Lamotrigine-Valproic Acid Interaction Leading to Stevens-Johnson Syndrome.

Lamotrigine (LTG) is currently indicated as adjunctive therapy for focal and generalized tonic-clonic seizures and for treatment of bipolar disorder and neuropathic pain. A common concern with LTG in children is the frequency of appearance of skin rash. The intensity of this adverse effect can vary from transient mild rash to Stevens-Johnson syndrome (SJS), which can be fatal mainly when LTG is coadministered with valproic acid (VPA).

Role of CYP2C9, CYP2C19 and EPHX Polymorphism in the Pharmacokinetic of Phenytoin: A Study on Uruguayan Caucasian Subjects.

Phenytoin (PHT) oxidative route leads to its main metabolite p-hydroxyphenytoin (p-HPPH), by means of CYP2C9 and CYP2C19. Formation of p-HPPH proceeds via a reactive arene-oxide intermediate. This intermediate can also be converted into PHT dihydrodiol by microsomal epoxide hydrolase (EPHX).

Inhibition of lipid raft-dependent signaling by a dystrophy-associated mutant of caveolin-3.

Specific point mutations in caveolin-3, a predominantly muscle-specific member of the caveolin family, have been implicated in limb-girdle muscular dystrophy and in rippling muscle disease. We examined the effect of these mutations on caveolin-3 localization and function. Using two independent assay systems, Raf activation in fibroblasts and neurite extension in PC12 cells, we show that one of the caveolin-3 point mutants, caveolin-3-C71W, specifically inhibits signaling by activated H-Ras but not by K-Ras.

Role of cholesterol in developing T-tubules: analogous mechanisms for T-tubule and caveolae biogenesis.

Recent work has suggested that caveolae biogenesis and transverse-tubule (T-tubule) formation in muscle cells share similar underlying features. We compared the properties of caveolin-1 (cav-1)-positive caveolae, in epithelial cells, with caveolin-3 (cav-3)-positive precursor T-tubules, in differentiating C2C12 muscle cells, using the cholesterol-binding drug, Amphotericin B (AmphB). Treatment of MDCK epithelial cells with acute high doses or chronic low doses of AmphB caused a loss of surface caveolae and the rapid redistribution of cav-1, and exogenously expressed cav-3, from the cell surface into modified endosomes.

Molecular characterization of caveolin association with the Golgi complex: identification of a cis-Golgi targeting domain in the caveolin molecule.

Caveolins are integral membrane proteins which are a major component of caveolae. In addition, caveolins have been proposed to cycle between intracellular compartments and the cell surface but the exact trafficking route and targeting information in the caveolin molecule have not been defined. We show that antibodies against the caveolin scaffolding domain or against the COOH terminus of caveolin-1 show a striking specificity for the Golgi pool of caveolin and do not recognize surface caveolin by immunofluorescence.

Intracellular localization of phosphatidylinositide 3-kinase and insulin receptor substrate-1 in adipocytes: potential involvement of a membrane skeleton.

Phosphatidylinositide (PI) 3-kinase binds to tyrosyl-phosphorylated insulin receptor substrate-1 (IRS-1) in insulin-treated adipocytes, and this step plays a central role in the regulated movement of the glucose transporter, GLUT4, from intracellular vesicles to the cell surface. PDGF, which also activates PI 3-kinase in adipocytes, has no significant effect on GLUT4 trafficking in these cells. We propose that this specificity may be mediated by differential localization of PI 3-kinase in response to insulin versus PDGF activation.

Transcriptional repression by the orphan steroid receptor RVR/Rev-erb beta is dependent on the signature motif and helix 5 in the E region: functional evidence for a biological role of RVR in myogenesis.

RVR/Rev-erb beta/BD73 is an orphan steroid receptor that has no known ligand in the "classical' sense. RVR binds as a monomer to an element which consists of an A/T-rich sequence upstream of the consensus hexameric half-site. However, RVR does not activate transcription and blocks transactivation of this element by ROR/RZR.

Constitutive expression of the orphan receptor, Rev-erbA alpha, inhibits muscle differentiation and abrogates the expression of the myoD gene family.

Rev-erbA alpha is an orphan steroid receptor that is expressed in skeletal muscle. Rev-erbA alpha binds to single/tandem copies of an AGGTCA motif, is transcribed on the noncoding strand of the c-erbA- alpha gene locus, and is postulated to modulate the thyroid hormone (T3) response. T3 induces terminal muscle differentiation and regulates fiber type composition via direct activation of the muscle-specific myoD gene family (e.

Requirement for phosphoinositide 3-kinase in insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes.

Insulin stimulates glucose transport in muscle and fat cells by inducing the redistribution of a specific glucose transporter, GLUT4, from intracellular vesicles to the cell surface. Phosphoinositide (PI) 3-kinase has been implicated as a key intermediate in insulin-stimulated glucose transport by studies that have examined the effects of wortmannin and LY294002, which are thought to be specific inhibitors of this enzyme. However, the specificity of these compounds for PI 3-kinase has recently been questioned.

Mutational analysis of phospholipase C-beta 2. Identification of regions required for membrane association and stimulation by guanine-nucleotide-binding protein beta gamma subunits.

Members of the beta isozyme subfamily of the phosphoinositide-specific phospholipases C (PLC beta) have recently been shown to be stimulated by both guanine-nucleotide-binding protein alpha and beta gamma subunits. The alpha subunits of the Gq class activate PLC beta isozymes in the order of PLC beta 1 > or = PLC beta 3 >> PLC beta 2, which is different from the order of PLC beta 3 > PLC beta 2 > PLC beta 1 for beta gamma subunit stimulation. The C-terminal region of PLC beta 1, in particular the sequence between Thr903 and Leu1142, has been shown to be involved in interacting with activated alpha q subunits and to contain a region required for efficient membrane association of PLC beta 1 [Park, D.

Activation of phosphatidylinositol lipid-specific phospholipase C-beta 3 by G-protein beta gamma subunits.

A novel member of the inositol lipid-specific phospholipase C family, PtdIns-PLC beta 3, is shown to be activated by beta gamma subunits of the heterotrimeric GTP-binding protein, transducin. The activation is a direct effect since it is observed with the purified proteins. Furthermore, the activation is blocked by the GDP-liganded alpha subunit of transducin, confirming that the effect is due to free beta gamma subunits.

Isozyme-selective stimulation of phospholipase C-beta 2 by G protein beta gamma-subunits.

Hydrolysis by phospholipase C (PLC) of phosphatidylinositol 4,5-bisphosphate is a key mechanism by which many extracellular signalling molecules regulate functions of their target cells. At least eight distinct isozymes of PLC are recognized in mammalian cells. Receptor-controlled PLC is often regulated by G proteins, which can be modified by pertussis toxin in some cells but not in others.

Identification, purification and characterization of a novel phosphatidylinositol-specific phospholipase C, a third member of the beta subfamily.

The partial sequence of a novel PtdIns-specific phospholipase C of the beta subfamily (PtdIns-PLC beta 3) is described. Based upon the predicted protein sequence, monospecific antibodies have been raised and used to identify a suitable source for purification of the protein. Fractionation of HeLa S3 cells revealed that immunoreactive PtdIns-PLC beta 3 is membrane associated; purification (approximately 1000-fold) from this fraction yielded a single immunoreactive protein of 158 kDa, with a specific activity of 136 mumol.

A double-blind crossover comparison of flecainide and slow-release mexiletine in the treatment of stable premature ventricular complexes.

In 24 patients with stable premature ventricular contractions (PVCs) greater than or equal to 100/h, Lown class greater than or equal to 2 the relative anti-arrhythmic efficacy of flecainide 150 mg twice daily and slow-release mexiletine 360 mg twice daily was evaluated in a double-blind placebo-controlled randomized crossover study. All the patients had normal ventricular function. Criteria of efficacy were: reduction greater than or equal to 70% of PVCs or reduction greater than or equal to 50% with abolition of Lown class greater than 2 arrhythmias or suppression of non-sustained ventricular tachycardias (nSVT).

[Evaluation of the intestinal absorption of iron orally administered as chondroitin sulfate in normal subjects].

The behaviour of sideremia has been studied in order to assess the intestinal absorption of iron of a new compound, ferric chondroitin sulfate after oral administration in 12 normal volunteers. After administration of 90 mg of iron as ferric chondroitin sulfate, sideremia rose from a basal value of 88 +/- 27 micrograms/dl to a value of 128 +/- 22 micrograms/dl at the third hour. Variance analysis showed that the increases were statistically significant (F = 27.

Effect of a single daily dose treatment of fenofibrate on plasma lipoproteins in hyperlipoproteinaemia IIb.

The safety and efficacy of a single daily dose of fenofibrate (200 mg) have been evaluated in 12 Type IIB hyperlipidaemic patients in a three-month study. At the same time the pharmacokinetics was studied to check whether this new dosage schedule would give a therapeutic plasma levels of fenofibrate. At the single daily dose of 200 mg, fenofibrate was highly effective, very well tolerated, and it reached therapeutic plasma levels without accumulation.

Bioavailability of rifampicin capsules.

In a 3-year bioavailability program 14 studies in 45 healthy volunteers were carried out to differentiate between experimental lots of rifampicin (RMP) capsules and marketed preparations of other manufacturers with lower bioavailability than Rifadin (RFD), used as standard reference drug. In each study single oral doses of 600 mg of 2-5 different RMP preparations were administered to 6-12 volunteers in fasting conditions according to a balanced crossover design. The pharmacokinetic parameters of RFD capsules were practically identical for the same batch tested at different times and for several batches tested in different groups of subjects.