Anemia and porphyria caused by N,N′-methylene-bis-acrylamide (MBA) in Mice and rats

The effects of N,N-methylene-bis-acrylamide (MBA), a cross-linking agent, on blood and bone marrow after repeated oral doses, were studied in mice and rats. Body weight, three major elements of the blood — erythrocytes, leucocytes and platelets — reticulocytes and bone marrow cells, were all reduced in either or both animals, especially in mice. Phenobarbital (PB) treatment did not greatly modify the effects of MBA in mice. An increase in free erythrocyte porphyrins and a decrease in ALA-D activity were observed in both animals. Urinary porphyrins were elevated in rats after MBA-dosing. PB-treatment did not significantly affect the elevation of porphyrins. After cessation of the MBA-dosing, all these changes were inclined to be restored to normal levels. Amounts of liver total porphyrins and microsomal P-450, and red cell fragility were within normal ranges in mice.     

(35)S]GTPγS binding and opioid tolerance and efficacy in mouse spinal cord

The present study examined efficacy of a series of opioid agonists and then using chronic in vivo treatment protocols, determined tolerance to opioid agonist stimulated [³⁵S]GTPγS (guanosine 5′-O-(3-[³⁵S] thio)triphosphate) binding in mouse spinal cord membranes and compared it directly to spinal analgesic tolerance. The [³⁵S]GTPγS binding assay was used to estimate efficacy (E_max and τ; Operational Model of Agonism) of a series of opioid agonists for G-protein activation in mouse spinal cord. The rank order of opioid agonist efficacy determined in the [³⁵S]GTPγS assay using the Operational Model and E_max was similar. These efficacy estimates correlated with historical analgesic efficacy estimates. For tolerance studies, mice were continuously treated s.c. for 7 days with morphine, oxycodone, hydromorphone, etorphine or fentanyl and [³⁵S]GTPγS studies were conducted in spinal cord membranes. Other mice were tested in i.t. analgesia dose response studies (tailflick). Tolerance to DAMGO ([D-Ala²,N-MePhe⁴,Gly-ol⁵]enkephalin) or morphine stimulated [³⁵S]GTPγS binding (decrease in E_max) was observed following etorphine and fentanyl treatment only. These treatment protocols downregulate μ-opioid receptor density whereas morphine, oxycodone and hydromorphone do not. Spinal analgesic tolerance was observed following all treatment protocols examined (morphine, oxycodone and etorphine). Opioid antagonist treatment that specifically upregulates (chronic naltrexone) or downregulates (clocinnamox) μ-opioid receptor density produced a corresponding change in opioid agonist stimulated [³⁵S]GTPγS binding. Although receptor downregulation and G-protein uncoupling are among potential mechanisms of opioid tolerance, the present results suggest that uncoupling in mouse spinal cord plays a minor role and that the [³⁵S]GTPγS assay is particularly responsive to changes in μ-opioid receptor density.     

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 anticonvulsant evaluation of A series of (R)- and (S)-N-Cbz-α-aminosuccinmide and their structure activity relationship

A series ofN-Cbz-α-aminosucinimides (1), combining common moieties of various anticonvulsants such as N-CO-C-N and cyclic imide in a single molecule, were synthesized from the corresponding (R)- and (S)-N-Cbz-aspartic acid (2). And theirin vivo anticonvulsant evaluations in MES and PTZ test were investigated. And also the rotorod test for neurotoxicity was investigated. All the tested compounds (1), except1c and1f, showed significant anticonvulsant activities in both MES and PTZ test. And the most active compound among them in MES test was (R)-N-Cbz-α-amino-N-methylsuccinimide (1b) (ED₅₀=52.5 mg/kg) and (S)-N-Cbz-aminosuccinimide((1d) was most active in PTZ test (ED₅₀=78.1 mg/kg). And the TD₅₀ values of the tested compounds were above 117.5 mg/kg. These pharmacological data were comparable to those of currently available anticonvulsants. And also we found that the pharmacological effects were dependent on theirN-substituted alkyl chains and their stereochemistry.     

(6S)或(7S)-甲氧基β-内酰胺类抗生素

(6S)或(7S)-甲氧基-β-内酰胺类抗生素具有良好的耐酶作用.目前已有多个品种上市,例如:头孢西丁、头孢美唑、拉氧头孢和替莫西林.其(6S)或(7S)-甲氧基造成的空间位阻是该类药物耐酶的关键所在.这种空间位阻作用使得其自身的结构对β-内酰胺酶稳定,从而解决或减少了大量使用β-内酰胺类抗生素而引起的细菌耐药性问题.化学合成这类药物可根据甲氧基取代C-6位氢原子的方法不同分为直接法和间接法.     

Effects of N,N′-methylene-bis-acrylamide (MBA) on mouse germ cells — sperm count and morphology,and testicular pathology

The sperm count and morphology, and testicular histopathology were studied in mice over a period of 75 days following a single oral administration of 50, 100, and 200 mg/kg N.N-methylene-bis-acrylamide (MBA). With a 50 and 100 mg/kg dose, the sperm abnormality reached a maximum at 30 days, whereas the sperm count reached a minimum at 35 days. The abnormality and decrease in sperm count were both dose dependent. Following the administration of 200 mg/kg MBA, the appearance of abnormal sperm showed a diphase pattern, i.e., first at 7–15 days without any reduction of the sperm count and second at 30 days after treatment. Testicular histopathological changes showed that resting spermatocytes, succeeding leptotene and zygotene spermatocytes were either absent or reduced 1–3 days after treatment with 200 mg/kg MBA. These early histopathological changes seemed to precede both the increase in abnormal sperm and the decrease in sperm count observed 30–35 days post-treatment, and also suggested that resting spermatocytes were most sensitive to MBA exposure among various spermatogenic cells.     

Kinetic studies on the intramolecular acyl migration of β-1-O-acyl glucuronides: Application to the glucuronides of (R)- and (S)-ketoprofen, (R)- and (S)-hydroxy-ketoprofen metabolites,and tolmetin by 1H-NMR spectroscopy

Conjugation of carboxylate drugs with D-glucuronic acid is of considerable interest because of the inherent reactivity of the resulting β-1-O-acyl glucuronides. These conjugates can degrade by spontaneous hydrolysis and internal acyl migration. β-1-O-acyl glucuronides and their acyl migration products can also react covalently with macromolecules with potential toxicological consequences. The spontaneous degradation of the diastereoisomeric β-1-O-acyl glucuronide metabolites of the racemic drug ketoprofen, two of its ring-hydroxylated metabolites and of tolmetin β-1-O-acyl glucuronide was investigated by ¹H-NMR spectroscopy in buffer solutions, at pH 7.4 and 37°C. A plot of the logarithm of the peak integrals against time revealed first-order kinetics. Degradation rates and half-lives were calculated for each glucuronide using first-order reaction equations. Tolmetin glucuronide had the fastest degradation rate, whilst all of the ketoprofen-related glucuronides had similar degradation rates. The degradation of the diastereoisomeric glucuronides was stereoselective, with the rate for the (S)-isomer always slower compared with the (R)-isomer by approximately a factor of 2.     

Anti-inflammatory and ulcerogenic effects of 3-(N,N-diethylamino)propylindometacin HCl

目的：考察盐酸３（Ｎ，Ｎ二乙胺）丙基吲哚美辛（ｐｒｏｄｒｕｇ）抗炎及致溃疡作用．方法：观察大鼠角叉菜胶（Ｃａｒ）性炎症反应及口服给药胃溃疡指数的变化．结果：腹腔给药显著抑制Ｃａｒ性趾水肿，３ｈ及５ｈ的抑制率分别为３６５７％和３４５６％，与等摩尔浓度的吲哚美辛（Ｉｎｄ）差异无显著性；足趾１０μｇ／ｐａｗ给药达到６４％的抑制率，再增加剂量不能增加效果；１４１８ｍｇ·ｋｇ－１的ｐｒｏｄｒｕｇ灌胃６小时后溃疡指数显著低于同摩尔数Ｉｎｄ．结论：该药为一抗炎作用强，致溃疡性低的药物．     

Synthesis and antifungal activity of sulfides,sulfoxides, and sulfones based on (1S)-(-)-β-pinene

Attachment of 2-mercaptoethanol and thioglycolic acid methyl ester to the double bond of (1S)-(-)-β-pinene yielded pinane sulfides with the cis configuration. Oxidation of sulfides with m-chloroperbenzoic acid yielded the corresponding sulfoxides and sulfones. The resulting compounds were screened for antimycotic activity and the dynamics of changes in antifungal properties in sulfides-sulfoxide-sulfone series were studied.     

When should a substance be designated as sensitizing for the skin ('Sh') or for the airways ('Sa')?

In the List of MAK and BAT Values compounds are designated with 'Sa' ('sensitizing for the airways') or 'Sh' ('sensitizing for the skin') if, according to scientific evidence, they are allergens. Mainly based on suggestions by a WHO working group and based on our own experience, extended criteria have been elaborated by the working group 'skin and allergy' of the Commission of the Deutsche Forschungsgemeinschaft for the Investigation of Health Hazards of Chemical Compounds in the Work Area, which are presented in this article. They serve as guidelines for deciding which substances have to be labelled 'Sa' and 'Sh', respectively, for the prevention of sensitization and subsequent allergic diseases in workers. Although in some special cases their strict application may not be deemed necessary or possible, the proposed new criteria should be used to make the procedure of classification of substances: 1) more rational, 2) more consistent, 3) more comprehensible, and 4) more transparent. This paper informs readers working scientifically or administratively in this field and invites a critical discussion of the issue.     

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.     

One-pot highly stereoselective synthesis of cyano aziridines via the CuCl-catalyzed aminochlorination of α,β-unsaturated nitriles and intramolecular S(N) 2 substitution

An efficient one-pot system has been developed for the synthesis of cyano aziridine by using α,β-unsaturated nitriles as the alkene substrates and N,N-dichloro-p-toluenesulfonamide (4-TsNCl(2) ) as the nitrogen source. A good scope of alkene substrates was achieved for this reaction. The one-pot reaction, via aminohalogenation and intramolecular S(N) 2 substitution, was very convenient to carry out at room temperature without the protection of inert gases. Modest to good yields and excellent have been obtained. This method provides an easy route to the cyano aziridine. The structure of the resulting products has been unambiguously confirmed by X-ray structural analysis.     

识别乙型肝炎病毒前S(2)抗原决定簇的单克隆抗体——前S(2)抗原决定簇及抗前S(2)抗体的特征

作者将小鼠骨髓瘤细胞与经乙型肝炎病毒(HBV)免疫的小鼠脾淋巴细胞融合,获得一株分泌单克隆抗体(McAb)的杂交瘤细胞,所产生的McAb能特异性地识别由HBV基因组前S(2)区编码的抗原决定簇。由这株杂交瘤细胞分泌的McAb Mo-F124能与HBV及重组HBsAg颗粒表面和前S(2)抗原决定簇反应。前S(2)抗原决定簇为前S(2)和S基因产物,即HBV包膜上的34KD糖蛋白,经金     

甲型流感(H1N1)疫苗

1 目前已有有效的抗甲型流感(H1N1)病毒的疫苗吗? 目前还没有,但是,这种疫苗的研制工作已在进行中.流感疫苗通常含有死的或减毒的流行病毒株.疫苗刺激机体免疫系统以防御感染,为了增强疫苗的保护作用,疫苗病毒应与流行"野型"病毒密切相配.由于这种H1N1病毒是新的,目前没有用这种特定病毒制备的疫苗.制备一种新流感疫苗可能需要5～6个月.     

甲型流感(H1N1)疫苗

1 目前已有有效的抗甲型流感(H1N1)病毒的疫苗吗? 目前还没有,但是,这种疫苗的研制工作已在进行中.流感疫苗通常含有死的或减毒的流行病毒株.疫苗刺激机体免疫系统以防御感染,为了增强疫苗的保护作用,疫苗病毒应与流行"野型"病毒密切相配.由于这种H1N1病毒是新的,目前没有用这种特定病毒制备的疫苗.制备一种新流感疫苗可能需要5～6个月.