Antiproliferative Activity Against MCF‐7 Breast Cancer Cells by Diamino‐Triazaspirodiene Antifolates

Two triazaspirodienes, having similar phenoxy propyloxy side chain, were identified as potent mammalian dihydrofolate reductase inhibitors; one having a 6,5‐spiro bicyclic ring system (IC₅₀ = 2.3 nm ) and the other a 6,6‐spiro bicyclic system (IC₅₀ = 6.9 nm ). They also showed more than 50% antiproliferative activity against the MCF‐7 breast cancer cells at 20 μm . This study demonstrated the potential lead of the diamino‐triazaspirodienes in anticancer chemotherapeutical agents’ discovery.     

使用皮下埋藏灌注器治疗肝癌导管并发症分析

目的 研究皮下埋藏灌注器治疗肝癌导管所致的并发症。方法 收集我院1990～2004年用该方法治疗肝癌患者共313例，其中肝动脉栓塞化疗234例，门静脉化疗33例，肝动脉栓塞化疗加门静脉化疗40例，腹腔置管化疗6例。结果 发生导管并发症共43例，发生率为13．7％，其中导管堵塞16例，导管移动、松脱7例，肝动脉胆管漏8例，灌注器皮下感染，皮瓣坏死12例，肝动脉插管与门静脉插管导管并发症的比率为2．6：1。结论 采用皮下埋藏灌注器治疗由肝癌导管所致的并发症，为数不少，应引起重视。     

Chemical Stability of an Admixture Combining Ziconotide and Bupivacaine During Simulated Intrathecal Administration

Objective. To determine the stability of an admixture combining ziconotide with bupivacaine hydrochloride during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods. An admixture containing ziconotide (25 µg/mL) and bupivacaine hydrochloride (5 mg/mL) was stored in SynchroMed® II pumps at 37° and in control vials at either 37° or 5°. Using high‐performance liquid chromatography, drug concentrations were determined from samples obtained at varying intervals during the 30‐day study. Results. After 30 days, pump ziconotide and bupivacaine hydrochloride concentrations measured an average of 86.9% and 99.4% of their initial concentrations, respectively. Control vials displayed similar degradation rates for both drugs. Statistical evaluation of the ziconotide 95% confidence interval indicated that the ziconotide concentration would meet or exceed 90% and 80% of initial concentration for 22 days and 45 days, respectively. Conclusions. An admixture containing 25 µg/mL ziconotide and 5 mg/mL bupivacaine hydrochloride was 90% stable for 22 days and 80% stable for 45 days (extrapolated) in SynchroMed® II infusion pumps.     

A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action.

Data now exist from which an accurate definition for serotonin toxicity (ST), or serotonin syndrome, has been developed; this has also lead to precise, validated decision rules for diagnosis. The spectrum concept formulates ST as a continuum of serotonergic effects, mediated by the degree of elevation of intrasynaptic serotonin. This progresses from side effects through to toxicity; the concept emphasizes that it is a form of poisoning, not an idiosyncratic reaction. Observations of the degree of ST precipitated by overdoses of different classes of drugs can elucidate mechanisms and potency of drug actions. There is now sufficient pharmacological data on some drugs to enable a prediction of which ones will be at risk of precipitating ST, either by themselves or in combinations with other drugs. This indicates that some antidepressant drugs, presently thought to have serotonergic effects in animals, do not exhibit such effects in humans. Mirtazapine is unable to precipitate serotonin toxicity in overdose or to cause serotonin toxicity when mixed with monoamine oxidase inhibitors, and moclobemide is unable to precipitate serotonin toxicity in overdose. Tricyclic antidepressants (other than clomipramine and imipramine) do not precipitate serotonin toxicity and might not elevate serotonin or have a dual action, as has been assumed.     

非体外循环冠状动脉旁路移植术中转体外循环的原因探讨

目的　探讨非体外循环冠状动脉旁路移植术 (OPCAB)中转体外循环的原因与技术方法。方法　分析术前预计完成的非体外循环冠状动脉旁路移植术 4 34例 ,中转为体外循环下手术者 10例 (2 .3% )。中转原因包括 :顽固性心律失常 2例 ,搬动心脏时顽固低血压 2例 ,右冠急性阻塞缺血引起心率下降和血压降低 2例 ,心脏明显扩大而难以完全再血管化 2例 ,因完成的血管桥不通畅在体外循环下重新吻合 2例。结果　中转体外循环后 9例在并行循环心脏跳动下完成手术 ,1例在低温室颤下完成手术 ,体外循环时间为 (131.5± 4 0 .1)min。远端吻合口数目平均为 (3.5± 1.0 )个 ,使用主动脉内球囊反搏 6例。本组无住院死亡者。术后室颤 1例 ,除颤成功 ;房颤 2例 ,药物治疗好转。随访术后 6个月突发心律失常死亡 1例 ,考虑为晚期缺血性心肌病。结论　OPCAB手术存在中转体外循环的可能性。随着技术方法的改进和操作经验的积累 ,可减少中转事件的发生 ,进一步增加OPCAB的安全性和可行性。     

质子磁共振波谱对创伤后应激障碍患者海马神经元异常的诊断价值

目的 探讨质子磁共振波谱（1HMRS）在诊断创伤后应激障碍（post traumatic stress disorder，PTSD）患者海马神经元异常中的价值。方法 对19例PTSD患者及19例健康对照组行常规MRI和1HMRS检查。结果 PTSD患者MRI检查未出现信号的异常。19例患者两侧海马均显示NAA／Cr明显减低，与健康对照组相比，差异有统计学意义（P〈0．01）；而患者两侧海马的Cho／Cr与健康对照组相比，差异无统计学意义（P〉0．05）。结论 1HMRS揭示了PTSD时海马存在着神经元的丢失或功能紊乱，而这些改变是构成PTSD的神经生物学基础之一。     

A neosynthesis of sodium channels is involved in the evolution of the sodium current in isolated adult DUM neurons

Short-term culture of isolated adult dorsal unpaired median (DUM) neurons of the cockroach Periplaneta americana has been used to study the evolution of the sodium current during the time in culture after axotomy and deafferentation treatment. An increase in the maximum peak amplitude of the sodium current recorded under voltage-clamp conditions with the patch-clamp technique in the whole-cell recording configuration, was only observed between 24h and 72h (75%) without any modification of the kinetics and the voltage-dependence of the current. A decrease in the level of foetal calf serum in the culture medium reduces the amplitude of the sodium current on all days but does not affect its time-course of development which was on the contrary completely abolished by both protein synthesis inhibitors, actinomycin D and cycloheximide. The results obtained in these neurons strongly suggest that a neosynthesis of sodium channel proteins is involved in the evolution of the sodium current induced by axotomy and deafferentation.     

In-situ measurements of gas permeability in fuel cell membranes using a cylindrical microelectrode

A new method to study permeation of gases in proton conducting membranes using a cylindrical microelectrode is presented. The focus of this work was to develop an in-situ method to study transport properties of hydrogen and oxygen close to real fuel cell operating conditions. The gas permeability is strongly affected by the change of water content in the membrane and it is therefore of advantage that, by using this method, measurements can be carried out over a wide range of relative humidities. The numerical method makes it possible to separate the diffusion coefficient and the concentration of dissolved gas in the membrane and also allows kinetic limitations to be taken into account. Chronoamperometric measurements on Nafion® 117 were successfully evaluated numerically. Experiments at temperatures of 25 and 60 °C with respect to oxygen permeation and at 60 °C for hydrogen permeation at relative humidities in the range 30–94% are presented. The reproducibility of data was excellent when measuring with different microelectrodes on the same membrane sample, but differed when measuring on different samples. In general, the permeability increases with increasing temperature and relative humidity.     

Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium

Summary The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.C1 and milrinone at A₁ adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A₁ adenosine receptors, all compounds inhibited ³H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations. As judged from the K_i-values, the rank order of potency was saterinone > sulmazole > UD-CG 212.C1 > milrinone. The new inotropic agents also displaced the binding of ³H-QNB at m-cholinoceptors. Except for saterinone, the concentration ranges of mean K_i-values were considerably higher at m-cholinoceptors than at A₁ adenosine receptors. The rank order of potency was saterinone > sulmazole > UD-CG 212.Cl > milrinone. Competition of the A₁ adenosine receptor agonist R-PIA to ³H-DPCPX-binding showed a biphasic curve with a shallow slope (Hill coefficient n_H = 0.63) and revealed two affinity states of the A₁ adenosine receptor. In the presence of guanine nucleotides [Gpp(NH)p], the competition curve showed one low affinity class of binding sites and was shifted to the right. In contrast, the competition curves of the new inotropic agents were characterized by a monophasic, steeper slope (mean Hill coefficient n_H = 0.98). Guanine nucleotides had no effect. Similar results were obtained with saterinone and carbachol at m-cholinoceptors. Competition with carbachol revealed three affinity states of the m-cholinoceptor, the superhigh affinity binding was reversed by Gpp(NH)p. Competition with saterinone revealed one class of binding sites which was not influenced by Gpp(NH)p. Accordingly, in isolated, electrically driven human atrial trabeculae, the negative inotropic effect of adenosine was antagonized concentration-dependently by saterinone, sulmazole and UD-CG 212.Cl. Similarly the negative inotropic effect of carbachol was antagonized concentration-dependently by saterinone. It is concluded that the new inotropic agents bind to A₁ adenosine receptors and that their interaction is of antagonist nature. This mechanism might contribute to their capacity to enhance force of contraction by stimulation of cAMP-formation in addition to phosphodiesterase inhibition. The effects of saterinone may be partially due to antagonism at m-cholinoceptors. This is presumably not the case with the other inotropic agents studied given their low affinity for this receptor.Send offprint requests to M. Böhm at the above addressSupported by the Deutsche Forschungsgemeinschaft     

Comparative effects of enoximone and theophylline on plasma catecholamines and haemodynamics in cardiosurgical patients

Summary The release of endogenous catecholamines in aorto-coronary bypass graft patients receiving either 0.5 mg/kg enoximone (n=10), 4.0 mg/kg theophylline (n=10) or saline solution (control,n=10) has been studied, as well as certain haemodynamic parameters. Adrenaline (A) and noradrenaline (NA) concentrations were not significantly changed by the administration of enoximone. Theophylline caused a small increase in NA (+ 40% in the 1st min) and a marked increase in A (approximately + 7000% in the 1st min), which still remained elevated at the end of the investigation period (+ 220% in the 30th min). The major haemodynamic effects of enoximone were a significant increase in cardiac index (CI; + 35%) and a decrease in pulmonary capillary wedge pressure (PCWP; −27%), pulmonary artery pressure (PAP; −21%), RVEDV and RVESV, while the heart rate (HR) remained almost unchanged. The dominant haemodynamic effects of theophylline were an increase in HR (+ 26%; arrhythmia in 3 patients), PAP (+ 22%), and RVEDV (+ 19%), while REVESV (+ 26%), MAP (−16%), CI (−14%), and RVEF (−15%) fell significantly. It is concluded that the haemodynamic actions of enoximone are not mediated by catecholamine release, whereas the adverse cardiovascular effects of theophylline might partly be explained by the significant increase in plasma adrenaline.