Effects of enkephalins and two enzyme resistant analogues on monoamine synthesis and metabolism in rat brain

Summary Methionine-enkephalin and leucineenkephalin, administered into the lateral ventricle of intact rats, increased the accumulation of DOPA by a naloxone-sensitive mechanism in different brain regions after inhibition of the aromatic l-amino acid decarboxylase. Because of the rapid enzymatic degradation of both enkephalins large doses (500 g) were required to enhance brain catecholamine synthesis. The two enzyme resistant enkephalin analogues d-Ala²-methionine enkephalin amide (DALA (4–256 g) and FK 33-824 (0.003–1 g) also increased the synthesis of DOPA, dose-dependently and by naloxone-sensitive mechanisms, but at much lower dosage level. The enkephalins markedly enhanced the brain tyrosine concentration but this effect was not antagonized by naloxone, probably because the enzymatic cleavage releases tyrosine from the administered peptides. In contrast, neither DALA nor FK 33-824 increased the brain tyrosine concentration. The formation of 5-HTP and the brain tryptophan concentration were also increased by the enkephalins, although these effects were not blocked by naloxone. The enkephalin analogues, however, enhanced the formation of 5-HTP and the brain tryptophan concentration by naloxonesensitive mechanisms. All four peptides accelerated the disappearance of dopamine, noradrenaline and 5-hydroxytryptamine after inhibition of monoamine synthesis. The results suggest that endogenous enkephalins, through the activation of opiate receptors, are involved in the short-term regulation of central monoaminergic systems.Preliminary data were presented at the Nobel Symposium 42, Principles for the Central Regulation of the Endocrine System, Stockholm, June 8–10, 1978, and at the 4th International Catecholamine Symposium, Asilomar Conference Center, Pacific Grove, California, September 17–22, 1978     

Exercise and heart disease. Epidemiology of the "exercise hypothesis"

The "exercise hypothesis" states that exercise protects against coronary heart disease. Reviewed herein is the epidemiologic evidence for and against the "exercise hypothesis." The weight of evidence supports the view that exercisers have a lower risk of coronary disease, but that vigorous exercise cannot always prevent progression of coronary atherosclerosis and does increase the risk of sudden death in persons with advanced coronary atherosclerosis. It is concluded that the "exercise hypothesis" is plausible, even likely, but still unproved.     

Primary chemotherapy in the treatment of children with bladder--prostate tumors in the Intergroup Rhabdomyosarcoma Study (IRS-II)

Twenty-nine children (24, male; 5, female) with non-disseminated rhabdomyosarcomas of the bladder or prostate were treated (1978-1980) by a primary chemotherapy regimen consisting of vincristine, actinomycin D, and cyclophosphamide ("Pulse" VAC), with or without local radiotherapy. During the initial 20 wk of chemotherapy, nine children achieved a Clinical Complete Response (CCR). Three of these are without evidence of disease (NED) and have functional bladders, two following partial cystectomy. Four who achieved a CCR subsequently relapsed or remained biopsy positive, but are at present NED following radiotherapy and anterior exenteration. Two patients who achieved CCR status relapsed and have died of disease. Twelve patients had a Clinical Partial Response (CPR) in less than 20 wk and two others in less than 40 wk. Seven of these are NED with intact bladders following chemotherapy-radiotherapy; and an additional patient is NED following partial cystectomy. Four patients in the CPR group have been treated by exenteration following failure to achieve complete response, and are NED. One patient has died, and one has progressive disease. Six patients had an inadequate response to chemotherapy (NR). Anterior exenteration was carried out in three, and two of these have survived. The overall results in these 29 patients are: (A) alive and disease-free with functional bladders, 11; (B) alive and disease-free following anterior exenteration, 10; and (C) dead or death from tumor anticipated, 8. The function of retained bladders (11) has been satisfactory.     

The ONG capsular lens,report of 100 implantations

This Capsular Lens (ONG, type IV, to be called O.C.L.) has been developed for routinely performed extracapsular cataract extraction with lens implantation. The fundamental surgical procedure was based on continuing experience with the bimanual aspiration-irrigation technique and system developed by the author in 1971. The biomechanical properties of the asymmetric partly flexible, haptic loops are designed to give tensionfree fixation in two capsular pockets. The plano-anterior position of the lens ensures well-defined irido-lenticular clearance and proper alignment of the convex side with the posterior capsule. Consequently no iridectomy or iridotomy is needed for proper aqueous flow.     

Synthesis of deuterium‐labeled 3‐O‐methyldopa and 4‐O‐methyldopa

Concise methods for the synthesis of 4‐hydroxy‐3‐[²H₃]‐methoxyphenylalanine (3‐O‐[²H₃]‐methydopa) and 3‐hydroxy‐4‐[²H₃]‐methoxyphenylalanine (4‐O‐[²H₃]‐methydopa) are described. The 3‐O‐[²H₃]‐methydopa is a valuable internal standard for the tandem MS quantification of 3‐O‐methyldopa, a metabolite of value in the diagnosis of aromatic l‐amino acid decarboxylase (AADC) deficiency. Copyright © 2003 John Wiley & Sons, Ltd.     

Effect of single and multiple administration of an O 6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model

The purpose of the present study was to examine the effect of O ⁶-benzylguanine (O ⁶-BG) on the antitumour activity and toxicity of 8-carbamoyl-3-methylimidazo [5, 1-d ] -1,2,3,5-tetrazine-4(3H)-one (temo-zolomide) in a human malignant melanoma xenograft model following single and multiple administration of the combination. O ⁶-BG irreversibly inactivates the DNA-repair protein O ⁶-alkylguanine-DNA alkyltransferase (AGT), which confers resistance to temozolomide. Preadministration of O ⁶-BG (35 mg/kg, i.p.) 1 h prior to temozolomide (i.p.) was examined using single and daily × 5 dosing regimens in athymic mice bearing subcutaneous A375P xenografts. The AGT activity of A375P tumors was 95 ± 8 fmol/mg protein (mean ± SE, n = 4). O ⁶-BG alone completely suppressed xenograft AGT activity within 1 h of administration but had no effect upon tumor growth. O ⁶-BG did not significantly increase the tumor growth delay induced by a single 200-mg/kg dose of temozolomide (P>0.05, two-tailed Mann-Whitney test) but did increase the associated mean body weight loss (P<0.025). In contrast, when the same dose of temozolomide was divided into five equal fractions (40 mg/kg) and given with O ⁶-BG on 5 consecutive days, a comparable increase in toxicity was accompanied by a very significant increase in tumor growth delay (P<0.0025), equivalent to that produced by a 3-fold greater dose of temozolomide alone. O ⁶-BG with temozolomide also produced a greater antitumour effect than an equitoxic dose of temozolomide alone on this schedule (P<0.005). These data indicate that the enhancement of temozolomide antitumour activity by O ⁶-BG preadministration is dependent upon the schedule of drug administration, with multiple dosing of O ⁶-BG + temozolomide producing the greatest effect. The results also suggest that prolonged administration of the combination can lead to an increase in the therapeutic index of temozolomide. Received: 8 September 1996 / Accepted: 8 February 1997     

Growth and survival of B-chronic lymphocytic leukaemia cells

Although chronic lymphocytic leukaemia of B-cell type (B-CLL) is the most common form of leukaemia in the Western world, several questions about the biology of B-CLL remain to be clarified. To obtain a conceptual model for B-CLL, defined as a relentless accumulation of resting B-CLL cells, it is particularly relevant to ask which cell type is the normal counterpart of B-CLL; what is the site of proliferation; which signals are involved in the recruitment and induction of proliferation and which signals contribute to the survival of the B-CLL cells? The significance of the studies on B-CLL cellsin vitro for the interpretation of thein vivo situation may be questioned since they oversimplify the multiple and complex cellular interactions that occurin vivo. However, thein vitro studies have been instrumental in elucidating signals that may regulate growth, differentiation and survival of B-CLL cells. This knowledge, herein reviewed, can be used to put forward a hypothesis on B-CLL cell regulationin vivo.     

三氧化二砷注射液治疗中晚期原发性肝癌15例报告

目的 评价三氧化二砷（As2O3）治疗中晚期原发性肝癌的近期疗效和不良反应。方法 中晚期原发性肝癌共15例，采用单药三氧化二砷（As2O3）静脉滴注10mg/d,连续10天为1周期,间歇3周重复。结果 PR 3例,NC 8例,PD 4例，有效率20%,主要的不良反应为轻度的骨髓抑制和肝功能损害。结论 三氧化二砷（As2O3）治疗中晚期原发性肝癌确实有效,不良反应少,值得推广。     

反相高效液相色谱法测定肠安胶囊中黄芩苷的含量

目的 :建立以反相高效液相色谱法测定肠安胶囊中黄芩苷含量的方法。方法 :色谱柱为C18,流动相为甲醇 -0 07 %磷酸溶液 (44∶56),流速为1ml/min ,检测波长为280nm ,柱温为室温。结果 :黄芩苷进样量在0 1054μg～1 0540μg范围内与峰面积呈良好的线性关系 (r=0 9996) ,平均加样回收率为97 44 % (RSD=2 92 % ,n=5)。结论 :本方法简便、准确、快速 ,可用于该制剂的含量测定。     

由苍蝇传播引起E．coli O157：H7感染爆发的评估模型的建立

目的 建立苍蝇对E．coli O157：H7传播作用的定量危险性评估模型。方法 在Excel工作表中模拟E．coli O157：H7的粪口传播过程，利用@RISK软件对模型进行Monte Carlo模拟。结果 由此交叉污染途径引起人群感染的概率为10^-5～10^-3／餐。模型预测的结果与爆发调查数据基本吻合。通过模型分析可知，苍蝇排泄物中的含菌量及苍蝇的数量是影响人群感染危险性的重要因素。结论 以苍蝇污染途径模拟E．coli O157：H7感染危险性的定量评估模型，该模型是一个非常有用的评估危害与危险性关系的评估工具。