Guardians at the gate: patent protection of therapeutic monoclonal antibodies through product life cycle management--Part 3.

Product life cycle management, which necessarily utilizes a multi-disciplinary approach, is an essential tool for companies that develop or market therapeutic monoclonal antibodies (mAbs). Too little attention to such a plan, or use of the wrong resources, could substantially curtail a product's life span. The most difficult part of the therapeutic antibody business is the development of high-quality, safe and effective products.

Thiopurine S-methyltransferase pharmacogenetics in a large-scale healthy Italian-Caucasian population: differences in enzyme activity.

Aims: To investigate the influence of genotype, age and gender on the thiopurine S-methyltransferase (TPMT) phenotype in healthy Italian-Caucasian subjects.

Materials & Methods: The study investigated the TPMT genotype and the TPMT phenotype of 943 healthy Italian-Caucasian subjects of different age and gender (age range: 0.08-68 years; 623 males 320 females).

Variable phenotypic expression of chylomicron retention disease in a kindred carrying a mutation of the Sara2 gene.

Chylomicron retention disease is a recessive inherited disorder characterized by fat malabsorption and steatorrhea and is associated with failure to thrive in infancy. We describe a kindred carrying a mutation of Sara2 gene causing a chylomicron retention phenotype. The proband was a 5-month-old baby, born of consanguineous, apparently healthy parents from Morocco, with failure to thrive.

Cancer abolishes the tissue type-specific differences in the phenotype of energetic metabolism.

Nowadays, cellular bioenergetics has become a central issue of investigation in cancer biology. Recently, the metabolic activity of the cancer cell has been shown to correlate with a proteomic index that informs of the relative mitochondrial activity of the cell. Within this new field of investigation, we report herein the production and characterization of high-affinity monoclonal antibodies against proteins of the "bioenergetic signature" of the cell.

Kinetic and thermodynamic barriers to chlorine transfer between amines in aqueous solution.

Third-order rate constants for the acid-catalyzed reversible reaction of N-chlorotaurine with benzylamine and dimethylamine were determined in water at 25 degrees C and I = 0.5 (NaClO4). The reaction with benzylamine shows inverse solvent deuterium isotope effects of kH/kD=0.

Lamellarin D bioconjugates II: Synthesis and cellular internalization of dendrimer and nuclear location signal derivatives.

The design and synthesis of Lamellarin D conjugates with a nuclear localization signal peptide and a poly(ethylene glycol)-based dendrimer are described. Conjugates 1-4 were obtained in 8-84% overall yields from the corresponding protected Lamellarin D. Conjugates 1 and 4 are 1.

Lamellarin D bioconjugates I: Synthesis and cellular internalization of PEG-derivatives.

Herein is reported the design and synthesis of poly(ethylene glycol) derivatives of Lamellarin D with the aim of modulating their physicochemical properties and improving the biological activity. Mono-, di-, and tri-PEG conjugates with improved solubility were obtained in 18-57% overall yields from the corresponding partially protected phenolic derivatives of Lamellarin D. Conjugates 1-9 were tested in a panel of three human tumor cell lines (MDA-MB-231 breast, A-549 lung, and HT-29 colon) to evaluate their cytotoxicity.

Long-standing mild hypertransaminasaemia caused by congenital disorder of glycosylation (CDG) type IIx.

A 32 year-old asymptomatic male came to our attention with a 21-year history, documented elsewhere, of puzzling increases in his serum transaminase level. At first, very low serum ceruloplasmin level suggested Wilson disease. Two liver biopsies showed mild portal inflammation, steatosis and mild fibrosis.

An evaluation of ureteral flow after doppler-guided uterine artery occlusion device placement during organ-preserving gynecologic procedures.

We studied the use of color Doppler ultrasonography for ureteral patency after placement of a transvaginal Doppler-guided uterine artery occlusion device before organ-preserving surgery for leiomyomata uteri. Our case series involved 7 patients in whom ureteral flow was assessed using color Doppler sonography before and after placement of a Doppler-guided uterine artery occlusion device. Bilateral ureteral flow was assessed at the trigone using a grading system.

N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), a powerful coupling reagent for bioconjugation.

Prodrugs are increasingly used as delivery vehicles for pharmaceutical agents that present solubility and/or pharmacokinetic/metabolic issues. In the course of the development of prodrugs for the antitumoral agent thiocoraline, standard coupling reagents and procedures failed to provide the desired target derivatives because of the lack of reactivity of its quinolinic alcohol. In contrast, the use of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) resulted in good yields of ester prodrugs of thiocoraline and could be applicable to other drugs with similar limitations.

Staging, response to therapy, and restaging of lymphomas with 18F-FDG PET.

Background: We undertook this study to determine the diagnostic accuracy of (18)FDG after three cycles and at the end of chemotherapy in non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL). We also evaluated the role of (67)Ga, bone marrow aspiration (BMA), and computed tomography (CT) in monitoring lymphoma treatment.

Methods: (18)FDG, (67)Ga, BMA, and CT were performed before chemotherapy on 40 untreated patients.

[Diagnosis and treatment of benign breast lesions during pregnancy].

Objectives: To retrospectively study the diagnosis and treatment of benign breast disease during pregnancy and breastfeeding at our department. To review the relevant literature.

Materials And Methods: From January 2001 to March 2005, a total of 91 pregnant or breastfeeding women (age range: 23-36 years) were diagnosed with benign breast pathology.

Nucleophilic substitution reactions of N-chloramines: evidence for a change in mechanism with increasing nucleophile reactivity.

Third-order rate constants (kNu)H (M-2 s-1) for the hydronium ion catalyzed reactions of a range of nucleophiles with N-chlorotaurine (1) in water at 25 degrees C and I=0.5 (NaClO4) are reported. The solvent deuterium isotope effects on hydronium ion catalysis of the reaction with 1 of bromide and iodide ion are (kBr)H/(kBr)D=0.

Effect of delta-aminolevulinic acid and vitamin E treatments on the N-methyl-D-aspartate receptor at different ages in the striatum of rat brain.

We report the effects of the chronic treatments with the oxidant agent delta-aminolevulinic acid (ALA) and with the antioxidant vitamin E on the N-methyl-D-aspartate (NMDA) receptors in the striatum of 4-, 12- and 24-month-old male Wistar rats. ALA and vitamin E were administered daily for 15 days (40 mg/kg i.p.

Isolated liver transplantation in an infant with ultrashort gut.

Intestinal function in children with very short bowel syndrome and related intestinal failure may improve after isolated liver transplantation. An infant with an ultrashort gut, ileo-cecal valve, and whole colon received total parenteral nutrition from the first days of life. Enteral feeding failed because of the progressive dilatation of the jejunal portion and motility disorders.

Compatibility and stability of the novel anticancer agent ES-285 x HCl formulated with 2-hydroxypropyl-beta-cyclodextrin in infusion devices.

ES-285 x HCl is a novel marine-derived anticancer agent isolated from the clam Spisula polynyma. The compound is pharmaceutically formulated as a lyophilised product containing 25 or 50 mg ES-285 x HCl and 500 or 1000 mg 2-hydroxypropyl-beta-cyclodextrin per dosage unit and requires reconstitution with sterile water for injection before intravenous administration. The aim of this study was to determine the stability and compatibility of ES-285 x HCl in infusion devices.

Effect of delta-aminolevulinic acid treatment on N-methyl-D-aspartate receptor at different ages in the rat brain.

We report here the effects of the chronic treatment with the oxidant agent delta-aminolevulinic acid (ALA) on the N-methyl-D-aspartate (NMDA) receptors in 4-, 12- and 24-month-old male Wistar rats. ALA was administered daily for 15 days (40 mg/kg i.p).

Preparation and in vitro evaluation of chitosan nanoparticles containing a caspase inhibitor.

The aim of this work was to develop a formulation for Z-DEVD-FMK, a peptide which is a caspase inhibitor and has been used in experimental animal studies for a decade. Peptide loaded chitosan nanoparticles were obtained by ionotropic gelation process and Z-DEVD-FMK was quantified by an HPLC method. The influence of the initial peptide concentration on the nanoparticle characteristics and release behavior was evaluated.

Characterization of the promoter of the mouse c-Jun NH2-terminal/stress-activated protein kinase alpha gene.

We report the isolation of the mouse JNK/SAPKalpha gene, the determination of its exon/intron organization and the characterization of its promoter region. The mouse JNK/SAPKalpha gene spans a region of 36 kbp and contains 13 exons, which represent about 8% of the gene sequence. Major JNK/SAPKalpha splice variants (I and II) are generated by alternative splicing of exons 7 and 8, respectively, whereas minor variants (III and IV) are generated using cryptic sites located inside exon 9.

Effect of vitamin E treatment on N-methyl-D-aspartate receptor at different ages in the rat brain.

A comparative study using membrane homogenate binding, autoradiography, and Western blot assays was carried out to determine the age-related changes in N-methyl-D-aspartate (NMDA) receptors in 4-, 12- and 24-month-old male Wistar rats, treated or not with vitamin E. Vitamin E treatment was 20 mg/kg i.p.

The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa.

The influence of the surface characteristics of colloidal drug carriers in their interaction with different biological surfaces is becoming increasingly evident. In order to investigate the importance of these characteristics in their interaction with the ocular mucosa, we developed three types of nanocapsules that differ in their surface properties: poly- epsilon -caprolactone (PECL) nanocapsules, chitosan (CS)-coated PECL nanocapsules and poly(ethylene glycol) (PEG)-coated PECL nanocapsules. Two different approaches were used to form these polymer coated nanocapsules: (i) the electrostatic anchorage of the coating onto the PECL nanocapsules-in the case of CS-and (ii) the use of the previously synthesized copolymer PECL-PEG for the formation of the nanocapsules.

Biomimetic organization: Octapeptide self-assembly into nanotubes of viral capsid-like dimension.

The controlled self-assembly of complex molecules into well defined hierarchical structures is a promising route for fabricating nanostructures. These nanoscale structures can be realized by naturally occurring proteins such as tobacco mosaic virus, capsid proteins, tubulin, actin, etc. Here, we report a simple alternative method based on self-assembling nanotubes formed by a synthetic therapeutic octapeptide, Lanreotide in water.

Validation of a sensitive assay for thiocoraline in mouse plasma using liquid chromatography-tandem mass spectrometry.

A sensitive high-performance liquid chromatography-tandem mass spectrometry assay for thiocoraline, an anti-tumor depsipeptide, in mouse plasma is described. Echinomycin, a quinoxaline peptide, was used as an internal standard. Thiocoraline was recovered from the mouse plasma using protein precipitation with acetonitrile and followed by solid-phase extraction of the supernatant.