in need of an urgent EEG. METHODS: Over a six month period, all patients for whom an urgent EEG was ordered to identify NCSE were enrolled. Neurology residents examined the patients and filled out a questionnaire without knowledge of the EEG results. The patients were divided into two groups, NCSE and non-NCSE, depending on the EEG result. The clinical features were compared between the two groups. The sensitivity and specificity of the features were calculated. RESULTS: 48 patients were enrolled, 12 in NCSE and 36 not in NCSE. Remote risk factors for seizures, severely impaired mental state, and ocular movement abnormalities were seen significantly more often in the NCSE group. The combined sensitivity of remote risk factors for seizures and ocular movement abnormalities was 100%. CONCLUSIONS: There are certain clinical features that are more likely to be present in patients in NCSE compared with other types of encephalopathy. Either remote risk factors for seizures or ocular movement abnormalities were seen in all patients in NCSE. These features may be used to select which patients should have an urgent EEG.

Structural and kinetic studies of a cisplatin-modified DNA icosamer binding to HMG1 domain B.

The high mobility group (HMG) domain is a DNA-binding motif found in the non-histone chromosomal proteins, HMG1 and HMG2, and some transcription factors. Experimental evidence has demonstrated that HMG-domain proteins can play a role in sensitizing cells to the anticancer drug cisplatin. Fluorescence resonance energy transfer (FRET) experiments were performed in the present study to investigate structural changes that accompany complex formation between the HMG domain B of HMG1 and a cisplatin-modified, 20-base pair double-stranded DNA probe containing fluorescein and rhodamine tethered at its two ends. The binding affinity of HMG1 domain B for the cisplatin-modified DNA probe was investigated in fluorescence titration experiments, and a value of 60 +/- 30 nM was determined for the dissociation constant. Single photon counting methods were employed to measure the fluorescence lifetime of the fluorescein donor in the presence and absence of HMG1 domain B. These FRET experiments revealed a distance change that was used to estimate a bend angle of 80-95 degrees for the cisplatin-modified DNA upon protein binding. Stopped-flow fluorescence spectroscopic experiments afforded kinetic parameters for HMG1 domain B binding to the cisplatin-modified DNA probe, with kon = 1.1 +/- 0.1 x 10(9) M-1 s-1 and koff = 30 +/- 4 s-1.

Limited diagnostic value of routine cord blood bilirubin determinations.

In a retrospective study, cord blood bilirubin levels of 87 neonates who received standard phototherapy for neonatal hyperbilirubinemia were compared with the cord bilirubin levels of 95 neonates without neonatal hyperbilirubinemia, none of whom received phototherapy. There were no significant differences in the cord bilirubin levels between the two groups. These results suggest that routine determination of cord blood bilirubin levels is neither necessary nor cost effective.

Renal allograft rupture: a report of three cases and review of the literature.

This report reviews the features of 149 cases of renal allograft rupture, while adding a detailed description of 3 more cases to the English literature. From November, 1973 to November, 1979, 3 cases of renal allograft rupture occurred in 100 renal transplants performed at Research Medical Center, Kansas City, Mo., an incidence of 3.0%. Rupture developed between the 6th and 8th day after transplantation while patients required dialysis because of poor allograft function. All patients had surgical exploration and successful repair of laceration. Clinical and/or histological findings were consistent with acute rejection in all 3 cases. One graft functioned for 5 years with gradual loss of function. The other two grafts are functioning at the present time. Review of reported cases suggests that acute rejection is the most common cause of allograft rupture. Rupture of the renal allograft did not appear to increase the intensity of rejection, nor did it represent an irreversible rejection. Transplant nephrectomy can be avoided unless hemorrhage is uncontrollable from the site of laceration.

Mechanism of activation of renal Na+-K+-ATPase in the rat: effects of reduction of renal mass.

The mechanism of activation of renal Na+-K+-ATPase was studied in rats 2 wk after unilateral nephrectomy. The increase in enzyme specific activity was confined to the outer medulla and occurred without changes in the cellular contents of RNA or protein. Enzyme activation was accompanied by increases in the levels of the phosphorylated intermediate with little or no change in the apparent turnover numbers of the reaction. The specific activity of the ouabain-sensitive p-nitrophenylphosphatase also increased by uninephrectomy but to a larger extent than did Na+-K+-ATPase. Kinetic studies demonstrated an increase in Vmax for ATP, sodium, and potassium, and small increases in Km for ATP and K1/2 for potassium. There was no change in the activation energies or phase transition temperature to indicate alterations in the membrane environment of Na+-K+-ATPase. Adrenalectomy did not adversely affect activation. These results indicate that activation of renal Na+-K+-ATPase after reduction of renal mass occurs mainly by an increase in the number of sodium pump sites.