Rapid induction of behavioral and neurochemical tolerance to cocaethylene, a model compound for agonist therapy of cocaine dependence

Rationale: Tolerance to abused drugs may impact on patterns of abuse, and in the case of agonist therapies, may be beneficial in that it reduces the reward value of a given dose of abused drug. Cocaethylene, a psychoactive metabolite resulting from concurrent alcohol and cocaine consumption, was examined because of its use in human research studies of drug reward mechanisms, and its potential as a model compound for an agonist based therapy for cocaine dependence. Objective: Comparisons were made between cocaine and cocaethylene in the acute development of tolerance to the neurochemical and behavioral effects of cocaine. With chronic exposure, tolerance to the behavioral effects of cocaine was examined. Methods: In awake rats with a microdialysis probe in the nucleus accumbens and a jugular catheter, an IV bolus/3-h infusion of cocaine or cocaethylene and a subsequent cocaine challenge was administered while extracellular dopamine and locomotion were monitored. Chronic IV treatment with cocaine, cocaethylene, and a water control was accomplished for 7 days using osmotic minipumps attached to jugular catheters. Animals were then challenged with an IV bolus of cocaine. Results: With acute treatment, the IV bolus of cocaethylene at the beginning of the infusion period resulted in an initial behavioral activation equivalent to that caused by cocaine, after which there was a striking difference in that the cocaethylene group displayed a return to predrug levels of activity, while the cocaine group showed high levels of activity throughout the 3-h period. Both cocaethylene and cocaine resulted in an initial increase in the extracellular concentration of dopamine. However, after that initial increase, levels of dopamine dropped in the cocaethylene group while the cocaine group levels remained elevated. A 1-week infusion of cocaine or cocaethylene resulted in tolerance to the behavioral activating effects of a subsequent cocaine challenge. Conclusions: These results demonstrate a rapid induction of tolerance to the behavioral and neurochemical properties of cocaethylene, resulting in a diminished behavioral response to a cocaine challenge both acutely, and after 7 days. The relevance of these data for the use of cocaethylene as a model compound for an agonist approach to therapy for cocaine dependence is discussed. Received: 22 January 1999 / Final version: 16 April 1999     

动脉内溶栓治疗急性脑梗死

为了前瞻性研究局部动脉内溶栓治疗急性脑梗死的疗效,应用超导技术对３７例急性脑梗死病临近梗死部位的脑血管内注入溶栓药物治疗。其中２２例使用蝮蛇抗栓酶３号,１５例使用尿激酶溶栓,结果：２７．０３％的患者在６小时内溶栓,２４．３２％在７～１２小时内,２１．６３％在１３－２４小时内,２４．３２％在２５～４８小时内,２．７％在４８小时以后溶栓,溶栓后症状明显好转者占５９．５％,好转者２１．６％,无改善１８．     

反义胰岛素样生长因子—1mRNA治疗大鼠脑胶质瘤模型的动态MR研究

目的：动态观察大鼠Ｃ６胶质瘤模型的自然生长过程及反义ＩＧＦ－１ｍＲＮＡ对胶质瘤的治疗效果和治疗机制。方法：将３２只Ｗｉｓｔａｒ大鼠分成４组,每组８只,（１）对照组（Ｃ组）于右尾状核接种Ｃ６鼠胶质瘤细胞。（２）治疗组（Ｔ组）：于右尾状核接种Ｃ６细胞后的第７、１０天在接种点注射脂质体包裹的质粒Ｐ－ａｎｔｉ－ＩＧＦ－１,对胶质瘤进行治疗于右尾状核接种经反义ＩＧＦ－１ｍＲＮＡ转染的Ｃ６胶质瘤细胞。（４）Ｋ     

重组链激酶对急性心肌梗死溶栓治疗临床观察

目的：观察溶栓新药重组链激酶（ｒ－ＳＫ）在急性心肌梗死（ＡＭＩ）静脉溶栓治疗中的临床疗效和不良反应。方法：采用平行随机单盲对照的研究方法,以尿激酶（ＵＫ）为对照比较ｒ－ＳＫ对ＡＭＩ的溶栓治疗效果和不良反应。结果：ｒ－ＳＫ１５０万Ｕ对ＡＭＩ的溶栓再通率为８４．４％,而ＵＫ１５０万Ｕ仅为５６．７％（Ｐ＜０．０５）。不良反应除发冷外其他方面两组无差异。结论：国产ｒ－ＳＫ是一个血管再通率高,不良反应及出血并发症低,安全有效的溶栓药物。     

Unconventional cancer therapy —survey of patients with gynaecological malignancy

Although the benefits remain unproven, a considerable number of cancer patients use unconventional therapy, in many cases without the knowledge of the oncologist. At the oncological out-patient department of the women's clinic of the Justus-Liebig-University Giessen we conducted a survey of the various unconventional methods used. 38.8% (80/206) of the patients used unconventional therapies, mainly mistletoe extracts (50%), trace minerals (46%), megavitamins (39%), and enzymes (22%). The perceived etiology of cancer determined the choice for the various methods (p=0.00074). Users of unconventional methods suffered significantly more from conventional therapy, had less faith in their doctors, and felt more nervous and emotionally unstable after the diagnosis of cancer.     

Radiofrequency ablation in children

Radiofrequency (RF) catheter ablation has ushered in a new era in the management of patients with symptomatic tachyarrhythmias. By providing the ability to cure the underlying arrhythmic substrate, RF catheter ablation obviates the need for life-long antiarrhythmic drugs. In the reported series, the success has been high and the complications have been infrequent and relatively minor. Not unexpectedly, RF catheter ablation has become the treatment of choice for patients with symptomatic paroxysmal tachyarrhythmias. The role of radiofrequency catheter ablation in infants and small children remains controversial, and awaits a larger experience and longer follow-up data.     

Minimal synaptic delay in the saccadic output pathway of the superior colliculus studied in awake monkey

The synaptic organization of the saccade-related neuronal circuit between the superior colliculus (SC) and the brainstem saccade generator was examined in an awake monkey using a saccadic, midflight electrical-stimulation method. When microstimulation (50–100 A, single pulse) was applied to the SC during a saccade, a small, conjugate contraversive eye movement was evoked with latencies much shorter than those obtained by conventional stimulation. Our results may be explained by the tonic inhibition of premotor burst neurons (BNs) by omnipause neurons that ceases during saccades to allow BNs to burst. Thus, during saccades, signals originating from the SC can be transmitted to motoneurons and seen in the saccade trajectory. Based on this hypothesis, we estimated the number of synapses intervening between the SC and motoneurons by applying midflight stimulation to the SC, the BN area, and the abducens nucleus. Eye position signals were electronically differentiated to produce eye velocity to aid in detecting small changes. The mean latencies of the stimulus-evoked eye movements were: 7.9±1.0 ms (SD; ipsilateral eye) and 7.8±0.9 ms (SD; contralateral eye) for SC stimulation; 4.8±0.5 ms (SD; ipsilateral eye) and 5.1±0.7 ms (SD; contralateral eye) for BN stimulation; and 3.6±0.4 ms (SD; ipsilateral eye) and 5.2±0.8 ms (SD; contralateral eye) for abducens nucleus stimulation. The time difference between SC- and BN-evoked eye movements (about 3 ms) was consistent with a disynaptic connection from the SC to the premotor BNs.     

NMDA receptor-independent mechanisms responsible for the rate of rise of cumulative depolarization evoked by trains of dorsal root stimuli on rat spinal motoneurones

The mechanisms responsible for the rate of rise (RR) of cumulative depolarization induced by dorsal root stimulus trains were investigated with intracellular recordings from motoneurones of the rat isolated spinal cord. The NMDA receptor antagonists CPP or APV depressed the cumulative depolarization but not its RR which could still be fast enough to elicit action potential wind-up. RR size was correlated with a slow synaptic potential (detected in CPP or APV solution) with which it shared similar voltage dependence. The NK1 antagonist SR 140333 depressed cumulative depolarization, RR and slow synaptic potentials. It appears that the RR (and the ability to express wind-up) was determined by summation of slow synaptic potentials partly mediated via activation of NK1 receptors.     

A systems approach to cancer therapy

Conclusion The molecules described herein as antiangiogenic agents and antimetastatic agents represent a wide variety of molecular structures with a wide variety of biological effects and targets. Most often these agents have been generally classified as antiangiogenic or antimetastatic by their effects in an in vitro bio-assay system. The diversity in this group of molecules gives strength to the potential of this approach in therapeutic applications. The biological and biochemical pathways involved in angiogenesis are numerous and redundant. It is likely that there are many angiogenic factors and many pathways of invasion, therefore it is likely that blockade of more than one pathway related to angiogenesis and/or invasion will be necessary to impact on the natural progress of a malignant disease.The vasculature forms the first barrier to penetration of molecules into tumors. Although the antiangiogenic agent treatments administered in this study did not inhibit angiogenesis in these tumors completely, the vasculature present in the treated tumors may be impaired compared to control tumors. Overall, therefore, the best speculation is that the main targets for the antiangiogenic agents are extracellular matrix processes and/or tumor endothelial cells and that inhibition and/or impairment of these non-malignant functions can improve therapeutic responses when used in combination with cytotoxic therapies. The incorporation of antiangiogenic agents and/or antimetastatic agents into therapeutic regimens represents an important challenge. The successful treatment of cancer requires the eradication of all malignant cells and therefore treatment with cytotoxic therapies. The compatibility of antiangiogenic therapy and/or anti-invasion agents with cytotoxic chemotherapeutic agents is not obvious [316].The goal of the addition of any non-cytotoxic potentiator to a therapeutic regimen is to take a good therapy and, without additional toxicity, push it to cure.Cyclophosphamide is a good drug against the Lewis lung carcinoma although no long-term survivors of animals bearing Lewis lung carcinoma are achieved with cyclophosphamide treatment alone. Adding antiangiogenic agents to treatment of this tumor with cyclophosphamide produced a cure rate of 40–50%, meaning that both the primary and metastatic disease has been eradicated in these animals. Cures were achieved only when the antiangiogenic treatments extended from days 4–18 post Lewis lung tumor implantation. The results obtained with the addition of antiangiogenic agents to cytotoxic anticancer therapies in in vivo models of established solid tumors have been very positive and provide direction for future clinical trials including these antiangiogenic agents. Two conclusions may be drawn. First, combinations of antiangiogenic and/or antimetastatic agents evoke a greater effect on tumor response to therapy than does treatment with single agents of these classes. Second, treatment with antiangiogenic agents and/or antimetastatic agents can interact in a positive way with cytotoxic therapies.     

Electric and magnetic fields (EMF): What do we know about the health effects?

Because we use electric power throughout our homes and workplaces, we are all subject to electric and magnetic fields (EMF) that are created by the voltages and currents present in electrical conductors and electrical equipment. Interest in the health effects of electric-power EMF has been motivated by several epidemiologic studies showing weak associations between surrogate measures of low-level EMF exposure and both childhood cancers and adult cancers. Due to the ubiquitous presence of electric power, the public health implications of this association are potentially very significant; however, good evidence for a causal relationship between exposure to EMF and any health effect has not been found. Yet, uncertainty, plus the suggestive epidemiologic findings, have fueled public anxiety and media attention. To put this potential health threat into perspective, it is important to consider the strength of the epidemiology, the availability of supporting animal studies, and mechanistic or biophysical information about the interaction of EMF with matter. Any discussion of steps that might be taken to avoid potential EMF health-effects needs to incorporate a perspective on how hypothetical EMF risks relate to other hazards to life and health.Work presented at the 23rd Congress on Occupational and Environmental Health in the Chemical Industry (Medichem 1995) The Chemical Industry as a Global Citizen - Balancing Risks and Benefits, 19-22 September 1995, Massachusetts Institute of Technology, Cambridge, Massachusetts