汝安膜祛腐生肌及抗菌作用研究

目的研究汝安膜的祛腐生肌及抗霉菌作用。方法制做大鼠感染模型,用汝安膜药液涂于感染创面1d1次,连用5d;制做白色念珠菌培养皿,观察汝安膜药液的抑菌环及测定其抗菌效价。结果汝安膜具有较强的祛腐生肌作用,有效率达100%,对白色念球菌具有较强的抑制作用。结论汝安膜可较强抑制细菌及霉菌的生长繁殖,促进组织再生,为临床治疗阴道炎,宫颈炎提供了可靠的理论依据。     

In vitro evaluation of the growth inhibition and apoptosis effect of mifepristone (RU486) in human Ishikawa and HEC1A endometrial cancer cell lines

PURPOSE: To determine the growth inhibitory effects of mifepristone on endometrial cancer cell growth and evaluate its effect on apoptosis using HEC-1-A and Ishikawa human endometrial cancer cell lines. METHODS: The human endometrial cancer cell lines, HEC-1-A and Ishikawa, were cultured in vitro. MTT assays were completed in order to estimate the IC(50) of mifepristone. Both cell lines were then treated with the respective IC(50) values. Immunohistochemistry assays were performed to investigate the expression of estrogen receptors alpha and beta (ERalpha/beta), progesterone receptor alpha and beta (PR alpha/beta), cyclooxygenase-2 (COX-2), bax, p53, and bcl-2. Flow cytometry analysis was performed to study cell cycle arrest and apoptosis. RESULTS: The estimated IC(50) of mifepristone for HEC-1-A and Ishikawa was found to be 16 and 19 mug/ml respectively. At this concentration, there was no change in either ERalpha/beta or PR alpha/beta in Ishikawa. However, PR beta expression increased with time of treatment in HEC-1-A. Expression of p53 was increased with duration of treatment in both cell lines. Consequently a decrease in bcl-2 and an increase in COX-2 expression were seen in HEC-1-A and Ishikawa cells, respectively. Lastly, flow cytometry analysis confirmed an accumulation of cells in G0 phase after 72 h of treatment in both cell lines. CONCLUSIONS: Mifepristone demonstrates activity in both HEC-1-A and Ishikawa cells at clinically relevant concentrations based on an oral human dose of about 200 mg/day. While its mechanism of action remains unknown, this data supports an increase in apoptosis that may be due to p53 activation rather than hormone receptor mediation. Additional studies are needed to help further identify mifepristone mechanism of action.     

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.     

不同剂量的米非司酮治疗子宫肌瘤的疗效比较

为了观察两种不同剂量的米非司酮（ＲＵ４８６）治疗子宫肌瘤的疗效，我们治疗了３３例子宫肌瘤病人，非随机分为两组进行前瞻性研究。１９例每天服用２５ｍｇＲＵ４８６（Ａ组），１４例每天服用１２．５ｍｇ（Ｂ组），都从月经第１￣３天开始服药，连续用３个月，治疗前及治疗后３个月均Ｂ超观察子宫及子宫肌瘤的大小。结果：Ａ组子宫肌瘤缩小３８．６７％，子宫缩小１０．３８％，Ｂ组子宫肌瘤缩小２５．９４％，子宫缩小１２．６     

Effect of quinine on autoreceptor-regulated serotonin release in the rat hippocampus

The involvement of K⁺ channels in the autoregulation of terminal serotonin (5-hydroxytryptamine, 5-HT) release was investigated by microdialysis in the hippocampus of conscious rats. Extracellular 5-HT was increased concentration-dependently by the K⁺ channel blocker quinine (10, 100 and 1000 μM in perfusate), and tetrodotoxin (10 μM) but not fluoxetine (5 μM) exerted a partially attenuating influence. The 5-HT_1/2/6 receptor antagonist methiothepin (50 μM) increased dialysate 5-HT, most likely through 5-HT_1B autoreceptors tonically activated in the hippocampus of awake rats as opposed to the previously reported lack of effect 5-HT_1B autoreceptor blockade in anesthetized rats. The effect of methiothepin was greatly reduced by preperfusion with quinine (100 μM), consonant with a role for quinine-sensitive K⁺ channels in the autoregulation of 5-HT release in the hippocampus by 5-HT receptor antagonism. In contrast, the reduction in dialysate 5-HT induced by the 5-HT₁ receptor agonist RU 24969 (1 μM), in the presence of fluoxetine (5 μM), persisted in the co-presence of quinine, consonant with the involvement of (extrasynaptic?) 5-HT autoreceptors not coupled with quinine-sensitive K⁺ channels.     

RU24969-induced behavioural syndrome requires activation of both 5HT1A and 5HT1B receptors

The behavioural profiles of the mixed 5HT_1A/B agonist RU24969 and the more selective 5HT_1B agonist anpirtoline were compared. Both compounds induce an increase in activity as measured in photocell activity cages. The behaviours displayed by the rats receiving each treatment differed markedly, with RU24969 inducing flat body posture and circling of the cage perimeter (1.25−10 mg/kg SC), whereas anpirtoline increased ambulation characterised by a hopping motion (1.25−5.0 mg/kg SC). The effects of RU24969 were attenuated by both the 5HT_1A antagonist WAY100635 (0.03−1.25 mg/kg SC) and the 5HT_1B/D antagonist GR127935 (1.0−5.0 mg/kg SC). Anpirtoline-induced behaviour was attenuated by GR127935 across the same dose range but was largely unaffected by WAY100635 even at doses above those which had blocked the effects of RU24969. Coadministration of the selective 5HT_1A agonist 8-OH-DPAT (0.03−1.25  mg/kg SC) with anpirtoline (2.5 mg/kg) induced a dramatic increase in locomotor activity and a behavioural syndrome identical to that produced by RU24969. Thus it would appear that a synergistic effect of stimulation of both 5HT_1A and 5HT_1B receptors underlies the behavioural effects of RU24969, while anpirtoline acts mainly via stimulation of 5HT_1B receptors only. Received: 31 October 1996/Final version: 24 February 1997     

Effects of adrenalectomy and type I or type II glucocorticoid receptor activation on 5-HT1A and 5-HT2 receptor binding and 5-HT transporter mRNA expression in rat brain

We evaluated the effects of adrenalectomy (ADX) and replacement with glucocorticoid receptor agonists on serotonin (5-HT) 5-HT_1A and 5-HT₂ receptor binding in rat brain. 5-HT_1A receptor binding was increased in the CA2–CA4 and the dentate gyrus of the hippocampus 1 week after ADX. This effect was prevented by the systemic administration of aldosterone (10 μg/μl/h) but not by RU28362 (10 μg/μl/h). No significant effect was observed on 5-HT₂ receptor binding in rat cortex. The expression of 5-HT transporter mRNA was unchanged in the raphe nucleus as measured by in situ hybridization.     

Tamoxifen and RU39411 synergize with mifepristone to produce preimplantation pregnancy loss by increasing embryo transport (rat)

Tamoxifen is a non-steroidal antiestrogen that possesess antagonistic as well a agonistic properties, while RU39411 is an antiestrogen that is known to possess only antagonistic properties. These steroid antagonists were administered orally to rats, with or without mifepristone, an antiprogestational agent, prior to implantation on Day 2 of pregnancy. The status of pregnancy was assessed on Day 14. Low doses of tamoxifen reduced litter size and weight and inducing embryonic absorption in some animals; a dose of 0.25 mg/Kg prevented pregnancy in all animals. RU39411 also had a dose-dependent effect on pregnancy, but a higher dose (0.5 mg/Kg) was required to achieve the same degree of pregnancy prevention. Addition of mifepristone to both antiestrogens had a synergistic effect on reducing litter size and weight.

To determine the mechanism by which antiestrogens terminate pregnancy in rats, oviducts and uteri of treated rats were examined for the presence of embryos on Day 3 and 4 of pregnancy, times when most embryos would be expected to be in the oviducts. Most of the embryos of the treated animals were found in the oviducts on Day 3 of pregnancy. By Day 4, only a few embryos were still present in oviducts. These observations suggest acceleration of embryo transport by Day 4 of pregnancy. There was no accumulation of embryos in the uterus. Since acceleration of embryo transport through the reproductive tract in rat is induced by low doses of estrogens, it is likely that the agonistic action of tamoxifen is responsible for pregnancy prevention in these experiments. The fact that RU39411 also prevents pregnancy by a similar mechanism suggests that this estrogen antagonist also has some estrogen agonist effects on the oviduct. The fact that both antiestrogens also affected embryo weight could suggest the action of the antihormones on other mechanisms controlling embryo development.     

Monoamine oxidase B expression is selectively regulated by dexamethasone in cultured rat astrocytes

The influence of dexamethasone on monoamine oxidase (MAO) A and B expression and activity was investigated in primary cultures of rat type 1 astrocytes cultured under serum free, defined conditions. Dexamethasone treatment resulted in a dose- and time-dependent induction of MAO-B, but not of MAO-A, activity. The selective MAO-B increase was substantially reduced by the antagonist RU 486, thus suggesting a glucocorticoid receptor-mediated action of the hormone. Kinetic analysis showed an increase inV_max of MAO-B with no change in apparentK_m. The dexamethasone-induced selective rise in MAO-B activity appeared to be due to enhanced enzyme synthesis, since MAO-B mRNA was markedly increased by dexamethasone treatment and the recovery of MAO-B activity after its irreversible inhibition by deprenyl was more pronounced in the presence than in the absence of the hormone. Furthermore, the dexamethasone effect was abolished by the protein synthesis inhibitors actinomycin D or cycloheximide. The present study demonstrates that dexamethasone is able to selectively induce MAO-B in type 1 astrocytes and leads to speculation of a possible role for glucocorticoids in the increase in brain MAO-B associated with neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases.     

The roman strains of rats as a psychogenetic tool for pharmacological investigation of working memory: example with RU 41656

This study examined the effects of RU 41656, a dopaminergic D₂ agonist, on the differential working memory performances and on the differential activities of the neurochemical systems of the Roman high (RHA) and Roman low (RLA) avoidance strains of rats. Compared with RLA, RHA performed worse in three tests of working memory (spontaneous alternation, radial maze and object recognition) and had higher levels of exploratory locomotor activity. Hippocampal and frontal cortex choline acetyltransferase (ChAT) activities were loer in RHA. Frontal cortex DA and DOPAC levels, hippocampal and striatal 5-HT and NA levels were higher in RHA. RU 41656 induced a significant improvement in working memory performance of RHA, whereas in RLA it had no effect. It decreased exploratory locomotor activity in both strains. ChAT activity in hippocampus was not affected by RU 41656 in either strain, whereas in frontal cortex it was increased in RHA but not in RLA. Hippocampal NA levels were decreased by RU 41656 in RHA but not in RLA. These results confirm previous data concerning the promnesic effect of RU 41656 and extend the finding that the Roman strains are a psychogenetic model for the behavioural, neurochemical and psychopharmacological study of the working memory in rats.