Fluvastatin in combination with other lipid-lowering agents.

Fluvastatin, a new synthetic inhibitor of HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, has been studied in several models to examine its effects when used in combination with other lipid-modifying agents such as derivatives of fibric acid (bezafibrate), resins (cholestyramine), and niacin. The combination of fluvastatin with bezafibrate has been studied in a double-blind trial involving patients with well-documented familial hypercholesterolaemia. Fluvastatin 40 mg/day, combined with either bezafibrate 400 mg/day or cholestyramine 8 g/day, resulted in reductions in levels of low-density lipoprotein cholesterol (LDL-C), these being indistinguishable between the groups; however, significantly greater increases in levels of high-density lipoprotein cholesterol (21.

Development and pharmacology of fluvastatin.

Fluvastatin is the first synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor to be approved for clinical use, and has been studied extensively in humans since 1986. It is structurally distinct from the other currently available HMGCoA reductase inhibitors (lovastatin, simvastatin, and pravastatin), leading to unique biopharmaceutical properties relative to the other agents of this class. Absorption of fluvastatin is virtually complete across all species, including man, and is not affected by the presence of food.

Biochemical and pharmacologic assessment of autonomic function.

Autonomic failure produces distinct pathophysiological abnormalities that differ according to the site and nature of the lesion(s). Although the anatomic organization and processes mediating chemical neurotransmission in the autonomic nervous system facilitate clinical investigation, limited access to the central compartment hampers evaluation of central neurotransmitter metabolism and neuropeptide function. As illustrated in the discussions of noradrenergic and cholinergic function, several indirect strategies have been used to assess the biochemical and neuropharmacologic consequences of autonomic dysfunction.

Effects of substrate binding and pH on the secondary structure of carnitine acetyltransferase.

Carnitine acetyltransferase (CAT) exists as a monomer in solution as demonstrated by dynamic light scattering measurements. Under these conditions, interactions between CAT and its substrates, L-carnitine and acetyl-CoA, were studied by circular dichroism (CD) and fluorescence spectroscopy over a wide range of substrate concentrations. CD data indicated that the binding of L-carnitine and acetyl-CoA caused changes in the secondary structure of the protein.

p21ras links Fc epsilon RI to NF-AT family member in mast cells. The AP3-like factor in this cell type is an NF-AT family member.

Very recently, an AP3-like transcription factor regulating the chemokine gene MARC and an NF-AT family member regulating IL-5 were the first components of the transcription factor repertoire to be described as activated in mast cells after an allergic triggering. In this study, we show that with respect to cross-competition in a gel shift analysis using an NF-AT consensus oligonucleotide binding site, the antigenicity to a recently generated serum against T cell NF-AT, and the sensitivity to macrolide immunosuppressants, the AP3-like activity on the MARC promoter is indistinguishable from that described for NF-AT in T cells. Additionally, we show that this factor functions on the MARC chemokine promoter without the AP1 cofactor, a situation reminiscent of the function of NF-AT in Th2-type T cells.

The polypeptide chain of eukaryotic initiation factor 5A occurs in two distinct conformations in the absence of the hypusine modification.

Eukaryotic initiation factor 5A (eIF-5A) requires posttranslational modification of lysine at position 50 to hypusine for its biological activity. We have expressed an unmodified variant of eIF-5A in Escherichia coli and show that it has structural properties different from those of the native protein in terms of its near- and far-UV circular dichroism spectra and its equilibrium unfolding transition with guanidinium chloride. In contrast to the hypusine-modified protein, which unfolds in a two-state process, the complex unfolding transition of unmodified eIF-5A suggests that this variant occurs in two differently folded conformations, F1 and F2.

Isolation and structural characterization of different isoforms of the hypusine-containing protein eIF-5A from HeLa cells.

Posttranslational modification of a specific lysine residue in eukaryotic initiation factor 5A (eIF-5A) is essential for cell viability and proliferation. The product of this modification is hypusine, an amino acid unique to eIF-5A. We have purified and characterized one major and three minor isoforms of human eIF-5A from HeLa cells.

Regulation and targeting of T-cell immune responses by IgE and IgG antibodies.

A set of chimeric antibodies with identical F(ab')2 fragments specific for the hapten 5-iodo-4-hydroxyl-3-nitrophenacetyl (NIP), but with different human Fc parts (gamma 1, gamma 2, gamma 3, gamma 4, epsilon), was used to compare the role of IgG and IgE antibodies in antigen presentation by human Epstein-Barr virus (EBV) B cells. Two or three molecules of NIP were coupled to one molecule of Der pI (Der pI-(3)NIP), a major allergen of Dermatophagoides pteronyssinus. Both monomeric IgG and performed complexes of various Der pI/IgG ratios failed to bind significantly to the Fc receptor for IgG on B cells (Fc gamma RII; CD32).

Differential activation of peroxisome proliferator-activated receptors by eicosanoids.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate gene transcription in response to peroxisome proliferators and fatty acids. PPARs also play an important role in the regulation of adipocyte differentiation. It is unclear, however, what naturally occurring compounds activate each of the PPAR subtypes.

Development of limited sampling strategies for characteristics of a pharmacokinetic profile.

New approaches for empirical and model-based development of constrained, limited sampling strategies for the estimation of one or more characteristics of a pharmacokinetic (PK) profile are evaluated. The methods (i) permit a specification of an overall risk function weighted by each estimation objective, (ii) require only a few sampling times for each of one or more new individuals, (iii) permit tight time constraints, such as those imposed by outpatients, and (iv) recognize variations across individuals, but determine optimal sampling times that are the same for all individuals. The methods are applied to a 4-way crossover pharmacokinetic study of two formulations of cyclosporin G, under fed and fasted conditions, in renal transplant patients.

A nonlinear mixed-effects pharmacokinetic model comparing two formulations of cyclosporine in stable renal transplant patients.

A nonlinear mixed-effects model simultaneously modeled two pharmacokinetic (PK) variables in patients administered cyclosporine twice daily: (i) concentration of drug in blood at the end of the 12-hr dosing interval (C12) and (ii) area under the concentration-time curve within the dosing interval (AUC). For two formulations (Neoral and Sandimmune), the model assessed the following: nonlinearity with respect to dose, interoccasion (intraindividual) variability, interindividual variability, and within- and across-individual correlation between C12 and AUC. Data were pooled from six clinical studies in stable renal transplant patients administered each formulation.

Quantitative structural activity relationship study of bis-tetraazacyclic compounds. A novel series of HIV-1 and HIV-2 inhibitors.

This work describes a study of quantitative structural activity relationships (QSAR) of bis-tetraazamacrocyclic compounds. These compounds represent a novel class of very potent and selective anti-HIV inhibitors, with a new mode of action. The QSAR study correlates structural features of the compounds with anti-HIV activity, resulting in a model which has a high predictive capacity (predictive r2 = 0.

Efficacy and pharmacokinetics of two formulations of cyclosporine A in patients with psoriasis.

The efficacy and pharmacokinetic profiles of two oral formulations of cyclosporine A (Sandimmune and Neoral; Sandoz Pharmaceuticals, East Hanover, NJ) were evaluated in 37 patients with moderate to severe plaque psoriasis in a randomized, double-blind, modified, crossover study. Cyclosporine A (150 mg twice daily), administered in either formulation, reduced the severity of plaque lesions: 94% of all patients reported at least moderate improvement and 70% reported complete clearing. Approximately 2 weeks of therapy were required for drug exposure to stabilize on either formulation.

Metabolic pathways of 4-[(3-methoxyphenyl)methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6- disilacyclohexane (MPSC) hydrochloride, a silicon-containing xenobiotic, in rat, dog, and man.

1. The metabolic pathways of Sandoz compound 58-112, 4-[(3-methyoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6- disilacyclohexane (MPSC) hydrochloride were evaluated in rat, dog, and man after a single oral dose. 2.

The nomenclature of chemokines.

Migration of leukocytes to injured tissues is a hallmark of inflammation. The recruitment phase of cells can be subdivided into three steps: the rolling phase, the firm adhesion phase, and the transendothelial migration phase. Each step is mediated by a complex interplay of endothelial/leukocyte surface molecule interactions (mostly of selectin and integrin families) as well as a group of small, secreted peptides, called chemokines.

Consequences of IgE/CD23-mediated antigen presentation in allergy.

Allergen-specific IgE antibodies are responsible for the generation of immediate-type hypersensitivity reactions. However, as described here by Geert Mudde, Roy Bheekha and Carla Bruijnzeel-Koomen, IgE may also be involved in the uptake and processing of allergens. Such IgE-mediated antigen presentation may lead to a continuous (over) activation of the immune system due to high titers of IgE and the presence of large numbers of allergen-specific Th2 cells.

Over-expression and characterization of active recombinant rat liver carnitine palmitoyltransferase II using baculovirus.

The cDNA encoding rat liver carnitine palmitoyltransferase II (CPT-II) was heterologously expressed using a recombinant baculovirus/insect cell system. Unlike Escherichia coli, the baculovirus-infected insect cells expressed mostly soluble active recombinant CPT-II (rCPT-II). CPT activity from crude lysates of recombinant baculovirus-infected insect cells was maximal between 50 and 72 h post-infection, with a peak specific activity of 100-200 times that found in the mock- or wild-type-infected control lysates.

Identification of a new member of the human eIF-5A gene family.

Using an oligodeoxynucleotide generated by rapid PCR amplification of 5'-cDNA ends (5'-RACE) as a detection probe, we have isolated a new genomic clone encoding the human eukaryotic initiation factor 5A (eIF-5A). Sequence analysis revealed that the eIF-5A coding region is identical to the corresponding cDNA but interrupted by three introns. In a plasmid shuffle experiment we show functional replacement of the essential homologous gene in Saccharomyces cerevisiae by this human eIF-5A.

IgG isotype-specific auto-antibodies bind preferentially to cross-linked membrane Ig.

Under equilibrium conditions, the affinities of five anti-IgG2a mAb isolated from virus-infected mice were comparable to other high-affinity auto-antibodies. Similar to rheumatoid factors, these anti-IgG2a auto-antibodies bound to aggregated or complexed IgG2a with 50 to 1500-fold higher avidity than their monomeric counterparts. Despite their high functional affinity to IgG2a, flow cytometric analysis revealed no binding or marginal mAb binding to four distinct lines of B cells expressing different densities of membrane-anchored IgG2a.

Overexpression of human apolipoprotein A-I in transgenic rats and the hyperlipoproteinemia associated with experimental nephrosis.

Hyperlipoproteinemia contributes both to kidney disease progression and the development of atherosclerosis. Elevated high density lipoprotein cholesterol and apolipoprotein A-I (apoA-I) serum levels are independent factors protective against the atherosclerotic process. We examined the effects in a transgenic rat model of human apoA-I expression on the hyperlipoproteinemia and edema after puromycin aminonucleoside-induced nephrosis in three groups of animals: low line (TgR[hAI]low, human plasma apoA-I = 16.

Cyclophilin A, the major intracellular receptor for the immunosuppressant cyclosporin A, maps to chromosome 7p11.2-p13: four pseudogenes map to chromosomes 3, 10, 14, and 18.

Cyclophilin A (CyP-A), the major intracellular receptor for the immunosuppressant cyclosporin A (CsA), is a member of the immunophilin class of proteins, which all possess peptidyl-prolyl cis-trans isomerase activity and, therefore, are believed to be involved in protein folding and/or intracellular protein transport. The CyP-A protein is encoded by a single gene; in addition, 15 pseudogenes have been identified. Recently, specific binding of CyP-A to the human immunodeficiency virus type 1 (HIV-1) gag protein has been reported.

SDZ PRI 053, an orally bioavailable human immunodeficiency virus type 1 proteinase inhibitor containing the 2-aminobenzylstatine moiety.

A series of inhibitors of human immunodeficiency virus type 1 (HIV-1) proteinase containing the 2-aralkyl-amino-substituted statine moiety as a novel transition-state analog was synthesized, with the aim to obtain compounds which combine anti-HIV potency with oral bioavailability. The reduced-size 2-aminobenzylstatine derivative SDZ PRI 053, which contains 2-(S)-amino-3-(R)-hydroxyindane in place of an amino acid amide, is a potent and orally bioavailable inhibitor of HIV-1 replication. The antiviral activity of SDZ PRI 053 was demonstrated in various cell lines, in primary lymphocytes, and in primary monocytes, against laboratory strains as well as clinical HIV-1 isolates (50% effective dose = 0.

Metabolism of cyclosporin G in the mouse, rat, and dog.

Cyclosporin G (CsG; Sandoz compound OG 37-325) is a cyclic undecapeptide with potent, immunosuppressive activity and is currently in clinical testing for prevention of transplanted solid organ rejection. Although structurally similar to cyclosporin A (CsA), results in animals suggest that CsG has a reduced potential for nephrotoxicity when compared with CsA, while retaining equivalent therapeutic efficacy. In the present study, the major metabolic pathways of CsG in the mouse, rat, and dog were investigated using radiolabeled drug substance to determine if interspecies differences in metabolism exist.