Phase I study of the pharmacokinetics and safety of single and multiple doses of intravenous N-acetylcysteine in healthy Chinese subjects.

OBJECTIVE: The aim of the study was to determine the pharmacokinetics (PK) and safety of single and repeat doses of intravenous (IV) N-acetylcysteine (NAC) in Chinese subjects. PATIENTS AND METHODS: A total of 24 healthy male and female Chinese subjects aged 19-40 years were enrolled in this open-label phase I study. All subjects received a single dose of NAC 600 mg IV on day 1 and, after a 3-day washout, received repeat doses of NAC 600 mg IV (twice daily on days 4 and 5 and once on day 6). RESULTS: Following a single dose, plasma NAC concentrations peaked rapidly, starting to fall at the end of the 5-minute infusion in a multiphasic manner. Mean Cmax was 83.30 µg/mL (CV% 30.7%), median Tmax was 0.083 h (range 0.08-0.25 h), and mean AUC(0-12 h) was 81.87 h*µg/mL (CV 14.0%). Following repeat dosing, Cmax was approximately 20% higher than after a single dose, with similar Tmax. Total exposure AUC(0-12) was 13% higher at steady state than after single dosing. The accumulation ratio was approximately 1.13, indicating only a slight accumulation with multiple dosing. NAC was eliminated with T1/2 of approximately 8 hours. Around 15% of the total NAC dose was excreted in the urine in the 32 hours post-dose, keeping with extensive NAC metabolism and transformation. Renal clearance of NAC was 995.2 mL/h (CV 50.2%). IV NAC was well tolerated after both single and multiple dosing. CONCLUSIONS: This is the first robust study evaluating the PK and safety of IV NAC 600 mg in Chinese subjects and provides important data if this agent is to be used IV as a mucolytic in this population.

Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy.

Polyglutamine pathologies are neurodegenerative diseases that manifest both general polyglutamine toxicity and mutant protein-specific effects. Dentatorubral-pallidoluysian Atrophy (DRPLA) is one of these disorders caused by mutations in the Atrophin-1 protein. We have generated several models for DRPLA in Drosophila and analysed the mechanisms of cellular and organism toxicity. Our genetic and ultrastructural analysis of neurodegeneration suggests that autophagy may have a role in cellular degeneration when polyglutamine proteins are overexpressed in neuronal and glial cells. Clearance of autophagic organelles is blocked at the lysosomal level after correct fusion between autophagosomes and lysosomes. This leads to accumulation of autofluorescent pigments and proteinaceous residues usually degraded by the autophagy-lysosome system. Under these circumstances, further pharmacological and genetic induction of autophagy does not rescue neurodegeneration by polyglutamine Atrophins, in contrast to many other neurodegenerative conditions. Our data thus provide a crucial insight into the specific mechanism of a polyglutamine disease and reveal important differences in the role of autophagy with respect to other diseases of the same family.

Functional polymorphisms of DEFB1 gene in type 1 diabetes Brazilian children.

We analyzed three functional 5' un-translated region beta-defensin 1 (DEFB1) single nucleotide polymorphism (SNPs) in a group of 170 type 1 diabetes (T1D) patients. In order to evaluate the SNPs influence on the disease onset and the development of other autoimmune disorder, such as celiac disease (CD) and autoimmune thyroid disease (AITD), patients were stratified according to the presence of AITD, CD, and both AITD and CD. As control group, we studied 191 healthy children and adolescent not presenting a familiar historic of T1D, CD or AITD. DEFB1 SNPs were in Hardy-Weinberg equilibrium both in healthy controls and T1D patients, as well in the T1D patients stratified according to the presence of other autoimmune disorder(s). Allele, genotype, and haplotype frequencies of T1D patients globally considered were comparable to healthy controls ones. No evidence of any association of DEFB1 SNPs with the onset of AIDT, CD, and both AITD and CD on T1D patients was evidenced. Only a minor trend was found for an increased frequency of the - 20 G allele in T1D patients only presenting AITD vs. T1D patients not presenting AITD or CD, as well as an increase of those haplotypes comprising the - 20 G allele when compared with the GCA haplotype. We also evaluated the influence of functional DEFB1 SNPs on the age of T1D onset: no significant statistical conclusion was achieved. Further studies are envisaged, in order to elucidate the possible role of functional DEFB1 polymorphisms in the onset of TD1 and other autoimmune-related disorders.

[Bacterial L-asparaginase and glutamin(asparagin)ase: some properties, structure and anti-tumor activity]. / Bakterial'nye L-asparaginazy i glutamin(asparagin)azy: nekotorye svoistva, stroenie i protivoopukholevaia aktivnost'.

Experimental material on structurally and functional organization, regulation of biosynthesis and activity, mechanism of action, genetic determinants, heterologous expression of bacterial L-asparaginases is accumulated. The modern approaches to isolation and purification of these enzymes, some questions of practical using in oncology in the schedules combined chemotherapy of leukemia the native and modified forms of L-asparaginases are discussed. The some results before carried out in the IBMC RAMS and number institutes of the Russia on study bacterial L-asparaginases and glutamine(asparagine)ases are summarized.

[Biological properties of glutamin-(asparagin-)ase from Pseudomonas boreopolis 526]. / Biologicheskie svoistva glutamin(asparagin)azy iz Pseudomonas boreopolis 526.

Glutamine(asparagine)ase from Ps. boreopolis 526 has an antineoplastic effect on lymphoid leukemia P-388. The enzyme half-life in the mouse serum is 8.5 hours. Glutamine(asparagine)ase has no cross-antigenicity with L-asparaginase from E. coli (Bayer, FRG). Specific antibodies against L-asparaginase (Bayer, FRG) do not influence the activity of glutamine(asparagine)ase.

[The effect of preparations of microbial glutamin(asparagin)ase on cultured tumor cells]. / Deistvie preparatov glutamin[asparagin]azy iz mikroorganizmov na opukholevye kletki v kul'ture.

Glutamin (asparagin)ase from Pseudomonas boreopolis 526 is shown to produce a cytotoxic effect on the human ovary carcinoma cells (CaOv line), Fisher lympholeukemia (L-8 line) and Burkitt's lymphoma cells (P3HR line). A significant inhibition of the DNA synthesis is found in L-8 and P3HR cell lines. The enzyme is less active in the cells of the CaOv line.

[Effect of glutamin(asparagin)ase preparations from microorganisms on DNA synthesis in tumor cells]. / Vliianie preparatov glutamin(asparagin)azy iz mikroorganizmov na sintez DNK v opukholevykh kletkakh.

The effect of glutamin (asparagin)ase from Pseudomonas fluorescens and Pseudomonas boreopolis 526 on DNA synthesis by tumor cells, lines CaOv and L8, has been studied. The L8 cells have been demonstrated highly sensitive to the enzyme.

[Improved procedure for isolation and purification of methionine gamma-lyase from Pseudomonas putida]. / Usovershenstvovannyi metod vydeleniia i ochistki metionin-gamma-liazy iz Pseudomonas putida.

An improved, simplified and relatively rapid procedure is developed for isolation and purification of a new antitumor enzyme--methionine gamma-lyase from Pseudomonas putida. The method includes five steps instead of seven steps in previous procedure with a good yield of the enzyme. The purified enzyme was shown to be homogeneous by the criteria of disc gel electrophoresis. The highly homogeneous preparations of the enzyme exhibited the absorption maxima at 280 and 420 nm. The detailed studies on antileukemic activity of the methionine gamma-lyase are currently in progress.

[Cytotoxic effect of methionine-gamma-lyase on neoplastic cells in culture]. / Tsitotoksicheskii éffekt metionin-gamma-liazy na rakovye kletki v kul'ture.

The influence of methionine-gamma-lyase from Pseudomonas putida on DNA synthesis by CaOv and L-8 cell lines has been studied. The agent has been demonstrated to inhibit the incorporation of 3H-thymidine into L-8 cell line and to have no effect on CaOv cells.