Aminoglycoside therapy Current use and future prospects

The microbiological, pharmacokinetic, toxicological and clinical aspects of aminoglycosides are reviewed. Aminoglycosides still have an important place in serious infections in neutropenic patients, endocarditis andPseudomonas aeruginosa infections, all in combination with beta-lactams. Monotherapy (with streptomycin) is indicated in less common diseases like tularaemia and bubonic plague. Several experimental studies support a oncedaily dosing regimen for aminoglycosides (comparable or better efficacy with less ototoxicity and nephrotoxicity). Only a very limited number of prospective comparative studies have been performed, and much more data on efficacy, development of resistance and toxicity is needed before once-daily administration can be recommended. The choice of an aminoglycoside should be based primarily on the local sensitivity patterns and cost. Differences in ototoxicity and nephrotoxicity are usually minor. If the acquisition costs of amikacin decline, it is to be expected that amikacin will be the aminoglycoside of choice.     

Self-administration in baboons and the discriminative stimulus effects in rats of bupropion,nomifensine, diclofensine and imipramine

The behavioral effects of the antidepressants nomifensine, diclofensine, bupropion, and imipramine were examined using a cocaine substitution drug self-administration procedure in baboons and a cocaine drug discrimination procedure in rats. Intravenous self-administration of the antidepressants was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a fixed-ratio 80-response or 160-response schedule of intravenous injection. Each drug injection was followed by a 3-h time-out allowing a maximum of eight injections per day. The antidepressants or their vehicles were substituted for cocaine for a period of 15 days, followed by a return to the cocaine baseline. Nomifensine, diclofensine, and bupropion all maintained self-administration behavior at levels above those maintained by their respective vehicles. Some doses of nomifensine, diclofensine, and bupropion maintained levels of behavior similar to those maintained under baseline cocaine conditions. High doses of imipramine maintained levels of behavior above those maintained by its vehicle, but the amount of behavior maintained under these conditions was extremely small. In a second experiment rats were trained to discriminate 32 µmol/kg cocaine (IP 10 min presession) from no drug in a two-lever food reinforced drug discrimination procedure in which responding on one lever was reinforced following ten consecutive responses when the session was preceded by cocaine administration, while responding on the other lever was similarly reinforced in the absence of cocaine pretreatment. Cocaine, nomifensine, diclofensine, and bupropion all dose-dependently occasioned cocaine-appropriate responding. Imipramine did not occasion cocaine-appropriate responding over a range of behaviorally active doses.     

Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice,drug discrimination procedure

The discriminative stimulus properties of (+)-lysergic acid diethylamide (LSD) and lisuride hydrogen maleate (LHM), were compared in a three-choice, water reinforced (FR 20) situation in which rats were required to press one lever following LSD (0.08 mg/kg), a second lever following LHM (0.04 mg/kg), and a third lever following saline. Reliable drug-appropriate responding was established in 72 sessions. Dose-response tests with LSD and LHM indicated that, as dose increased, the per cent of responding on the lever associated with the particular training drug also increased; little or no cross-transfer occurred between LSD and LHM. In generalization tests, the serotonin (5-HT) agonist quipazine substituted for LSD but not LHM while the dopamine (DA) agonist apomorphine mimicked LHM but not LSD; an unrelated compound, pentylenetetrazol (PTZ), produced responding on the saline-appropriate lever. In combination tests, 5-HT antagonists (e.g., BC-105 and low doses of pirenperone) blocked responding on the LSD lever while DA antagonists (e.g., haloperidol and much higher doses of pirenperone) blocked LHM-appropriate responding. These data suggest that the three-lever (D-D-N) procedure is similar to, but can be more sensitive than the two-lever (D-N) procedure (because it can differentiate between LSD and LHM); they therefore at least partially support the hypothesis that three-choice discriminations can be conceptualized as two separate, two-choice (D-N) discriminations (Jarbe and Swedberg 1982). The results also confirm suggestion that the stimulus effects of LSD and LHM are mediated by different mechanisms; the primary action of LSD is serotonergic (5-HT₂), while that of LHM is dopaminergic (White 1986).Some of these data were presented at the meeting of the Society of Neuroscience, Toronto, 1988 (Satellite Session of the Society for the Stimulus Properties of Drugs). They were also submitted (in somewhat different form) to the Graduate School of the University of South Carolina in partial fulfillment of the requirements for an MA degree (in Experimental Psychology)     

Fat metabolism and its response to infusion of insulin and glucose in patients with advanced chronic obstructive pulmonary disease

Summary. In order to investigate fat metabolism and the regulation of lipolysis and blood fuel metabolites by insulin, nine patients with chronic obstructive pulmonary disease (COPD) with chronic hypoxaemia and seven healthy control subjects of similar age were investigated by determination of the turnover rate of free fatty acids (TOR), using 1-¹⁴C-oleic acid as a tracer, and arterial concentrations of FFA, glycerol and 3-hydroxybutyrate. The measurements were performed in the basal state and during insulin and glucose infusion, aiming at euglycaemia at insulin levels of 50 and 100 mU l^-1. The subjects' ages were 64±2.7 and 66±1.1 (mean±SEM) years in the COPD and control groups, respectively. TOR was 0.73±0.06 and 0.52±0.02 mmol min^-1 (P<0.05) in the basal state, 0.33±0.04 and 0.30±0.02 at an insulin level of 50 mU I^-1 and 0.32±0.08 and 0.24±0.02 at an insulin level of 100 mU I^-1, in the COPD and control groups, respectively. Arterial FFA concentration was 0.98±0.08 and 0.75±0.06 mmol 1^-1 (P<0.05) in the basal state in the COPD and control groups, respectively. During the clamp, the decrease in FFA mirrored that in TOR. The results show that the state of lipolysis is increased in severe COPD patients with chronic hypoxaemia. Furthermore, the results suggest a reduced effect of insulin in lipolysis.     

Carbohydrate metabolism in children receiving growth hormone for 5 years

Carbohydrate metabolism was evaluated by fasting and postprandial glucose, insulin, and hemoglobin (Hb)A_1c levels in children with chronic renal insufficiency and various other growth disorders treated with growth hormone. Mean fasting and postprandial glucose remained unchanged throughout the 5-year study period in all four study groups. Median fasting insulin levels rose from lownormal levels into the normal range after 5 years of growth hormone. Average fasting insulin level after 5 years was 10 mU/l. Median postprandial insulin values also rose, yet remained within the normal range at the 5-year mark. Mean Hb A_1c levels remained within low to middle end of the normal range in the patients with growth hormone deficiency, Turner syndrome, and idiopathic short stature. Mean Hb A_1c levels at the 5 years were slightly elevated to 6.3% for the patients with chronic renal insufficiency.     

Effect of KB-2796, a new diphenylpiperazine Ca antagonist, on voltage-dependent Ca currents and oxidative metabolism in dissociated mammalian CNS neurons

The effects of KB-2796, 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine-2HCl, on the low- and high-voltage activated Ca²⁺ currents (LVA and HVA I_Ca, respectively) and on oxidative metabolism were studied in neurons freshly dissociated from rat brain. KB-2796 reduced the peak amplitude of LVA I_Ca in a concentration-dependent manner with a threshold concentration of 10⁻⁷ M when the LVA I_Ca was elicited every 30 s in the external solution with 10 mM Ca²⁺. The concentration for half-maximum inhibition (IC₅₀) was 1.9 × 10⁻⁶M. At 10⁻⁵ M or more of KB-2796, a complete suppression of the LVA I_Ca was observed in the majority of neurons tested. There was no apparent effect on the current-voltage (I-V) relationship and the current kinetics. KB-2796 delayed the reactivation and enhanced the inactivation of the Ca²⁺ channel for LVA I_Ca voltage- and time-dependently, suggesting that KB-2796 preferentially binds to the inactivated Ca²⁺ channel. KB-2796 at a concentration of3.0 × 10⁻⁶M also decreased the peak amplitude of the HVA I_Ca without shifting the I-V relationship. In addition, KB-2796 reduced the oxidative metabolism (the formation of reactive oxygen species) of the neuron in a concentration-dependent manner with a threshold concentration of3 × 10⁻⁶M. It is suggested that the inhibitory action of KB-2796 on the neuronal Ca²⁺ influx and the oxidative metabolism, in combination with a cerebral vasodilatory action, may reduce ischemic brain damage.     

白蛋白微球作为肝靶向给药载体的研究

用均匀设计方法和计算机技术筛选了乳化化学交联法制备白蛋白微球的六个因素,十二个水平。优化出最佳制备工艺,制备了平均粒径0.41～0.47μm的白蛋白微球。将此工艺制备的¹²⁵I-白蛋白微球做动物体内研究,结果表明微球iv后主要浓集在肝脏,可达注入总剂量的68%,此微球在靶组织肝脏的变化规律可用二室模型契合。     

药物敏感试验指导肺癌合并恶性胸腔积液的顺铂联合其他药物胸腔内化疗

目的用药物敏感试验预测肺癌合并恶性胸腔积液癌细胞对顺铂联合其他药物的敏感度，观察其在指导此类患者的顺铂联合其他化疗药物胸腔内化疗的价值。方法将44例胸腔积液癌细胞阳性肺癌患者随机分为两组：药物敏感试验组（20例，有2例因体外药物敏感试验失败而被排除）和对照组（22例）。药物敏感试验组患者用三磷酸腺苷-肿瘤细胞药物敏感试验（ATP-TCA）法分别检测胸腔积液癌细胞对顺铂加香菇多糖、顺铂加甘露聚糖肽、顺铂加A群链球菌制剂、顺铂加干扰素、顺铂加金黄色葡萄球菌滤液制剂、顺铂加卡介苗多糖核酸、顺铂加红色诺卡菌细胞壁骨架、顺铂加白细胞介素-2的敏感度，并选择抑瘤率最高的联合化疗药物对患者进行胸腔内化疗，观察治疗后胸腔积液完全缓解率及胸腔积液癌细胞转阴率，并与对照组比较。结果药物敏感试验组患者对各联合化疗药物敏感的例数为：顺铂加香菇多糖14例、顺铂加甘露聚糖肽18例、顺铂加A群链球菌制剂17例、顺铂加干扰素10例、顺铂加金黄色葡萄球菌滤液制剂16例、顺铂加卡介苗多糖核酸15例、顺铂加红色诺卡菌细胞壁骨架17例、顺铂加白细胞介素-216例。药物敏感试验组完全缓解率为65．0％，对照组为27．3％（P〈0．05）。药物敏感试验组胸腔积液癌细胞转阴率为80．0％，对照组为45．5％（P〈0．05）。结论用药物敏感试验指导肺癌合并恶性胸腔积液的胸腔内个体化化疗可提高完全缓解率和胸腔积液癌细胞转阴率，该方法具有临床实用价值。     

Investigation of Direct Causes of Drug Relapse and Abstainers’ Demands in a Compulsive Detoxification Center in Wuhan City of China

Objective To identify the direct causes of drug relapse and abstainers’ demand, and to develop programs for the prevention of drug relapse. Methods Abstainers in a Compulsive Detoxification Center in Wuhan City, capital of Hubei Province were randomly selected. An investigation on the direct causes of drug relapse and abstainers’ demands was conducted with multiple-choice questionnaires and face to face interviews. Data were analyzed with SPSS 12.0. Results The direct causes leading to drug relapse included: temptation to use drug again by themselves or by their drug mates, seeking pleasure and ecstasy from drug use, relatively well off living, mental stress, irritation, demoralization, family conflicts, unemployment, feeling distrusted by the family, lack of care and love from the family, and discrimination by others. abstainers’ demands after detoxification and returning to the society included: care and support from the family, employment assistance, changing living environment, understanding by others, support from the society, and keeping far away from drugs. Conclusions Environmental factors are the direct causes of drug relapse, and negative irritation is its predisposing causes. Leaving former residence, more care and help given by both the family and the society and raising their overall quality of life are the demands of abstainers.     

药物洗脱支架直接置入治疗A型和B_1型病变的临床观察

目的　评价直接置入药物洗脱支架 (CYPHERTM,codis)在A或B1 型病变的冠心病患者治疗中的安全性、可行性。方法　 6 2例接受CYPHERTM 支架直接置入的患者 (直接支架组 )和一般情况匹配的 5 1例球囊扩张后行冠脉支架术的患者 (常规支架组 ) ,比较两组的一般情况 ,冠脉造影及介入治疗即刻和临床随访结果。结果　直接支架组介入操作时间明显短于常规支架组 [(17.2± 8.6 )比 (2 6 .3± 7.1)min ,P <0 .0 1],直接支架组平均扩张压明显高于常规支架组 [(14± 3)比 (12± 1.9)atm ,P<0 .0 1],两组无一例发生介入治疗相关的严重心脏事件。随访期间两组严重心脏不良事件发生率无显著差异。结论　A或B1 型病变的冠心病患者CYPHERTM 支架直接置入术可缩短介入操作时间 ,即刻效果、并发症及中期临床随访与常规支架组差异无显著性意义