Effects of intraperitoneal administration of hexasodium N,N,N′,N′-ethylenediaminetetramethylenephosphonate on rat bone metabolism

The influence of hexasodium N,N,N′,N′-ethylenediaminetetramethylenephosphonate (EDITEMP.Na₆) on biochemical parameters in bone has been studied to help explain recently reported histological and pathological changes in bone induced by this agent. A single, intraperitoneal (ip) injection of EDITEMP.Na₆ (350 μmol/kg on Day 0) significantly decreased the activity of serum alkaline phosphatase (Alp) in mature male Wistar rats for up to 10 days following the injection. However, in immature rats the initial EDITEMP.Na₆-induced reduction of serum Alp activity preceded a steady increase in serum Alp activity, which was significantly elevated between Days 6 and 13. This increase coincided with a significant increase in bone Alp activity (an indicator of bone formation) on Day 8. Diaphyseal acid phosphatase (Acp) activity (an indicator of bone resorption) was significantly reduced, on Days 4 and 8 but not on Day 1, following treatment with EDITEMP.Na₆. Repeated exposure of immature male Wistar rats to EDITEMP.Na₆ (70 μmol/kg/day, ip for 7 days) also led to a significant and persistent increase in serum and bone Alp activities and a reduction in diaphyseal Acp activity. The data are in accord with published histomorphological evidence of reduced bone resorption and suggest delayed mineralization of osteoid tissue laid down during the treatment with EDITEMP.Na₆. There were only transient and limited changes in bone DNA content and [³H]thymidine incorporation throughout the studies, indicating the absence of marked cytotoxicity or altered bone cell proliferation associated with EDITEMP.Na₆-induced changes in phosphatase enzyme activities.     

Synthesis of N1-Retinoyi-5-fluorouracil

Although 5-fluorouracil is one of the most widelyused cytotoxic drugs in the treatment of solid tumors inmany organs, it has a severe drawback in its serious side-effects (e.g. gastrointestinal and bone marrow toxicity)and the properties (e.g. low lipophilicity) leading tovarious delivery problems. The low lipophilicity of 5-fluorouracil may be a predominant factor for its poorbiomembrane permeability.     

Synthesis, characterization, and antimicrobial activity of copper(II) complexes with N,N′-propanediyl-bis-benzenesulfonamide and N,N′-ethanediyl-bis-2-methylbenzenesulfonamide

Copper(II) complexes of new aryldisulfonamides (L ₁  = N,N′-bis[(2-methylphenyl)sulfonyl]ethylenediamine) and L ₂  = N,N′-propanediyl-bis-benzenesulfonamide with 1,10-phenanthroline have been synthesized and characterized by using elemental analyses, FT-IR, LCMS, conductivity, and magnetic susceptibility techniques. The structures of [Cu(phen)₂]L₁ (1) and [CuL₂(phen)₂] (2) compounds have been determined. Complex (1) has also been characterized by single crystal X-ray diffraction. The complex (1) crystallizes in the triclinic system, space group P1, with cell constants a = 12.9353(8) Å, b = 13.8543(9) Å, c = 14.4513(10) Å, α = 103.593(5)°, β = 113.713(5)°, γ = 106.104(5)°, and Z = 1. The antibacterial activities of synthesized compounds were studied against Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis, and B. cereus and Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, and Yersinia enterocolitica by microdilution (as MICs in μg/mL) and disk diffusion (as diameter zone in mm) method. The biological activity screening showed that (1) has more activity than (2) against the tested bacteria.     

Synthesis and Biological Evaluation of Ω-(N,N,N-Trialkylammonium)alkyl Esters and Thioesters of Carboxylic Acid Nonsteroidal Antiinflammatory Agents

A series of novel -(N,N,N-trialkylammonium)alkyl ester and thioester derivatives [RCOM(CH₂) _n NR ₃ ⁺ X ^–, M = O or S, n = 2–6, X = I or Cl] of 11 nonsteroidal antiinflammatory carboxylic acid agents (naproxen, ketorolac, indomethacin, ibuprofen, sulindac, ketoprofen, flufenamic acid, mefenamic acid, zomepirac, etodolac, and tifurac) was prepared and evaluated for their antiinflammatory, analgesic, and gastrointestinal erosive properties. In general, each prodrug retained the antiinflammatory activity characteristic of the corresponding parent drug but exhibited moderately to greatly reduced gastrointestinal erosive properties and significantly reduced analgetic potencies. This profile is likely due to a combination of factors including the rate of hydrolysis of the esters in the stomach, gut, and plasma, changes in the locus of absorption of the prodrug or nonsteroidal antiinflammatory drug (NSAID), and altered metabolic disposition patterns resulting from these changes. The results obtained from the compounds of this series indicate that esters of this general class may offer a means to modulate both the aqueous/lipid solubility and the hydrolytic/enzymatic cleavage indices of NSAID prodrugs which potentially possess a more favorable therapeutic ratio of antiinflammatory to gastrointestinal erosive activities.     

Protective Effect of N‐Acetylcysteine Against Arsenic‐Induced Depletion In Vivo of Carbohydrate

N‐acetylcysteine (NAC), a synthetic aminothiol, possesses antioxidative and cytoprotective properties. The present study evaluates the effect of NAC supplementation on arsenic‐induced depletion in vivo of carbohydrates. Arsenic (as sodium arsenite) treatment (i.p.) of male Wistar rats (120–140 g b.w.) at a dose of 5.55 mg/kg body weight (35% of LD₅₀) per day for a period of 30 days produced a significant decrease in blood glucose level (hypoglycemia) and a fall in liver glycogen and pyruvic acid contents. The free amino acid nitrogen content of liver increased while that of kidney decreased after arsenic treatment. Arsenic also enhanced the liver lactate dehydrogenase activity whereas glucose 6‐phosphatase activity in both liver and kidney decreased significantly following arsenic treatment. Transaminase activities in liver and kidney were not significantly altered except the glutamate–pyruvate transaminase activity that was reduced in kidney after arsenic treatment. Oral administration of NAC (163.2 mg/kg/day) for last 7 days of treatment prevented the arsenic‐induced hypoglycemia and glycogenolytic effects to an appreciable extent. There was also recovery of liver pyruvic acid as well as liver and kidney free amino acid nitrogen content after NAC supplementation. Arsenic‐induced alteration of glucose 6‐phosphatase activity in both liver and kidney was also counteracted by NAC. It is suggested that carbohydrate depletion in vivo due to exposure to arsenic can be counteracted by NAC supplementation.     

Synthesis antimicrobial and anticancer activity of N′-arylmethylidene-piperazine-1-carbothiohydrazide

Ten newly synthesized thiosemicarbazones of piperazine (3a–3j) were evaluated for their antibacterial and antifungal activity against non-pathogenic strains of Escherichia coli (NCIM 2068), Klebsiella pneumonia (NCIM 2957), Staphylococcus aureus (NCIM 2079), and Bacillus subtilis (NCIM 2921); pathogenic strains of Vibrio cholerae, protease, Candida albicans and Aspergillus niger. All the 10 compounds (3a–3j) were found to be better than Ciprofloxacin against B. subtilis and four molecules (3c, 3d, 3e, and 3h) against S. aureus. Compound 3j, a derivative of benzophenone, has been identified as a potent and promising candidate against C. albicans. The compounds were also evaluated for their anticancer activity against HBL-100 and HL60 cell lines. Compound 3a, a p-hydroxy benzaldehyde derivative, has been identified as a potent and promising candidate.     

N3,N7-diaminophenothiazinium derivatives as antagonists of α7-nicotinic acetylcholine receptors expressed in Xenopus oocytes

Derivatization of phenothiazine (PTZ, 1) has been a commonly used method to develop drugs with various pharmacological properties. In the present study, a series of PTZ derivatives 1-11 were investigated on the inhibition of the cloned α7 subunit of the human nicotinic acetylcholine receptor (α7-nAChR) expressed in Xenopus oocytes by using the two-electrode voltage-clamp technique. In the first series of experiments, the effect of unsubstituted phenothiazine 1 on α7-nAChRs was compared with that of the N3,N7-diaminophenothiazin-5-ium derivative 2, and of sequentially methylated derivatives 3-6. In the second set of experiments, the effects of N3,N7-tetra-ethyl- to n-hexylphenothiazin-5-ium derivatives 7-11 were tested. Despite the lack of activity found for 1, a reversible inhibition of α7-nAChRs, ranging from moderate to potent, was observed as a result of a sequential amine- and methylamine substitution of 1. The inhibition of ACh (100 μM)-induced currents was concentration-dependent with IC(50) values ranging from 0.4 to 16.8 μM. However, an optimal inhibitory activity was achieved by prolongation of alkyl chains up to propyl size, as found in PTZ derivative 8, whereas further lengthening of alkyl chains to n-butyl-, n-pentyl-, or n-hexyl groups resulted in inactive derivatives 9-11. The results evidently suggest the presence of a lipophilic binding pocket of narrow tolerability on the receptor protein. These results emphasize the importance of amine and/or alkylamine moieties for the inhibitory effect of PTZ derivatives and provide further insights for the development of novel antagonists targeting α7-nAChRs.     

Sustained Release of Naltrexone from Poly(N‐Isopropylacrylamide) Microgels

The release of the opioid antagonist naltrexone from neutral poly(N‐isopropylacrylamide) (PNIPAAM) microgels and negatively charged PNIPAAM microgels containing acrylic acid groups (PNIPAAM‐co‐PAA) has been studied at various microgel and drug concentrations. The release curves were found to be well represented by the Weibull equation. The release rates were observed to be dependent on the microgel concentration. At most conditions, the release from the charged microgels was slower than for the neutral microgels. In addition, the charged microgels exhibited a release lag time, which was dependent on the microgel concentration. No significant lag time could be observed for the neutral microgels. Increasing the naltrexone concentration did not significantly affect the release rates from the neutral microgels, but the release from the charged microgels became faster. The microgels did not exhibit any significant cytotoxic effect on HeLa cells at the tested concentrations. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:227–234, 2014     

Does the polymorphism of cytochrome P-450 2E1 affect the metabolism of N,N-dimethylformamide?

The aim of this study was to clarify whether phenotypic variation exists when subjects with different genotypes of cytochrome P450 2E1 (CYP2E1) are exposed to N,N-dimethylformamide (DMF). The genotypes of CYP2E1 were confirmed in 123 healthy male volunteer subjects. Of the 123 subjects, the numbers of c1 homozygotes, c2 heterozygotes, and c2 homozygotes were 77, 45, and 1, respectively. Seven of the c1 homozygotes, five of the c2 heterozygotes, and the one c2 homozygote (mean age: 22.7 years, range: 20-27 years) were exposed to DMF vapor twice, once via the skin and once via the lung, for a total of 8 h per subject at a concentration below 10 ppm, the occupational exposure limit recommended by the Japan Society for Occupational Health, the American Conference of Governmental and Industrial Hygienists, and Deutsche Forschungsgemeinschaft, at 27 degrees C and 44% relative humidity. Exposure levels were 6.2+/-1.0 ppm in dermal exposure and 7.1+/-1.0 ppm in inhalation exposure. Urine samples were collected until 72 h after exposure. The half-lives of urinary N-methylformamide (NMF) were obtained as the phenotype. The average urinary NMF half-lives of the c1 homozygotes, the c2 heterozygotes, and the c2 homozygote were 3.86+/-1.90, 4.38+/-1.53, and 4.2 h after dermal exposure, and 1.58+/-0.42, 1.84+/-0.61, and 3.2 h after respiratory exposure. The NMF half-lives of the c1 homozygotes were not significantly different from those of the c2 heterozygotes, and there were no differences between the NMF half-lives on the subjects with and without the c2 allele. Even though the data were obtained from only one c2 homozygote, it is noteworthy that the NMF half-life of this subject was slightly less than that of the c1 homozygotes after respiratory exposure.     

Isotopic analysis of N and O in NO3 − by selective bacterial reduction to N2O for groundwater pollution

We describe a method to determine the nitrogen and oxygen isotopic composition of nitrate in groundwater samples (¹⁵N/¹⁴N and ¹⁸O/¹⁶O, respectively), which is based on the analysis of nitrous oxide gas (N₂O) that is produced quantitatively from nitrate by denitrifying bacteria. This method which is simple, inexpensive and effective in the removal of nitrite is greatly selective for NO₂ ^? and was used for mixed samples containing both NO₂ ^? and NO₃ ^? with little or no measurable cross-contamination. The precision of δ¹⁵N and δ¹⁸O are 0.3 and 0.17 ‰ respectively, compared to that of 0.1 and 0.5 ‰ abroad (Brand et al. in Org Geochem 21:585–594, 1994; Begley and Scrimgeour in Anal Chem 69(8): 1530–1535, 1997; Kornexl et al. in Rapid Commun Mass Spectrom 13(16):1685–1693, 1999; Böhlke et al. in Rapid Commun Mass Spectrom 17:1835–1846, 2003; Gehre and Strauch in Rapid Commun Mass Spectrom 17(13):1497–1503, 2003; Werner in Isot Environ Health Stud 39:85–104, 2003).     

Effect of different oxygen pressures and N,N′-diphenyl-p-phenylenediamine on adriamycin® toxicity to cultured neonatal rat heart myocytes

The effect of different oxygen pressures and the antioxidant DPPD (N,N′-diphenyl-p-phenylenediamine) on Adriamycin (doxorubicin) cytotoxicity in highly purified cardiac myocytes was investigated to evaluate the involvement of free radicals in the mechanism of toxicity. Adriamycin exposure caused a time-dependent decrease in viability measured as intracellular potassium ion release or lactate dehydrogenase retention. Incubation of myocytes in 16, 172 or 834 μM oxygen during exposure to 200 μM Adriamycin for 6 hr killed 13, 42 and 56% of the cells in the respective cultures. DPPD prolonged viability in the latter two oxygen concentrations and protected against lipid peroxidation measured as production of malondialdehyde and 4-hydroxynonenal. Addition of superoxide dismutase decreased the Adriamycin-induced cell killing to 6% after a 4-hr incubation, as compared to 24% in cultures exposed to Adriamycin only. Adriamycin exposure decreased the concentration of reduced glutathione, and the toxicity of the drug was increased when glutathione reductase was inhibited by the addition of BCNU (1,3-bis-2-chloroethyl-1-nitrosourea). No significant effect on Adriamycin toxicity was observed after inhibition of glutathione synthesis by treatment with BSO (buthionine sulfoximine). It is concluded that free radicals play an important role in Adriamycin toxicity to heart myocytes, and that the cell killing mechanism is likely to be related to induction of lipid peroxidation.     

Protolytic constants of nizatidine,ranitidine and N,N′-dimethyl-2-nitro-1,1-ethenediamine; spectrophotometric and theoretical investigation

The prototropic exchange equilibria of two drugs, nizatidine (I) and ranitidine (II), and also of structurally related the N,N′-dimethyl-2-nitro-1,1-ethenediamine molecule (III) were investigated. From the changes in electronic spectra in media of various acidity several protonation constants were determined. For nizatidine pK values were −0.82, 1.95, and 6.67; for ranitidine pK values were 1.95 and 8.13; and for III was 2.60. The hydroxylation equilibrium constant in strongly alkaline media was determined too. Corresponding pK_a values were 13.23 for I, 13.26 for II and 13.76 for III. Molecular orbital calculations of electronic spectra confirmed that pK 1.95 for I and II, and pK 2.60 for III, are associated with C-protonation of nitroethenediamine fragment, while all pK_a values correspond to the addition of HO⁻ anion at the same double bond.     

Inhibitory effects of N4 on membrane phospholipase A2 from porcine pancreas

AIM: To explore the potential mechanism of anti-inflam matory actions by N_(14). METHODS: Microplate assay and radioimmunoassay were applied respectively to investigate effects of N_(14) on porcine pancreatic phospholipese A_2(PLA_2) and cyclooxygenase of rabbit platelet. RE     

EC通过开展N＆N的章程

欧洲委员会（EC）称，纳米科学和纳米技术（N＆N）是一门新兴科学，将对经济、社会和环境带来重大积极影响，欧洲在该领域处于领先地位。然而，关于这些技术影响人类健康和环境的认识仍存在空白，同时还有伦理相关问题和对基本权利的尊重问题。     

In Vitro Antileishmanial,Trypanocidal, and Mammalian Cell Activities of Diverse N,N′ -Dihetaryl Substituted Diamines and Related Compounds

The leishmaniasis and Chagas diseases constitute a serious public health problem worldwide with few and ineffective treatment options. The search for new antiparasitic candidates at the initial steps of drug discovery and development is still necessary. The synthesis of 22 de novo synthetized N,N′-dihetaryl-alkyldiamine derivatives and in vitro antiparasitic activity were evaluated for the first time against intracellular and extracellular forms of Leishmania (Leishmania) infantum, L. (Viannia) panamensis, L. (Leishmania) amazonensis, and Trypanosoma cruzi. Additionally, the toxicity on mammalian cells was determined. Some of these substituted N,N′-diamines (25–35 % of the tested compounds) showed interesting results against free-living forms of parasites with activities at the inhibitory concentration (IC₅₀) level of 1.96 to 28.83 μM for L. (L.) infantum promastigotes and IC₅₀ of 0.02 to 5.31 μM for T. cruzi epimastigotes. No activity at the IC₅₀ level on intracellular amastigotes of T. cruzi was observed. However, N¹,N²-dibenzylethane-1,2-diamine 5a revealed an important activity against the intracellular amastigotes of L. infantum (IC₅₀ 25.42 μM ±0.33) and L. panamensis (IC₅₀ 58.20 μM ±3.23), while their analogue N¹,N⁴-dibenzylbutane-1,4-diamine 5c resulted in activity only against L. panamensis (IC₅₀ 11.19 μM ±0.20) without toxicity on Vero and THP-1 mammalian cells. The active compounds against intracellular parasites with low toxicity in mammalian cells may be considered for future studies in experimental models.