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1.
Acta Neurol Scand ; 138(3): 203-211, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29732549

ABSTRACT

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.


Subject(s)
Anticonvulsants/pharmacokinetics , Dibenzazepines/pharmacokinetics , Adult , Aged , Anticonvulsants/adverse effects , Dibenzazepines/adverse effects , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Humans , Male , Middle Aged , Seizures/drug therapy
2.
J Pharmacol Exp Ther ; 283(2): 947-54, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9353418

ABSTRACT

Although nitrosothiols have been suggested to act as regulators of cell (patho)physiology, little is known about the pharmacology of nitrosylated proteins as nitric oxide (NO.) congeners. We describe the molecular consequences of nitrosylating bovine serum albumin (BSA) at multiple specific sites and demonstrate that the product S-nitrosoproteins exert NO.-like activity. The content of nucleophilic nitrosylation sites (i.e., free sulfhydryl groups) in native BSA was increased by either reduction with dithiothreitol or thiolation with N-acetylhomocysteine. Fourteen moles of nitrogen monoxide (NO)/mol BSA equivalent were then selectively positioned on either the endogenous sulfhydryl groups of reduced BSA or the homocysteine moieties of thiolated BSA, respectively. Each resulting S-nitrosoprotein adduct was an oligomeric mixture across the >2000 kDa to approximately 66 kDa molecular mass range. The BSA-derived S-nitrosoproteins were immunoreactive with antibodies against native BSA but evidenced compromised long-chain fatty acid binding. Both types of BSA-derived S-nitrosoproteins suppressed human coronary artery smooth muscle cell proliferation to a similar degree (IC50 approximately 70 microM NO. equivalents) and were significantly more effective antiproliferative agents than a standard NO. donor, DETA NONOate. Antiproliferative bioactivity reflected the NO functionalities carried by each protein, but was independent of molecular mass of the nitrosylated BSA adducts. These data exemplify the rational design and characterization of protein-based S-nitrosothiols as NO. congeners and suggest that such agents could have therapeutic potential as NO delivery systems.


Subject(s)
Nitric Oxide/pharmacology , Nitroso Compounds/pharmacology , Serum Albumin, Bovine/pharmacology , Cell Division/drug effects , Cells, Cultured , Chromatography, Gel , Fatty Acids/metabolism , Humans , Muscle, Smooth, Vascular/drug effects , Nitric Oxide/metabolism , Nitroso Compounds/analysis , Serum Albumin, Bovine/analysis
3.
Arch Biochem Biophys ; 343(1): 131-9, 1997 Jul 01.
Article in English | MEDLINE | ID: mdl-9210655

ABSTRACT

Nitric oxide (NO.) and NO. donors incite NAD- [i.e., mono(ADP-ribosylation)] and NADH-dependent posttranslational protein modifications by an as yet unknown mechanism. A route of pyridine nucleotide-dependent, NO.-stimulated protein modification has recently been hypothesized [S. Dimmeler, and B. Brune, (1992) Eur. J. Biochem. 210, 305-310; J. S. Stamler (1994) Cell 78, 931-936]. An essential feature of this proposed mechanism is NADH nitrosation, for a nitroso-NADH adduct is considered to be a key reactant in the generation of pyridine nucleotide-modified protein. To evaluate at the molecular level the ability of NADH to act as a nitrosation substrate, the potential effects of NO., the nitrosothiols S-nitrosoglutathione and S-nitrosocysteine, the nitrosating agent tert-butyl-nitrite, and the NO. metabolite peroxynitrite on the molecular and functional (i.e., hydride-transfer) properties of NADH have been directly assessed at physiological pH. Exposure of NADH to NO. or nitrosothiol altered neither the hydride-transfer capability of the pyridine nucleotide nor its ultraviolet spectrum in ways suggestive of NADH nitrosation. As determined by NMR spectroscopy, NADH was refractory to the well-recognized nitrosating agent tert-butyl nitrite. Consequently, it appears that NADH is an unfavorable substrate for nitrosation under physiological conditions. These data are inconsistent with the proposal that NO. or a NO.-derived nitrosating agent interacts with NADH to generate the nitroso-NADH hypothesized to be essential to NO.-stimulated, pyridine nucleotide-dependent protein modification. Peroxynitrite, a possible source of nitrosating compounds, readily oxidized NADH to NAD, but demonstrated no potential to form a nitroso-NADH adduct. The facility with which NADH is oxidized to NAD has implications for peroxynitrite-mediated tissue damage.


Subject(s)
NAD/chemistry , Nitric Oxide/chemistry , Magnetic Resonance Spectroscopy , Nitric Oxide/metabolism , Protein Processing, Post-Translational
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