Behavioral and biochemical evidence for a long-lasting decrease in GABAergic function elicited by chronic administration of FG 7142

Chronic treatment with the beta-carboline derivative FG 7142 (15 mg/kg i.p. twice a day for 10 consecutive days) produced a long-lasting enhancement of shock-induced suppression of drinking in rats, without affecting unpunished behaviour. This proconflict effect was observed up to 15 days after withdrawal from FG 7142. A significant sensitization to seizures induced by isoniazid, a drug known to inhibit GABAergic transmission, was also found to occur after long-term (25 days) withdrawal. Moreover, the density of low-affinity GABA receptors was decreased by 30% in the cerebral cortex of rats repeatedly injected with FG 7142 at 5 and 15 days after withdrawal. The capacity of high-affinity GABA receptors, as well as the apparent dissociation constants for both high- and low-affinity GABA receptors were unchanged. Similar modifications in [3H]GABA binding were also observed in the cerebellum. The enhancement of punishment suppressed behaviour, the sensitization to isoniazid-induced convulsions and the decrease in the density of low-affinity GABA receptors suggest that chronic administration of FG 7142 induces a persistent down-regulation of GABAergic transmission in the central nervous system.     

反相高效液相色谱法检测小鼠血浆中FG020326方法的建立

目的建立测定多药耐药(multidrugresistance,MDR)逆转剂FG020326在KM小鼠血浆中血药浓度的方法。方法将KM小鼠(20·0~25·1)g随机分组,每组6只,♀♂各半,尾静脉注射,给药量为30mg·kg-1,分时取血、处理。采用反相色谱柱,应用外标法测定FG020326在KM小鼠血浆中的血药浓度。结果在所建立的方法学下,FG020326的保留时间为7·9min;标准曲线为Y^=0·0144X-0·0285(r=0·9998),在162·5~41600μg·L-1血浆浓度范围内呈良好的线性关系,最低检测浓度40μg·L-1(S/N=3);在650、2600、20800μg·L-1低、中、高3个浓度下的绝对回收率为68·66%~84·63%,相对回收率为92·58%~110·88%;日内及日间RSD均小于3·2%(n=5)。在室温及冷冻-解冻试验中,FG020326具有良好的稳定性,RSD分别小于1·3%和6·0%。尾静脉单次给药后,FG020326在体内过程符合二室模型,T12α为0·088h,T21β为5·33h,AUC0~∝为14183h·μg·L-1,Vd为0·37L。结论该方法快速、准确、简便,能够满足FG020326药代动力学研究要求。     

FG syndrome in a premature male

A 30-week premature male infant is presented with dolichocephaly, frontal bossing, down-slanting palpebral fissures, hypertelorism, long philtrum, micrognathia, cleft palate, and imperforate anus. He is the fifth patient to be presented with FG syndrome and sensorineural deafness. The patient's syndromic manifestations became more obvious during an inpatient observation period of 3 months.     

The effect of the β-carboline FG 7142 on the behaviour of male rats in a living cage: An ethological analysis of social and nonsocial behaviour

The effects of FG 7142, a -carboline benzodiazepine receptor partial inverse agonist, on the social behavior of pair-housed rats were investigated. Four 6-min dyadic social encounters in a living cage were observed in a paradigm in which one member of a pair of rats was injected. The four injection groups (n=8) were vehicle control, and FG 7142 at 2.5, 5.0 and 10.0 mg/kg, respectively. All injections were administered 2 min before the start of the first observation trial. Compared to the effects of vehicle alone, FG 7142 decreased aggressive behaviour but did not change the level of total social interaction. Thus there were compensating increases in approaching and avoiding behaviours following the administration of FG 7142. Locomotion declined marginally and immobility increased in FG 7142-injected rats. FG 7142 decreased the incidence of self-grooming. The evidence is consistent with a relatively selective reduction in intraspecies aggression in male rats after the injection of the -carboline inverse agonist.     

Discriminative stimulus properties of β-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors

The discriminative stimulus properties of three -carboline derivatives were studied in three groups of rats trained, respectively, to discriminate diazepam (2.5 mg/kg IP), chlordiazepoxide (CDP, 5 mg/kg IP) or pentylenetetrazol (PTZ, 15 mg/kg IP) from saline in standard procedures employing two-lever operant chambers. Two -carbolines, ZK 91296 and ZK 93423, substituted for the benzodiazepines in both CDP- and diazepam-trained rats. The neutral benzodiazepine antagonist Ro 15-1788 blocked the diazepam discriminative stimulus and the ability of ZK 91296 to substitute for diazepam. A third -carboline, FG 7142, was not identified as benzodiazepine-like in generalization tests in either diazepam- or CDP-trained rats, but when administered together with CDP antagonized the benzodiazepine discriminative stimulus. In rats trained to discriminate PTZ from saline (a discrimination which is thought to depend on the anxiogenic properties of PTZ) the PTZ cue was antagonized by diazepam and ZK 93423, and partially antagonized by ZK 91296. The PTZ cue generalized to FG 7142 and this generalization was partially antagonized by Ro 15-1788. These results suggest that the three -carbolines provide more than one kind of discriminative stimulus, consistent with the classification of ZK 93423 as an agonist at central benzodiazepine receptors, with ZK 91 296 as a partial agonist, and with FG 7142 as an inverse agonist. Pharmacologically, ZK 93 423 and ZK 91 296 may exhibit anxiolytic qualities, whereas FG 7142 produces anxiogenic effects.     

大鼠中脑至上丘的传入投射

目的：研究大鼠中脑核团到上丘的传人纤维投射。方法：应用荧光金(FG)逆行追踪技术研究大鼠上丘传人纤维的中脑起源。结果：对侧上丘(SC),同侧下丘(IC),外侧丘系背侧核(dll),中央灰质(CG)和双侧黑质(SN),中脑深核(dpM),视束核(ot),二叠体旁核(pbg)观察到FG逆行标记细胞。结论：上丘存在复杂的纤维联系,参与多种生理活动。     

Effects of benzodiazepine receptor ligands on the performance of an operant delayed matching to position task in rats: opposite effects of FG 7142 and lorazepam

The effects of a series of benzodiazepine (BZ) receptor ligands, ranging from a full agonist through to partial inverse agonists, were examined on short term working memory in the rat. The behavioural paradigm used was a discrete trial, operant delayed matching to position task, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. The benzodiazepine receptor (BZR) full agonist lorazepam (0.25, 0.375 and 0.5 mg/kg) dose and delay dependently impaired matching accuracy. Lorazepam also increased the latency to respond and decreased the number of nose pokes made into the food tray during the delays. In contrast, the BZR partial agonist ZK 95 962 (1, 3, 10 mg/kg) did not affect matching accuracy, but did increase the speed of responding. The BZR antagonist ZK 93 426 (1.25, 5, 25 mg/kg) had no effects in this paradigm. The BZR weak partial inverse agonists Ro 15-4513 (0.1, 1 and 10 mg/kg) and ZK 90 886 (1, 3 and 10 mg/kg) did not affect accuracy of performance. However, both of these drugs increased the latency to respond and decreased nose poke responses. These motoric effects were particularly strong following 10 mg/kg Ro 15-4513. This shows that the effects of drugs on the accuracy of responding and on the speed of responding can be dissociated. The BZR partial inverse agonist FG 7142 had effects on matching accuracy that were dependent upon dose. The lowest dose of FG 7142 (1 mg/kg) significantly improved accuracy, whereas the highest dose (10 mg/kg) impaired accuracy. This impairment induced by FG 7142 (10 mg/kg) was accompanied by an increase in the latency to respond and a decrease in the number of nose pokes. Taken together, these results show that the accuracy of delayed matching performance can be modulated in opposite ways by the BZR full agonist lorazepam and a low dose of the BZR partial inverse agonist, FG 7142.     

Effects of benzodiazepine receptor partial inverse agonists in the elevated plus maze test of anxiety in the rat

The present series of experiments examined the effects of five benzodiazepine receptor (BZR) partial inverse agonists on the behaviour of rats on an elevated plus maze. The drugs were tested in a standard plus maze with 3-cm walls added to the open arms, as this has been shown to increase the sensitivity of the plus maze to anxiogenic-like drug effects (Jones and Cole 1995). The drugs tested were FG 7142 (0–100 mg/kg),-CCE (0–30 mg/kg), ZK 132 556 (0–100 mg/kg), ZK 90 886 (0–30 mg/kg) and Ro 15–4513 (0–30 mg/kg). In addition, to allow a comparison with previous studies, the effects of three reference substances, DMCM (0–2.5 mg/kg), pentylenetetrazol (PTZ; 0–30 mg/kg) and yohimbine (0–5 mg/kg), were also examined. These three reference compounds produced a dose-dependent reduction in the duration of open arm exploration and the total number of open arm entries, indicative of anxiogenic-like effects. DMCM produced significant effects at the doses of 1.25 and 2.5 mg/kg, PTZ at 30 mg/kg, and yohimbine at 5 mg/kg. The BZR partial inverse agonist FG 7142 (10, 30 and 100 mg/kg) also reduced the duration of open arm exploration and the total number of arm entries. The minimally effective dose resulted in a receptor occupancy of approximately 80%. Ro 15–4513 also produced anxiogenic-like effects, but only at a dose (30 mg/kg) that resulted in a receptor occupancy of approximately 95%. In contrast, the other BZR partial inverse agonists, ZK 132 553 and ZK 90 886, did not significantly reduce the duration of open arm exploration, even at doses that produced greater than 95% receptor occupancies.-CCE also did not reduce open arm exploration at any dose tested (0–30 mg/kg). The GABA shift, a biochemical index of intrinsic activity, indicates that these latter three compounds are more inverse agonistic than Ro 15–4513. In summary, these results demonstrate that not all BZR receptor partial inverse agonists have anxiogenic-like activity in the rat plus maze, and that the GABA shift, a biochemical index of intrinsic efficacy, does not predict which BZR partial inverse agonists are anxiogenic.     

血浆纤维蛋白原与冠心病患者胆固醇、血液流变学的相关性及药物干预的研究

目的：研究血浆纤维蛋白原（ｆｉｂｒｉｎｏｇｅｎ,ＦＧ）与冠心病（ＣＨＤ）患者胆固醇、血液流变学的相关性及腹蛇抗栓酶（ＡＨＶＡＴ）的治疗效果。方法：观察６６ 例ＣＨＤ 患者血浆ＦＧ、胆固醇（ＣＨＯ）及血浆粘度、低切变血粘度、红细胞聚集指数等血液流变学指标与６０ 例正常人对照。将６６例ＣＨＤ患者随机分为ＡＨＶＡＴ治疗组３２ 例及肝素治疗组３４ 例,观察治疗前后上述指标的变化。结果：ＣＨＤ组血浆ＦＧ、ＣＨＯ、血浆粘度、低切变血粘度、红细胞聚集指数均明显高于正常对照组（Ｐ＜ ０．０１）。ＣＨＤ组患者血浆ＦＧ 水平与ＣＨＯ、血浆粘度、低切变血粘度、红细胞聚集指数呈直线相关（Ｐ＜ ０．０５, Ｐ＜ ０．０１）。用ＡＨＶＡＴ治疗后上述指标明显下降（Ｐ＜ ０．０５）。结论：血浆ＦＧ 升高与ＣＨＯ 升高有关,血浆ＦＧ 升高可导致ＣＨＤ患者血浆粘度、低切变血粘度及红细胞聚集指数的升高,用ＡＨＶＡＴ 治疗可降低ＣＨＤ患者血浆ＦＧ及ＣＨＯ水平,从多方面改善血液流变学指标     

Why do we not want to recommend influenza vaccination to young children? A qualitative study of Australian parents and primary care providers

IntroductionInfluenza vaccination has been shown to be safe and effective against influenza and in the prevention of complicating secondary respiratory illnesses. However, its uptake in young children remains low. This study explored the views, attitudes and practices of parents and primary care providers (PCPs) on their knowledge and acceptance of influenza vaccination in children under 5.MethodsUsing a cross-sectional qualitative research design, we conducted 30 in-depth interviews with PCPs (i.e., general practitioners, practice nurses, maternal and child health nurses, and pharmacists) and five focus groups with parents (n = 50) between June 2014 and July 2015 in Melbourne, Australia. Data were thematically analysed.ResultsParents thought the vaccine could cause influenza, and influenza vaccination was not necessary for their children as they needed to build their own ‘immunity’. Parents said that they would consider vaccinating their children if recommended by their GP and if the influenza vaccine was part of the immunisation schedule. PCPs also expressed concerns regarding the efficacy of the vaccine as well as out-of-pocket costs incurred by families, and uncertainty regarding the mortality and morbidity of influenza in otherwise healthy children. However, they said they would recommend the vaccine to high-risk groups (e.g. children with chronic disease(s), and asthma).ConclusionDespite the established safety of influenza vaccines, barriers to uptake include concerns regarding the iatrogenic effects of vaccination, its administration schedule, and knowledge of influenza severity. Updated information on influenza and the efficacy of the vaccine, and incorporating influenza vaccination into the immunisation schedule may overcome some of these barriers to increase influenza vaccination in this vulnerable cohort.