Acute systemic and antiischemic effects of epanolol in patients with coronary artery disease

Summary Antiischemic effects of ₁-blocking agents are based on intrinsic negative inotropic and chronotropic properties. Partial ₁-agonistic activity, although useful in preserving cardiac function, may counteract such antischemic properties by modulating the intrinsic negative cardiac effects of beta-blockade. To investigate the acute hemodynamic and antiischemic profile of epanolol, a cardioselective ₁-antagonist and partial agonist, 20 patients with left coronary artery disease underwent two incremental atrial pacing tests, 45 minutes before (APST I) and 15 minutes after (APST II) 4 mg intravenous epanolol, administered over 5 minutes. Additional measurements were carried out at 1, 3, 5, 10, and 15 minutes after epanolol, at basal and fixed heart rates. Epanolol immediately reduced heart rate with a maximum of 10% at 15 minutes and decreased contractility (Vmax) by 7% (both p<.05), whereas cardiac output fell temporarily by 9% (p<.05). Other hemodynamic parameters did not change, except for a significant 11% reduction in myocardial oxygen demand. Despite comparable pacing conditions, both the double product and contractility decreased significantly less during APST II, resulting in a 17% lower myocardial oxygen consumption (p<.05). Myocardial ischemia was markedly reduced, indicated by normalization of lactate metabolism [lactate extraction 16±7% vs. –7±8% (APST I)], less ST depression (21%), and modulation of LV end-diastolic pressure postpacing (all p<.05 vs. APST I), whereas angina was absent or less in 14 patients. None of the patients reported an adverse effect. Thus, under resting conditions intravenous epanolol induces moderate, short-lasting negative chronotropic and inotropic effects, but does not alter cardiac pump function or vascular resistance, reflecting its additional ₁-agonistic properties. Alternatively, during pacing it still reduces ischemia through negative inotropic effects and diminishes myocardial oxygen demand, reflecting its ₁-antagonistic profile.     

Macromorphology and histology of intramuscular hemorrhages in cases of drowning

In a prospective autopsy series of 39 cases of fatal drowning, the detailed dissection of the skeletal muscles of the neck, anterior / posterior trunk and the upper extremities in layers revealed intramuscular hemorrhages of different size and shape in 20 cases (51.3 %). Light microscopy examination showed a premortal (vital/agonal) type of muscular alteration in 7 (50 %) out of 14 macroscopical hemorrhage-positive cases. These hemorrhages and histological muscle alterations are attributed to agonal convulsions, hypercontraction and overexertion of the affected muscle groups. As long as no cutaneous or subcutaneous hematomas above the hemorrhages can be found, these autopsy findings (with special reference to histology) can serve as an additional criterion concerning the differentiation of drowning and another cause of death. Received: 31 July 1998 / Received in revised form: 31 August 1998     

Exercise induces a change in plasma fibrinogen concentration: fact or fiction?

This study examined the effect of exercise on plasma fibrinogen concentrations with simultaneous measurements of plasma volume changes. Eight moderately active males aged 26.6±3.6 years (mean±SD) completed maximal (VO₂max) and submaximal (75% VO₂max for 30 minutes) exercise trials separated by 7 days. Venous blood samples were obtained at rest, immediately postexercise, and following 30 minutes of recovery. Whole blood was analysed for haematocrit and haemoglobin, while citrated plasma was assayed for fibrinogen levels. Values of haematocrit and haemoglobin before and after exercise were utilised for the estimation of plasma volume changes. Plasma volume decreased (p<0.05) immediately following both maximal (−17.7±5.1%) and submaximal (−14.3±4.1%) exercise. Exercise resulted in decreased plasma fibrinogen levels (maximal exercise: from 266.3±14.5 to 222.2±23.9 mg·dL⁻¹; submaximal exercise: from 239.5±45.4 to 209.7±42.4 mg·dL⁻¹) only when postexercise raw data were corrected for the contraction of plasma volume. It is concluded therefore that changes in plasma volume in response to exercise should be taken into account when interpreting exercise effects on plasma fibrinogen concentration.     

Respiratory health and fluoride exposure in different parts of the modern primary aluminum industry

Objective: The aim of this cross-sectional study was to investigate possible acute and long-term respiratory health effects of work at different working places in the primary aluminum industry. Method: A cross-sectional study was carried out on 78 potroom workers, 24 foundry workers, and 45 carbon-plant workers (n = 147, exposed group), and 56 control workers (watchmen, craftsmen, office workers, laboratory employees) of a modern German prebake aluminum plant. The survey consisted of pre- and postshift spirometric and urinary fluoride measurements. Results: Potroom workers had significantly lower preshift results with regard to forced vital capacity (FVC, 99.5% versus the 107.2% predicted; P < 0.05) and peak expiratory flow (PEF, 85.2% versus the 98.4% predicted; P < 0.01) as compared with controls. In a multiple regression model a small but significant negative correlation was found between postshift urinary fluoride concentrations and FVC, FEV₁, and PEF. Across-shift spirometric changes were observed only in FVC among carbon-plant workers (103.0 ± 13.3% predicted preshift value versus 101.2 ± 13.6% predicted postshift value; P < 0.05). Conclusions: The results suggest that lung function impairment in the modern primary aluminum industry may be only partly due to fluoride exposure and that working in aluminum carbon plants may cause acute lung function changes. Received: 8 July 1998 / Accepted: 31 October 1998     

Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials

Objective: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event limits for analysis during study implementation. Subjects and methods: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5–97.5% interval of distribution of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had been specified in previous articles. Results: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal values and the 2.5–97.5% interval for each laboratory parameter. Conclusion: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies. Received: 30 July 1998 / Accepted in revised form: 25 November 1998     

胰原性区域性门脉高压症血流动力学的临床研究

目的：研究胰原性区域性门脉高压症静脉血流动力学改变。方法：利用彩色多普勒及直接测量法测量血流动力学及脾静脉压力。结果：门静脉、肠系膜上静脉的血管直径、平均流速在两组间无差异。实验组脾静脉直径扩张,流速降低且静脉压力明显升高（Ｐ＜０．０５）。结论：胰原疾病可导致区域性门脉高压,正确的治疗方法是行脾脏切除术。     

A loudspeaker-driven system for rapid and multiple solution exchanges in patch-clamp experiments

A new and inexpensive system allowing rapid and synchronized changes of solutions around a membrane patch or a cell under voltage-clamp conditions is described. Four plastic capillary tubings (OD 640 m; ID 430 m) were glued together horizontally and attached to a coil of a commercially available loudspeaker. Servo-control of the position of the coil allowed the mouth of any of the capillaries to be positioned near the pipette tip within 6 ms. A high flow speed of the test solution was crucial to achieve rapid solution exchange. At a flow speed of 5 cm/s, complete exchange of the external environment of a frog ventricular cell was achieved within 20–30 ms. The time course of solution change was found to be 3–5 times faster at the tip of an open patch pipette. To preserve the physical integrity of the cell, the cell was usually perfused by a control capillary at a slow velocity (0.2 –0.4 cm/s) and test solutions flowing out of adjacent capillaries at high velocity (4–5 cm/s) were applied to the cell only for short periods. Determination of the three-dimensional contamination profile around the mouth of the control capillary allowed the optimal conditions for the use of the system to be established and possible sources of contamination to be avoided between adjacent capillaries with unmatched flow speeds. Successive and multiple changes in external solutions could be easily synchronized with voltage-clamp depolarizations to examine the time course of the effect of drugs on voltage-operated ion channels. An example of this application is given with rapid applications of the dihydropyridine agonist (-)BayK 8644 to the L-type Ca²⁺ channel current in frog ventricular myocytes.     

Tubular and interstitial factors in the progression of glomerulonephritis

All recent studies of the outcome of different forms of progressive glomerulonephritis concur that a major factor, apparently determining outcome, is the presence and severity of tubulointerstitial changes, and not the degree of glomerular alteration. Moreover, at the time of biopsy, tubulointerstitial changes correlate much better with the glomerular filtration rate. These at first surprising findings are not only useful clinically, but should make us think about our models of how progression takes place in so-called glomerular nephritides. In fact, a major tubulointerstitial infiltrate of immune-competent cells is present in all forms of progressive glomerulonephritis, and again correlates with outcome. In addition, it is now clear the tubular epithelium is capable of synthesising and secreting a number of factors important in fibrogenesis, and of displaying major histocompatibility complex class II antigens and leucocyte-adhesion molecules. Tubular cells could thus present peptides to T helper cells and amplify, or maybe even initiate, immune reactions. Finally, fibrogenesis within the kidney is at last being studied, long after studies have been performed on liver and lung. In the past, too much attention has been paid to reversible inflammation and not enough to irreversible cirrhosis of the kidney.Abbreviations used Ig immunoglobulin, e. g. IgA, IgG, IgM etc. - TBM tubular basement membrane - GBM glomerular basement membrane - WHO World Health Organization - MHC major histocompatibility complex - CD cluster determinant - NK natural killer - IL-1 interleukin-1 - IL-2 interleukin-2 - TNF- tumour necrosis factor alpha - ADCC antibody-dependent complement mediated cytolysis - ACE angiotensin-converting enzyme - m macrophage - ICAM-1 intercellular adhesion molecule-1 - ELAM-1 endothelial leucocyte adhesion molecule-1 - VCAM-1 vascular cell adhesion molecule-1 - LFA leucocyte function associated molecule, e. g. LFA-1, LFA-3 - C complement e. g. C3=third component of complement, etc. - TGF- transforming growth factor beta - TGF- transforming growth factor alpha - PDGF platelet derived growth factor - PAS periodic acid Schiff - TCR T cell receptor - PTEC proximal tubular epithelial cell - GM-CSF granulocyte colony stimulating factor - M-CSF monocyte colony stimulating factor - FGF fibroblast growth factor     

Comparison of renal function and psychomotor performance in workers exposed to elemental mercury

Summary Renal function and psychomotor performance (eye-hand coordination, arm-hand steadiness) of a group of 43 workers exposed to mercury vapor were examined. Their mean age and average duration of exposure to mercury were 38 and 5 years, respectively. The results were compared with those obtained in a matched group of 47 control workers. Increased proteinuria and albuminuria were found slightly more prevalent in the Hg-exposed group than in the control workers. These results are in agreement with those found during a previous study carried out in another group of workers also exposed to elemental mercury (Bucket et al. 1980). The scores of the psychomotor tests were less satisfactory in the Hg workers than in the control workers, the arm-hand steadiness test being more discriminative than the eye-hand coordination test. Preclinical changes in psychomotor function can be detected independently of the presence of signs of renal dysfunction. No clear-cut relationships were found between the prevalence of abnormal psychomotor scores and the level of mercury in blood (HgB) or in urine (HgU). Increased prevalences of abnormal psychomotor scores seem however to occur for HgB between 1 and 2 g/100 ml and for HgU between 50 and 100 g/g creatinine. Therefore, a biologic threshold limit value of 50 g/g creatinine is proposed for urinary mercury to prevent the development of preclinical effects on the central nervous system. A similar critical HgU level based on renal dysfunction prevalences has been suggested in a previous study.This study was supported by a grant from the Commission of the European Communities     

Effect ofβ-adrenergic blockade on haemodynamic responses to dynamic and isometric exercise in angina pectoris

Summary The effect of treatment for 1–4 weeks with metoprolol, a ₁-selective blocking agent, or alprenolol, on the heart rate and blood pressure response to isometric exercise was studied in two groups of 12 patients with angina. Measurements were made during the peak effect of metoprolol 10, 40 or 50 mg, and alprenolol 200 mg as Aptin^® Durules^®. After 1 min of sustained handgrip at 50% of maximal voluntary contraction, systolic (6–15%) and diastolic (8–12%) blood pressure after both drugs was significantly lower than without any -blockade; Heart rate was decreased by 19–22% by metoprolol but not by alprenolol. The blood pressurerise during handgrip was not attenuated by either drug. The rise in heart rate was significantly reduced (by 36–50%) by metoprolol 40 and 50 mg and alprenolol 200 mg. No patient experienced angina during handgrip. In contrast, all but one were restricted by angina during bicycle exercise without treatment, at a level that produced the same increase in heart rate as the handgrip test, viz. 3 min at a load of 33 W). The cardiovascular response to sustained handgrip is too small to provide a useful challenge for determination of the anti-anginal efficacy of drugs. However, slight ECG changes of ischaemia did occur during handgrip, which were reversed by -blockade.