Synthesis and pharmacological evaluation of a series of dibenzo[a,d]cycloalkenimines as N-methyl-D-aspartate antagonists.

A series of 73 dibenzo[a,d]cycloalkenimines were synthesized and evaluated for their ability to displace (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]-(+)-10) from its specific binding site on rat cortical membranes. A number of the more active compounds (Ki ranging from 0.006 to 0.21 microM) were evaluated for N-methyl-D-aspartate (NMDA) antagonist activity in the rat cortical slice (Kb ranging from 0.08 to 0.9 microM) and anticonvulsant activity in the mouse against NMDA induced convulsions. The ED50 values ranged from 0.22 to 7.76 mg/kg and correlated reasonably well with the Kb determination. In the dibenzo[a,d]cyclohepten-5,10-imine series, the (+)-5S,10R enantiomer displayed consistently higher levels of biological activity. While substitution at the 3-position of (+)-10 with electronegative atoms generally increased in vitro activity, a loss of potency relative to (+)-10 (MK-801) was observed in vivo for all of the compounds tested.     

Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.     

Effect produced by acute and chronic administration of the selective 5-HT3 receptor antagonist BRL 46470 on the number of spontaneously active midbrain dopamine cells in the rat

This study examined the effect of acute and chronic administration of the selective 5-HT₃ receptor antagonist BRL 46470A, an analog of granisetron, on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (A9 or SNC) and the ventral tegmental area (A10 or VTA) in the rat. In the A10 area, the acute administration of BRL 46470A decreased the number of spontaneously active DA cells at a dose of 0.1 mg/kg (0.28 μmol/kg) ip, yet increased the number of spontaneously active DA cells at a dose of 0.3 mg/kg (0.84 μmol/kg). The chronic administration (21 days) of BRL 46470A appeared to produce a multiphasic dose-response curve. Thus, the chronic treatment with BRL 46470A increased the number of spontaneously active A10 DA cells at 0.03 (0.084 μmol) and 0.3 mg/kg, but decreased the number of spontaneously active A10 DA cells at a dose of 0.1 mg/kg. In contrast, BRL 46470A did not decrease the number of spontaneously active A9 DA cells after either acute or chronic administration (0.01-0.3 mg/kg). However, BRL 46470A did increase the number of spontaneously active A9 DA cells at acute and chronic doses similar to those that were effective in A10. The iv administration of (+)-apomorphine (APO) not only failed to reverse the decrease produced by chronic administration of BRL 46470A at 0.1 mg/kg, but further decreased the number of spontaneously active A10 DA cells. Similar to the results obtained with granisetron, the pretreatment of naive rats with either 0.01 or 0.1 mg/kg iv of BRL 46470A significantly potentiated (2-fold) the suppressant action of APO on the basal firing rate of A10, but not A9 DA cells. Overall, our results indicate that similar to granisetron, chronic BRL 46470A at 0.1 mg/kg selectively decreases the number of spontaneously active A10 DA cells, via a mechanism not related to depolarization inactivation. Presently, it is not clear what factors may contribute to the multiphasic dose-response curve of BRL 46470A. © 1994 Wiley-Liss, Inc.     

Iotrol versus metrizamide in lumbar myelography: a double-blind study

In a prospective, randomized, double-blind study, 49 patients underwent lumbar myelography using iotrol (24 patients) or metrizamide (25 patients). The diagnostic imaging adequacy of iotrol was comparable with that of metrizamide. After iotrol myelography, adverse reactions were fewer, less severe, and of shorter duration than were those following metrizamide myelography. Thirteen of 24 patients (54%) receiving iotrol reported some adverse reactions compared with 24 of 25 patients (96%) receiving metrizamide. Five moderate and one severe adverse reaction occurred in the group receiving iotrol. Fourteen moderate and eight severe adverse reactions occurred in the group receiving metrizamide. Thirty-eight patients underwent electroencephalography both before and after myelography (19 iotrol and 19 metrizamide). None of the EEGs obtained after iotrol myelography changed from baseline, while seven of the EEGs obtained after metrizamide myelography showed changes from baseline. Iotrol was judged superior to metrizamide as a contrast medium in this patient population.     

臂丛神经根性损伤膈神经移位术对青壮年患者早期呼吸功能的影响

目的研究臂丛神经损伤膈神经移位术对青壮年患者早期呼吸功能的影响.方法对16例接受膈神经移位治疗的患者,在术前、术后（10 d）进行肺功能指标的比较,同时定期进行门诊随访,观察呼吸系统自觉症状程度.结果13例术后出现了不同程度的供氧不足症状,16例全部出现一侧膈肌抬高,术后第10天肺活量（VC）、肺活量预计值百分数（VC%）分别比术前减少37.98%和26.88%,两者差异有统计学意义（tvc=11.532、tvc%=0,P＜0.01）.其它项目如残气量（RV）较术前轻度下降,肺总量（TLC）下降值达到术前肺总量的36.49%,残气量/肺总量比值（RV/TLC%）较术前上升了4.75%,上述各指标的差值均有统计学意义.1 s用力呼气量/用力肺活量比值（FEV1/FVC）和术前比基本无改变,但其差值有统计学意义.膈神经移位右侧（10例）与左侧（6例）术前、术后肺活量比较差异有统计学意义.术后随访8个月～2年,所有患者均无明显呼吸困难和胸闷等症状.结论膈神经移位术后对青壮年患者肺容量有较大的丧失,肺通气功能减弱和小气道阻力增加,但其丧失程度在机体自身代偿耐受范围内,不会导致急剧发生的严重呼吸功能障碍.建议对右侧臂丛神经根性损伤的患者,术前进行严格的肺、心功能检查,避免发生较为严重的并发症.