Di(isononyl) phthalate (DINP) and di(isodecyl) phthalate (DIDP) are not mutagenic

Recently there have been reports of liver and kidney tumors in rodents following long-term exposure to di(isononyl) phthalate (DINP). Mechanistic studies suggested that the liver tumors were a consequence of peroxisomal proliferation, whereas the kidney tumors (found only in male rats) were associated with induction of alpha(2u)-globulin. Because both peroxisomal proliferation and alpha(2u)-globulin are considered to be non-genotoxic carcinogenic processes, it seemed appropriate to investigate the genotoxic potential of DINP. Additional studies were also conducted on di(isodecyl) phthalate (DIDP), a structurally related substance that also induces peroxisomal proliferation, although it has not been tested in a carcinogenicity bioassay. The DINP was tested in Salmonella, in vitro cytogenetics and mouse micronucleus assays, whereas DIDP was evaluated in a mouse micronucleus test. All of these tests produced negative results, i.e. neither phthalate was mutagenic in any of the test systems. These data are consistent with results of other published and unpublished genotoxicity tests and provide support for the hypothesis that the liver and kidney tumors induced by DINP were the result of non-genotoxic processes.     

Allosteric interaction of zinc with recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) GABA(A) receptors

In a recent study we have provided evidence that inhibition of native GABA(A) receptors by zinc depends primarily on the allosteric modulation of receptor gating. Both the kinetics and the sensitivity of the GABA(A) receptor to zinc depend on subunit composition, especially on the presence of the gamma(2) subunit. To analyze the mechanism of action of zinc its effects have been tested on recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors expressed in HEK 293 cells. The currents produced by ultrafast application of GABA have been measured to assess the impact of zinc ions on GABA(A) receptor gating with resolution corresponding to the time scale of synaptic currents. While, as expected, zinc markedly reduced the peak amplitude of alpha(1)beta(2)-mediated currents, its effect on kinetics was significantly different from that observed for alpha(1)beta(2)gamma(2). In particular, unlike alpha(1)beta(2)gamma(2), zinc did not affect the onset of alpha(1)beta(2)-mediated responses. Moreover, zinc increased the extent of desensitisation of alpha(1)beta(2)gamma(2) receptors and reduced desensitisation of alpha(1)beta(2) ones. Quantitative analysis suggests that zinc exerts an allosteric modulation on both alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors. Zinc effects on alpha(1)beta(2)gamma(2) were qualitatively similar to those reported for native receptors.     

Serotonin(7) receptors (5-HT(7)Rs) and their ligands

Serotonin (5-HT) is involved in various physiological and pathological processes by interaction with 14 distinct receptor subtypes, grouped in seven classes of receptors (5-HT(1-7)) on the basis of amino acid sequence, pharmacology, and signal transduction pathways. The 5-HT(7)R is a G-protein coupled receptor with seven transmembrane domains. It was found by the application of molecular cloning and has been identified in rat, mouse, human, pig, and guinea pig. Although the biological functions of the 5-HT(7)Rs are poorly understood, preliminary evidence suggests that it may be involved in depression, control of circadian rhythms, and relaxation of vascular smooth muscles. For these reasons, the 5-HT(7)R has become a target for the development of novel drugs. This review will give a brief introduction of the pharmacology of 5-HT(7)R (molecular structure, distribution of 5-HT(7)R mRNA, localization of the 5-HT(7)R protein, functional correlates, and therapeutic potential) and a detailed survey of the 5-HT(7)R ligands, which have appeared in the literature in both papers and patents. Structure-activity relationships (SAR) of these ligands will also be described.     

Interactions between depressants (alcohol-type) and stimulants (amphetamine-type)

The rotarod disruption in rats by 1.5 g/kg of ethanol was prolonged by combining the depressant with 2 or 8 mg/kg d-amphetamine, but not after combinations with 4 or 6 mg/kg of the stimulant. The combination with 8 mg/kg d-amphetamine also induced a prolonged coma and lethality. Cocaine or methylphenidate in combination form with ethanol also showed prolonged disruption of rotarod performance, but severe depression and lethality were not observed at any dose combination. d-Amphetamine in combination with pentobarbital or diazepam also increased the duration of rotarod impairment. Amphetamine plus methaqualone did not prolong rotarod disruption, but rather showed a trend toward antagonism. These combinations of 8 mg/kg d-amphetamine with depressants other than alcohol did not cause prolonged coma and lethality. Lower doses of ethanol (0.25 and 0.5 g/kg) plus 8 mg/kg d-amphetamine induced a delayed impairment of rotarod performance in rats as well as a comatose state and lethality. Mice showed a similar trend for these interactions between alcohol and d-amphetamine but the influence was much less predictable. Analysis of alcohol levels in rat serum and brain indicated little effect of d-amphetamine on the rate of elimination of ethanol. On the other hand, 1.5 g/kg of ethanol prolonged the d-amphetamine decay from brain and serum. This latter interaction was not observed in rats treated with 8 mg/kg d-amphetamine plus 0.5 g/kg ethanol. Mice treated with 8 mg/kg d-amphetamine plus 2.25 g/kg alcohol showed little trend for changes in rate of elimination of either drug. The behavioral effects of the combination of d-amphetamine and ethanol cannot be explained adequately on the basis of altered pharmacokinetics of either drug.     

Bioaccumulation and toxicity of 4-nonylphenol (4-NP) and 4-(2-dodecyl)-benzene sulfonate (LAS) in Lumbriculus variegatus (Oligochaeta) and Chironomus riparius (Insecta)

The discharge of surfactants, such as 4-nonylphenol (4-NP) and linear alkylbenzene sulfonates (LAS), into water bodies leads to accumulation of the chemicals in the sediments and may thus pose a problem to benthic organisms. To study the bioaccumulation of surfactants, Oligochaeta worm Lumbriculus variegatus was exposed to sediment-spiked, [14C]-labeled 4-NP and 4-(2-dodecyl)-benzene sulfonate (C12-LAS) in three different sediments (S1-S3). The sediments were characterized for organic carbon (OC) content and particle size distribution. The acute toxicity was examined by exposing L. variegatus and three to four instar Chironomus riparius (Insecta) larvae in water-only exposure to 4-NP and LAS at different concentrations. After 48-h exposure, lethal water concentrations (LC50) and lethal body residues (LBR50) were estimated using liquid scintillation counting. Chronic toxicity was evaluated in two different sediments by exposing first instar C. riparius larvae to sediment-spiked chemicals at different concentrations. After 10 days, the sublethal effects of surfactants were observed by measuring wet weight and head capsule length. Finally, another 10-day test was set up in order to measure the LAS body residues associated with sublethal effects in C. riparius in S2 sediment. The bioaccumulation test revealed that the bioaccumulation of both 4-NP and LAS increased as the sediment organic matter content decreased. It is assumed that the chemical binding to organic material decreased chemical bioavailability. The acute toxicity tests showed that L. variegatus was more tolerant of 4-NP, and C. riparius was more tolerant of LAS when based on water exposure concentration. The LBR-estimates revealed, however, that L. variegatus tolerated clearly higher tissue residues of both chemicals compared with C. riparius. Both chemicals had sublethal effects on C. riparius growth in sediment exposure, reducing larvae wet weight and head capsule size. 4-NP, however, showed an irregular dose-response pattern. The characteristics of the exposure media affected the bioaccumulation potential of both chemicals. Thus, exposure concentrations offered no prediction of body residue, and therefore it is proposed that organism body residue offered a more accurate dose-metric for chemical exposure than the chemical concentration of the environment.     

Developmental toxicity of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Two phthalate esters, di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), have been assessed for their potential to cause developmental toxicity in the rat. Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D79P or D911P daily by oral gavage (5 ml/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. Treatment resulted in no signs of maternal toxicity, as assessed by adjusted maternal bodyweight gain throughout gestation and clinical examinations, and no effects upon litter size, fetal survival or bodyweight. Pups of the high dose D79P and intermediate and high dose D911P groups showed increased incidences of supernumerary lumbar ribs. There was a significant increase in dilated renal pelves in pups of the low dose D79P and high dose D911P groups, but only for D911P was there a significant trend. Consequently, the no observed adverse effect level (NOAEL) for maternal toxicity for both D79P and D911P is 1000 mg/kg/day. The NOAEL values for developmental toxicity are 500 mg/kg/day D79P and 250 mg/kg/day D911P.     

Two-generation reproduction toxicity studies of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), based on high-normality linear oxo-alcohols, have been assessed for their impact upon reproductive performance in Sprague-Dawley rats. Rats were continuously exposed to either D79P or D911P at dietary levels of 0%, 0.1%, 0.5%, or 1.0% over two generations. Selected F(0) offspring (F(1) generation) were exposed to the same dietary concentration of D79P or D911P as the respective F(0) animals, and were mated to produce F(1) offspring. Both D79P and D911P markedly reduced body weight gain in F(0) and F(1) adult males at the highest dose, but females were affected to a lesser extent. There was no impairment of fertility, fecundity, or development in either generation, but body weights of offspring in the 1.0% D79P and 1.0% D911P groups were slightly and transiently reduced over the weaning period. Although decreases in the weight of several organs were accounted for by depressed body weight, ovary weights were reduced in both generations exposed to 1.0% D79P, and epididymidal weights were slightly reduced in adults of both generations exposed to 1.0% D911P. However, ovarian function-assessed by the oestrus cycle and mating behaviour-and epididymidal sperm concentration, motility, and morphology were unaffected by either substance. Treatment resulted in liver changes, particularly in males, characterised by increased liver weight in young animals, histopathologic changes and reduced organ weight in mature animals, and an increase in palmitoyl CoA oxidase activity. In conclusion, neither D79P nor D911P impaired reproductive function in rats when administered in the diet at levels that induce systemic toxicity, and the NOAEL for effects on reproduction in the rat is 0.5% for both D79P and D911P.     

(Dichlorophenyl)alkenones and their oximes (author's transl)

(Dichlorophenyl)alkenones and Their Oximes Some dichlorobenzaldehydes are condensed with propanone or butanone to give the ketones 1 , 3 , and 4 . From 2,6-dichlorobenzaldehyde and butanone the crystalline aldol 7 is formed beside 3c and 4c . The oximes of all the unsaturated ketones were synthesized, and the oximes 2 and 5 were separated by thin-layer chromatography.     

N-(imidomethyl)-thiocyanates and -isothiocyanates (author's transl)

N-[Imidomethyl]-thiocyanates and -isothiocyanates From N-chloromethyl derivatives of phthalimides and of Δ⁴-cis-tetrahydrophthalimide as well as of isatin and of 3,3-dichloro-oxindole the N-thiocyanatomethyl derivatives 2c, 3c, 4c, 5c, 6c, 7c, 8c and corresponding isothiocyanates 1d, 3d, 5d, 6d, 7d have been prepared.     

槲皮素对大鼠钠钾腺苷三磷酸酶和钙镁腺苷三磷酸酶的影响(英文)

槲皮素(Que)ig 200mg·kg~(-1),qd×14d可显著降低大鼠心肌和脑钠钾腺苷三磷酸酶(Ⅰ)的活力及心肌钙镁腺苷三磷酸酶(Ⅱ)的活力;槲皮素100mg·kg~(-1)降低心肌Ⅰ的活力,但对脑Ⅰ无明显影响。实验结果提示,大鼠心肌Ⅰ对Que的反应较脑Ⅰ敏感;槲皮素也能显著抑制心肌Ⅱ的活力。     

Comparison of the radiorecovery activity of copper(II)2(3,5-diisopropylsalicylate)4 and copper(II) (chloride)2

Copper(II)₂(3,5-diisopropylsalicylate)₄ [Cu(II)₂(3,5-DIPS)₄] and copper(II)(chloride)₂ [Cu(II)Cl₂ were used to treat γ-irradiated female C57BL/6 mice after irradiation at levels LD50/30 to compare their efficacy in facilitating recovery from radiation-induced systemic inflammatory disease accompanied by loss of body mass and in increasing survival of irradiated mice. Doses of 5, 10 or 20 μmol Cu(II)Cl₂ or 5, 10 or 20 μmol [Cu(II)₂(3,5-DIPS)₄]/kg were administered subcutaneously 3 h after LD_50/30 irradiation and body mass and survival determined throughout the 30-day post-irradiation period compared with controls. Treatment with Cu(II)₂(3,5-DIPS)₄ or Cu(II)Cl₂ facilitated recovery of radiation-induced systemic inflammatory disease, recovery of body mass, and increased survival. Treatment with 5, 10 or 20 (μmol [Cu(II)₂(3,5-DIPS)₄]/kg produced a 44%, 67% or 44% increase in survival, respectively, compared with the vehicle-treated control group. Treatment with 5,10 or 20 μmol Cu(II)Cl₂/kg produced a 7%, 21% or 29% increase in survival, respectively, compared with the vehicle-treated control group. The recovery of radiation-induced loss in body mass and an increase in survival document that both Cu(II)₂(3,5-DIPS)₄ and Cu(II)Cl₂ are effective radiorecovery agents. In addition, Cu(II)₂(3,5-DIPS)₄ is a more effective radiorecovery agent than Cu(II)Cl₂.     

(S)-和(R)-盐酸氟西汀的合成

目的:研究光学活性盐酸氟西汀的合成工艺。方法:以苯乙酮为起始原料,经Mannich反应、还原、醚化3步反应合成外消旋氟西汀游离碱。外消旋体用L-( )-扁桃酸和D-(-)-扁桃酸反复交替拆分,分别得到了(S)-和(R)-型的盐酸氟西汀。结果:合成外消旋氟西汀游离碱的总收率为26.4%。拆分收率为42%。结论:该方法缩短了反应路线,操作简便,收率提高,适于工业生产。     

alpha-glucosidase (CHO) (Genzyme)

Genzyme General is developing recombinant human alpha-glucosidase, produced in mammalian cell culture, as a potential treatment for Pompe disease. By July 2004, enrollment was completed in two clinical trials and an observational study in adults. Genzyme was planning to file for regulatory approval in Europe during 2004, followed by filings in the US and Japan in mid-2005.     

(S)-(-)-Bromofosfamide (CBM-11): synthesis and antitumor activity and toxicity in mice

(S)-(-)-Bromofosfamide (CBM-11), an enantiomerically pure bromo analog of ifosfamide, was found to be potent against several model tumors in mice. Therapeutic indices of CBM-11 were more favorable as compared to those received for ifosfamide.