Effects of acute and chronic treatment with imipramine on 5-hydroxytryptamine nerve cell groups and on bulbospinal 5-hydroxytryptamine/substance P/thyrotropin releasing hormone immunoreactive neurons in the rat. A morphometric and microdensitometric analysis

Summary Groups of male rats were treated for a period of 14 days with imipramine (10mol/kg) given twice daily. Separate groups of rats received a single dose treatment using the same dose and experimental design as for the repeated treatment. Employing the avidin-biotin immunoperoxidase technique for immunohistochemistry 5-hydroxytryptamine (5-HT)-, substance P (SP)- and thyrotropin releasing hormone (TRH)-like immunoreactivities (IRs) were visualized in consecutive coronal sections of the brain stem and of the spinal cord. The IRs were studied by means of morphometric and microdensitometric procedures using automatic image analysis on profiles representing nerve terminal networks of the ventral horn of the cervical and lumbar enlargements of the spinal cord as well as their coexistence (5-HT/SP and 5-HT/TRH). With the same technique 5-HT IR was measured in the 5-HT nerve cell groups of the medulla oblongata (B 1, B 2, B 3) and of the nucleus raphe dorsalis (B 7) of the midbrain. In addition 5-HT and 5-hydroxyindolacetic acid (5-HIAA) levels were measured in the ventral and dorsal horns of the cervical and lumbar enlargements of the spinal cord using high performance liquid chromatography (HPLC). In the same parts of the spinal cord SP IR was studied by means of radioimmunoassay (RIA).The microdensitometric studies showed that chronic, but not acute, imipramine treatment selectively increased SP IR in the 5-HT/SP/TRH costoring nerve terminals of the medial part of the ventral horn in both the cervical and the lumbar enlargements. Furthermore, quantitative analysis of the entity of coexistence in the 5-HT nerve terminal networks of these areas showed that all the 5-HT nerve terminals contained SP and TRH IRs and that this phenomenon remained after acute and chronic imipramine treatment. The microdensitometric studies on the 5-HT nerve cell groups of the medulla oblongata and of the nucleus raphe dorsalis demonstrated that chronic, but not acute, imipramine treatment selectively increased 5-HT IR in the nerve cell bodies of the lateral part of group B 3 as evaluated from the median grey values. Acute, but not chronic, imipramine treatment significantly increased the field area of 5-HT IR of nerve cell bodies in group B 7, reflecting an increase in the mean profile area of the 5-HT IR nerve cell body profiles. Instead, the mean profile area of 5-HT IR cell bodies of group B 1 was acutely reduced by imipramine.The biochemical studies demonstrated that chronic imipramine treatment selectively reduced 5-HT utilization in the ventral horn of the spinal cord and selectively increased SP IR in the dorsal horn of the lumbar enlargement.In view of these observations it is suggested that chronic imipramine treatment specifically increases SP IR in the 5-HT/SP/TRH costoring nerve terminals of the ventral horn probably related to reduced SP release and reduced 5-HT utilization in these terminals. The results obtained in group B 7 may be explained by a regulation by the³H-imipramine raphe binding sites of fast axonal transport, an influence which may have therapeutic consequences. This mechanism may also be responsible for the increase in 5-HT IR seen upon chronic imipramine treatment in the lateral part of the 5-HT nerve cell body group B 3. Such an effect may lead to a metabolic down-regulation of group B 7, having a possible role for the antidepressant activity of imipramine. The reduction of the mean profile area of 5-HT IR cell bodies of group B 1 seen in the acute treatment can possibly be caused by, noradrenaline (NA) uptake inhibition in inhibitory NA terminals innervating the B 1 group. These results also illustrate the heterogeneities in the responses of the 5-HT nerve cell groups to antidepressant treatment. The ability of chronic imipramine treatment to increase SP IR in the dorsal horn of the lumbar enlargement may reflect the existence of a monoamine-SP interaction in the substantia gelatinosa due to the NA and/or 5-HT uptake blocking activity of imipramine. The existence of such an interaction may help to explain the antinociceptive effect of chronic imipramine treatment.Part of the paper was presented at the 17th International Congress of the International Society of Psychoneuroendocrinology, Bergen, June 29–July 4, 1986.     

Effects of acute continuous exposure of the rat to cigarette smoke on amine levels and utilization in discrete hypothalamic catecholamine nerve terminal systems and on neuroendocrine function

Summary The effects of acute continuous exposure to the smoke from 1–4 cigarettes have been studied in the male rat in terms of hypothalamic catecholamine levels and utilization as well as the secretion of anterior pituitary hormones. Catecholamine levels in discrete hypothalamic catecholamine nerve terminal systems were studied by quantitative histofluorimetry. Catecholamine utilization was studied by means of the tyrosine hydroxylase inhibition method using -methyl-(±)-p-tyrosine methyl ester. The serum hormone levels of adenohypophyseal hormones and of corticosterone were measured by the use of radioimmunoassay procedures. The results show that acute continuous exposure to unfiltered but not to filtered (Cambridge glass fibre filters) cigarette smoke leads to small but dose-dependent reductions of amine levels in most of the hypothalamic noradrenaline and dopamine nerve terminal system. These effects were associated with an enhancement of regional hypothalamic noradrenaline utilization but not of dopamine utilization in the median eminence. Furthermore, a reduction of TSH and prolactin serum levels was noted as well as increases in ACTH secretion. These results are partly different from those previously obtained with rats acutely exposed to intermittent unfiltered cigarrete smoke. This difference is suggested to be due to a temporary blockade of catecholamine release following acute continuous exposure to cigarette smoke.This work has been supported by a grant (1223) from the Council for Tobacco Research, New York, USA and by a grant from the Svenska Tobaks monopolet Send offprint requests to K. Andersson at the above address     

Involvement of cholecystokinin receptors in the control of striatal dopamine autoreceptors

Summary The interaction of locally perfused cholecystokinin-8 (sulphated) with systemically administered apomorphine was studied on the release of dopamine and its metabolites using microdialysis in the neostriatum of the halothane-anaesthetized male rat. Dialysate levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were assayed by high performance liquid chromatography in combination with electrochemical detection. Perfusion with cholecystokinin-8 (100 M but not 1 M or 10 nM) increased the dialysate levels of dopamine without affecting those of DOPAC or HVA. At low concentrations (1 M and 10 nM but not 1 nM), cholecystokinin-8 counteracted the inhibitory effect of apomorphine (0.05 mg/kg, s. c.) on dopamine release. This counteraction was antagonized by perfusion with the cholecystokinin-8 antagonist proglumide (3 M). At this concentration, proglumide perfused alone was without effect on basal or apomorphine-reduced levels of dopamine. The results indicate a facilitatory effect of cholecystokinin-8 on dopamine release in rat neostriatum only at high concentrations. At lower concentrations, cholecystokinin-8 appears to modulate dopamine release by an inhibitory effect on dopamine autoreceptors possibly involving an intramembrane interaction between presynaptic cholecystokinin-8 receptors and dopamine autoreceptors. Send offprint requests to K. Fuxe at the above address     

差示分光光度法测定制剂中硝苯啶的含量

利用硝苯啶溶液对光不稳定的性质,在波长350nm处测其光照前后的吸收度差值(△A),△A与硝苯啶乙醇溶液浓度在10～60μg/ml范围内呈线性关系。使用本法对硝苯啶片进行了含量测定,并对其类似物进行了干扰试验,排除了组分的干扰。该法的精密度日内为1.3%,日间为1.9%,平均回收率为99.96%。方法简便、快速,不需色谱等分离手段即可达到分析目的,专一性、重复性均较好,是分析硝苯啶制剂的一种新途径。     

Expression of fibrinogen receptors during activation and subsequent desensitization of human platelets by epinephrine

Epinephrine causes platelet aggregation and secretion by interacting with alpha 2-adrenergic receptors on the platelet surface. Platelet aggregation requires the binding of fibrinogen to a specific receptor on the membrane glycoprotein IIb-IIIa complex. Although the IIb-IIIa complex is identifiable on the surface of resting platelets, the fibrinogen receptor is expressed only after platelet activation. The current studies were designed to examine the effect of occupancy of platelet alpha 2-adrenergic receptors by epinephrine on the expression of fibrinogen receptors and on the aggregation of platelets. The ability of epinephrine to induce the expression of fibrinogen receptors was studied under two different conditions: acute stimulation (less than 1 min) and prolonged stimulation (50 to 90 min), the latter of which is associated with a reduction or "desensitization" of the platelet aggregation response. Expression of the fibrinogen receptor was monitored with 125I-fibrinogen as well as with 125I-PAC-1 (PAC-1), a monoclonal antibody that binds to the glycoprotein IIb-IIIa complex only after platelets are activated. Epinephrine caused an immediate increase in PAC-1 and fibrinogen binding that was dependent on occupancy of the alpha 2-receptor by epinephrine and on the presence of extracellular free Ca (KCa = 30 mumol/L). By itself, 1 mmol/L Mg was unable to support induction of the fibrinogen receptor by epinephrine. However, it did decrease the Ca requirement by about two orders of magnitude. Prolonged stimulation of unstirred platelets by epinephrine led to a 70% decrease in the aggregation response when the platelets were subsequently stirred. Despite their decreased aggregation response, desensitized platelets bound PAC-1 and fibrinogen normally, indicating that the loss of aggregation was not due simply to a decrease in fibrinogen receptor expression. Although desensitization was not affected by pretreatment of the platelets with aspirin, it was partially prevented when extracellular Ca was chelated by EDTA during the long incubation with epinephrine. These studies demonstrate that once platelet alpha 2-adrenergic receptors are occupied by epinephrine, extracellular Ca is involved in initiating the aggregation response by supporting the induction of the fibrinogen receptor and the binding of fibrinogen. Furthermore. Ca-dependent reactions subsequent to fibrinogen binding may be necessary for maximal platelet aggregation and are impaired when platelets become desensitized to epinephrine.     

Chlorambucil therapy in hairy cell leukemia: effects on lipid composition and lymphocyte subpopulations

Two patients with progressive hairy cell leukemia following splenectomy were treated with low-dose daily chlorambucil. Both had an objective hematologic response as determined by a return to normal hematocrit and platelet count. This was also reflected in the mononuclear cell fraction by the normalization of cholesterol content, cholesterol/phospholipid ratio, and the lymphocyte subpopulations. This article confirms previous reports on the efficacy of chlorambucil in this setting and describes some morphological, and biochemical concomitant events.     

Trastuzumab-induced cardiotoxicity in elderly women with HER-2-positive breast cancer: a meta-analysis of real-world data

Background: We conducted a meta-analysis to assess the overall risk of cardiac toxicity associated with trastuzumab treatment in elderly breast cancer patients.

Methods: We searched databases from PubMed, EMBASE and Cochrane Central Registry of Controlled Trials to identify relevant studies. Statistical analyses were conducted to calculate the incidence rate, overall hazard ratio (HR) and 95% CIs using a fixed effects model.

Results: A total of 116,342 and 360 elderly patients from five cohort studies and two randomized clinical trials (RCTs) were included for analysis. The pooled incidences of symptomatic congestive heart failure (CHF) and CHF/HF/CM were 6.4% (95% CI 4.1% – 9.4) and 16.4% (95% CI 16.19% – 16.61) in patients with median age of 67.5 years from two RCTs and in patients with median age of 67.5 (60 – 75), 71 (66 – 80+), 74.5 (65 – 89), 75 (66 – 81+) and 79.5 (60 – 99) from five cohort studies, respectively. Trastuzumab was significantly correlated with an increased risk of defined cardiac toxicities in five cohort studies (HR = 1.89, 95% CI 1.72 – 2.07, p < 0.00001) and two RCTs (HR = 3.00, 95% CI 1.71, 5.26, p < 0.00001). Sub-group analysis showed that the anthracycline-based chemotherapy increased the risk of CHF/HF and CM in patients among five cohort studies (HR = 2.16, 95% CI: 1.8 – 1.87, p < 0.00001).

Conclusion: Trastuzumab is likely associated with an increased risk of cardiac toxicity in elderly patients with HER-2-positive breast cancer. Carefully monitoring cardiac function in elderly patients receiving trastuzumab, particularly with concurrent use of anthracycline, is warranted.