Modeling of human dermal absorption of octamethylcyclotetrasiloxane (D(4)) and decamethylcyclopentasiloxane (D(5)).

In this study, data for human dermal absorption of octamethylcyclotetrasiloxane, D(4), and decamethylcyclopentasiloxane, D(5), through axilla skin in vivo are interpreted using pharmacokinetic models of dermal absorption by adding the dermal exposure route to inhalation physiologically based pharmacokinetics models developed previously. The compartmental model describing dermal absorption of these compounds included volatilization of the applied chemical from the skin surface, diffusion of absorbed chemical back to the skin surface and evaporation of this chemical from the skin surface after the applied dose had cleared from the application site, uptake from the skin compartment into blood, and a storage compartment within the skin. Data from exposures in volunteers (i.e., D(4) and D(5) concentrations in exhaled air and plasma) were used to estimate model parameters. In volunteers exposed to either D(4) or D(5), the maximum concentration of chemical in exhaled air reached a maximum at or prior to 1 h following administration of the test chemical. Based on model calculations, the percent of applied dose of D(4) that was absorbed into systemic circulation for men and women was 0.12 and 0.30%, respectively; for D(5) about 0.05% of the applied dose was absorbed for both men and women. For both D(4) and D(5), model calculations indicate that more than 83% of the chemical that reached systemic circulation was eliminated by exhalation within 24 h. These whole-body pharmacokinetic models for dermal absorption of two semi-volatile compounds provide a valuable tool for understanding factors controlling their dermal absorption through axilla skin and for applying results from these studies in consumer product risk assessments.     

Agonist binding and activation of the rat beta(1)-adrenergic receptor: role of Trp(134(3.28)), Ser(190(4.57)) and Tyr(356(7.43))

We investigated the role of Trp(134(3.28)), Ser(190(4.57)) and Tyr(356(7.43)) in agonist binding to, and activation of, the rat beta(1)-adrenergic receptor by comparing pK(i)s and functional responses of W134A, S190A and Y356F mutant receptors to wild type, all stably expressed in CHO cells. All three mutations significantly (P < 0.05) reduced adenylyl cyclase intrinsic activity (IA) compared to wild type in response to stimulation with both (-)-isoprenaline (53-88%) and (-)-RO363 (46-61%), and there was no significant correlation either between IA or pD(2) and pK(i) (P > 0.4), suggesting that changes in pK(i) were not sufficient to explain the fall in adenylyl cyclase activity. The most pronounced reduction in affinity (126-fold, P < 0.01) was displayed by xamoterol for the Y356F mutation, suggesting that xamoterol is able to directly interact with Tyr(356(7.43)). For the other agonists, the change in pK(i) values for the mutant receptors ranged from a 20-fold decrease to a 2-fold increase compared to the wild type. In a three-dimensional model of the rat beta(1)-adrenergic receptor, Trp(134(3.28)) and Tyr(356(7.43)) form part of a hydrophobic binding pocket involving residues in transmembrane helices 1, 2, 3 and 7. Our results suggest that Trp(134(3.28)) and Tyr(356(7.43)), together with Trp(353(7.40)), are able to interact via pi-pi interactions to stabilize the extracellular ends of transmembrane helices 3 and 7. Ser(190(4.57)) appears to be involved in a hydrogen bonding network, which maintains the spatial relationship between transmembrane helices 3 and 4. These interhelical interactions suggest that the three mutated residues stabilize the active receptor state by maintaining the proper packing of their respective transmembrane helix within the helix bundle, facilitating the appropriate movement and rotation of the transmembrane regions during the activation process.     

(S)-(-)-氨磺必利-D-(-)-酒石酸盐的合成

目的研究（S）-（-）-氨磺必利-D-（-）-酒石酸盐的制备方法。方法以4-氨基-2-甲氧基-5-巯基苯甲酸为原料,经乙基化、氧化得4-氨基-2-甲氧基-5-乙基磺酰基苯甲酸（4）,另由1-乙基-2-氨甲基吡咯烷经D-（-）-酒石酸拆分得S-（-）-1-乙基-2-氨甲基吡咯烷（6）,4与6缩合制得S-（-）-氨磺必利（7）,再与D-（-）-酒石酸成盐制得目标物S-（-）-氨磺必利-D-（-）-酒石酸盐（1）。总收率达25%（以4-氨基-2-甲氧基-5-巯基苯甲酸计算）。结果所得产物经元素分析,红外光谱、核磁共振谱及质谱确证了结构。结论本方法原料易得,反应条件温和,产品质量易控制。     

四-(三氟乙烷氧基)酞菁锌的光物理性质研究

目的研究2（3）,9（10）,16（17）,23（24）-四（三氟乙烷氧基）酞菁锌（ZnPcF）光物理性质（包括紫外吸收光谱、荧光光谱）和光敏化作用产生的单线态氧量子产率。方法采用紫外-可见分光光度法和荧光分光光度法分别测定ZnPcF的紫外-可见吸收光谱、荧光光谱;应用9,10-二甲基蒽为捕捉单线态氧的探针,通过测定光敏化过程中探针浓度的变化,计算ZnPcF的单线态氧（1O2）量子产率。结果与酞菁锌（ZnPc）相比,ZnPcF的紫外可见光谱和荧光光谱都有一定程度的红移。ZnPcF的摩尔消光系数（ε）为1.65×104 L·mol^-1·cm^-1,荧光量子产率为0.197,单线态氧量子产率为0.547。结论 ZnPcF有较大的摩尔消光系数、荧光及单线态氧量子产率,有进一步开发其抗肿瘤效果的前景。     

Regulation of human D(1), d(2(long)), d(2(short)), D(3) and D(4) dopamine receptors by amiloride and amiloride analogues

1. The modulatory effects of the allosteric effectors methylisobutylamiloride (MIA), benzamil and amiloride have been examined at human D(1), D(2), D(3) and D(4) dopamine receptors. The subtype selectivity and the mechanism of action of this allosteric regulation was examined. 2. In radioligand dissociation experiments each modulator accelerated dissociation from all four receptor subtypes indicating allosteric regulation. MIA displayed selectivity for the D(3) subtype for acceleration of radioligand dissociation. 3. In equilibrium binding (pseudo-competition) experiments the three compounds inhibited radioligand binding at the four receptor subtypes. Inhibition curves for D(1), D(2(short)), D(2(long)) and D(3) receptors were described by Hill coefficients exceeding unity and data were fitted best by a model that assumes binding of modulator to both the primary and allosteric binding sites of the receptor (the allosteric/competitive model). 4. At the D(4) subtype, Hill coefficients of unity described the binding data for amiloride and benzamil, consistent with competitive inhibition. The Hill coefficient for MIA at the D(4) subtype was less than unity and data could be fitted well by the allosteric/competitive model, but it was not possible to define unambiguously the modulatory mechanism. For this effect a better definition of the mechanism could be obtained by simultaneous analysis of data obtained in the presence of a range of concentrations of a purely competitive ligand. 5. MIA reduced the potency with which dopamine stimulated [(35)S]-GTPgammaS binding at the D(2) receptor. The effects of MIA could be described by the allosteric/competitive model with effects of MIA to inhibit the binding of dopamine but not its ability to induce a response.     

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.     

（S）—（＋）—2—氨基丙醇制备新工艺

(S) - ( ) - 2 -氨基丙醇 ( 1 )是合成左氧氟沙星的重要中间体 [1] ,随着左氧氟沙星作为国家基本药物在国内上市 ,开发适合我国国情的制备 1的简便新工艺显得很有必要。文献报道 [2 ,3 ] ,采用 Li Al H4 还原 L-丙氨酸 ( 2 )可以制得 1 ,该法的优点是反应过程简单 ,缺点是Li Al H4 价格昂贵 ,并且比较危险 ,同时后处理也比较复杂。另有文献报道 [4 ] ,先将 2酯化 ,然后采用较为便宜的 KBH4 还原制备 1 ,该法收率太低而不能用于工业化。为了提高收率 ,降低成本 ,我们对后一条合成路线进行了工艺研究 ,在将 2酯化得 L-丙氨酸乙酯 ( 3)…     

Psychopharmacological profile of 1-(m-(trifluoromethyl) phenyl) piperazine (TFMPP)

The effect of TFMPP, an agonist of the 5-HT1b receptors, was studied in mice on several psychopharmacological parameters. In contrast to imipramine-like drugs, TFMPP neither antagonized reserpine-induced hypothermia nor increased yohimbine-induced toxicity. Similarly to imipramine-like drugs, TFMPP antagonized oxotremorine-induced hypothermia and was active in the behavioural despair test. In addition, TFMPP normalized a social behavioural deficit induced by isolation. The effects of TFMPP on oxotremorine-induced hypothermia in the behavioural despair test and in the isolation-induced social behavioural deficit are all antagonized by d-1 propranolol. It is concluded that TFMPP seems to possess psychotropic activity resembling only in part that of imipramine-like drugs and that these actions may be mediated through 5-HT1b receptors.     

Inhibition of Poly(ADP-Ribose)Polymerase (PARP)

Recently, studies of B-cell physiology have continued to provide new and surprising insights into the nature of autoimmunity, highlighting novel potential immunointervention strategies. The meeting on ‘B cells and autoimmunity: new concepts and therapeutic perspectives’ brought together basic scientists and clinicians with research interests in a range of autoimmune diseases. Recent advances in different facets of B-cell biology were discussed in the prospect of understanding autoimmunity, and significant advances in our understanding of the mechanisms that regulate the autoimmune response at the B cell-level were described. Even though no single message emerged, it is clear that the B lymphocyte is truly destined to become a therapeutic target for the treatment of autoimmune disease.     

Effect of alpha-mercaptopropionylglycine (alpha-MPG) and sodium dipropylacetate (DPA) on antibody formation (I) (author's transl)]

The humoral immuno-response: A study was carried out to determine the effect of alpha-MPG and DPA on humoral antibody formation. The following results were obtained: The 1st and 2nd immuno-responses in rabbits to bacterial alpha-amylase were potentiated by treatment with both alpha-MPG and DPA given i.p. for 10 days after the 1st immunization, but the treatment after the 2nd immunization did not affect the 2nd immuno-response. Formation of hemolytic plaque forming cells (HPFC) in the spleen of mice immunized with 5 X 10(8) sheep red blood cells (SRBC) was potentiated by the administration of the both drugs given i.p. for 5 days before or after the immunization. No appreciable formation of HPFC was observed by immunization with 5 X 10(6) SRBC, and here alpha-MPG or DPA were without effects. Immunization with more than 5 X 10(7) SRBC resulted in an increase of HPFC in a dose-dependent fashion. Such an increase was further reinforced by treatment with both drugs. HPFC increased with a single dose of alpha-MPG at 48 hr before or 24 approximately 72 hr after the immunization and also increased with that of DPA at 24 hr before or immediately after the SRBC treatment.     

Mechanisms of anabolic androgenic steroid modulation of alpha(1)beta(3)gamma(2L) GABA(A) receptors

Modulation of GABA(A) receptors induced by both anabolic androgenic steroids (AAS) and the benzodiazepine (BZ) site agonist, zolpidem, show equivalent dependence upon gamma subunit composition suggesting that both compounds may be acting at a shared allosteric site. Here we have characterized modulation induced by the AAS, 17alpha-methyltestosterone (17alpha-MeT), for responses elicited from alpha(1)beta(3)gamma(2L) GABA(A) receptors and compared it to modulation induced by the BZ site agonists, zolpidem and diazepam. For responses elicited by brief pulses of 20 microM GABA, both the AAS and the BZ site compounds significantly increased the peak current amplitudes and total charge transfer, although 17alpha-MeT was an appreciably weaker agonist than either diazepam or zolpidem at alpha(1)beta(3)gamma(2L) receptors. Neither class of modulator enhanced peak current amplitudes for responses elicited by mM concentrations of GABA. BZ site compounds altered time constants of deactivation, desensitization, and recovery from desensitization, however 17alpha-MeT had no overall effect on these parameters. Experiments in which 17alpha-MeT and BZ site ligands were applied concomitantly indicated that potentiation elicited by 17alpha-MeT and zolpidem were additive and that potentiation by 17alpha-MeT could be elicited in the presence of concentrations of flumazenil that blocked BZ potentiation. Finally, kinetic modeling suggests that while effects of 17alpha-MeT can be simulated by altering receptor affinity, the data for these alpha(1)beta(3)gamma(2L) receptors were best fitted by simulations in which 17alpha-MeT increases transitions into the singly liganded open state. Taken together, our results suggest that 17alpha-MeT does not act at the high-affinity BZ site, but may elicit some of its effects at the low affinity BZ site or at a novel site.     

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.     

Physicochemical Properties and Pharmacological Activity of Mn(II), Fe(II), Co(II), Cu(II), AND Zn(II) Gluconates

Pharmaceutical Chemistry Journal -     

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.     

Effect of alpha-mercaptopropionylglycine (alpha-MPG) and sodium dipropylacetate (DPA) on antibody formation (III) (author's transl)]

Mechanisms of the immunostimulative activity. In the present paper, an investigation was carried out to clarify the mechanisms regarding immunostimulative activity of alpha-MPG and DPA. Phagocytosis of peritoneal macrophage was enhanced by high concentration of alpha-MPG, but was unaffected with DPA in vitro. Mice were immunized with an i.v. injection of sheep erythrocytes and 3 days later spleen cells were isolated and incubated with alpha-MPG and DPA FOR 24 HR. Although neither drug affected the number of recovered and living cells, hemolytic plaque forming cells were increased with alpha-MPG and there was a tendency to increase with DPA. Phytohemagglutinin-P and/or lipopolysacchride E. coli-induced blast formation was not reinforced by either drug in spleen cells of mice, and no mitogenic activity was found in the spleen cells. In the early stage of immuno-response to polyvinylpyrrolidone as a T cell independent antigen, the titre of antibody showed no increase after either drug. alpha MPG and DPA apparently act as potentiators in antigen modifications of macrophages.     

(R)-(-)-1-(2-萘基)-2-N-甲基氨基乙醇的合成

目的研究拟β-肾上腺素(R)-(-)-1-(2-萘基)-2-N-甲基氨基乙醇(1)的合成方法.方法以β-萘乙烯(2)为原料,通过烯烃的Sharpless不对称双羟化、环化、选择性开环、催化氢化、甲酰化、还原等6步反应制备目标产物.结果与结论设计的合成路线以β-萘乙烯计,6步反应总收率为39.3%,ee值高达97%～99%,合成路线易行.目标产物的结构经质谱、红外光谱、1H-NMR和13C-NMR确证.     

Pharmacological study of mequitazine (LM-209) (II). Anti-allergic action (author's transl)

The anti-allergic effect of Mequitazine (LM-209) which was found to have an anti-histaminic activity was investigated in guinea-pigs. The inhibitory activities of LM-209 on the Schultz-Dale reaction and ileum contraction by some mediators released from the sensitized guinea-pig lung were the same as those of clemastine fumarate (CL) but with 5 times the potency. LM-209 and CL, but these activities were less potent than in the case of disodium cromoglycate. The various anaphylactic reactions mediated by IgG in guinea-pigs were inhibited by LM-209, CL and chlorpheniramine maleate (CPM). The homologous PCA mediated IgE in rats was also inhibited by LM-209, CL and CPM, but the duration of the action with LM-209 was markedly longer. In experimentally-induced asthma, the decrease of respiratory rate and volume was significantly inhibited by LM-209, but was not affected by CL. Thus, LM-209 seems to inhibit the allergic reaction mainly by an antagonistic action on allergic mediators.