Comparative physiological pharmacokinetics of fentanyl and alfentanil in rats and humans based on parametric single-tissue models

The objectives of this investigation were to characterize the disposition of fentanyl and alfentanil in 14 tissues in the rat, and to create physiological pharmacokinetic models for these opioids that would be scalable to man. We first created a parametric submodel for the disposition of either drug in each tissue and then assembled these submodels into whole-body models. The disposition of fentanyl and alfentanil in the heart and brain and of fentanyl in the lungs could be described by perfusion-limited 1-compartment models. The disposition of both opioids in all other examined tissues was characterized by 2- or 3-compartment models. From these models, the extraction ratios of the opioids in the various tissues could be calculated, confirming the generally lower extraction of alfentanil as compared to fentanyl. Assembly of the single-tissue models resulted in a whole-body model for fentanyl that accurately described its disposition in the rat. A similar assembly of the tissue models for alfentanil revealed non-first-order elimination kinetics that were not apparent in the blood concentration data. Michaelis-Menten parameters for the hepatic metabolism of alfentanil were determined by iterative optimization of the entire model. The parametric models were finally scaled to describe the disposition of fentanyl and alfentanil in humans. Supported in part by the National Institute on Aging, RO1-AG-4594, and the Anesthesia/Pharmacology Research Foundation.     

Tissue distribution kinetics of tetraethylammonium ion in the rat

Tissue distribution kinetics of tetraethylammonium (TEA) ion in rats were studied following both constant-rate intravenous infusion and rapid intravenous injection of the drug. At a steady-state plasma concentration of 0.2 g/ml, the tissue-to-plasma (T/P) concentration ratio of the kidneys, liver, heart, gut, and lungs exceeded 1,indicating that TEA is localized in these tissues. In vitrotissue homogenate binding and slice uptake experiments provided no evidence of TEA binding to tissue constituents, suggesting that the high T/P concentration gradient is due to an active transport process. The maximum concentration of TEA in all tissues occurred within 5–15 min after rapid injection of a 2-mg dose. Except for the liver, the subsequent decline of TEA concentration in various tissues over a 5-hr period was slow compared to that in plasma. Consequently, the T/P ratio of liver and kidney remained relatively constant, while those of the other tissues increased continually with time. These features of TEA tissue distribution kinetics can be predicted by a physiologically based pharmacokinetic model which incorporates both active and passive transport processes for the passage of TEA between blood and the tissue mass.This work was supported in part by United States Public Health Service Grants No. GM-20852 (M. G. and D. D. S.), GM-15956 (D. D. S.), and RR-07037 (K. J. H.).     

Long-term measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion model

1. Rat bilateral common carotid artery occlusion (BCAO) was used as a chronic cerebral hypoperfusion model. We observed autoradiographically the long-term changes in regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCGU) after 2 days and 1, 4 and 8 weeks of BCAO and in controls. Regions evaluated included the cerebral cortex, white matter and basal ganglia. Pathological changes were also observed with Klüver-Barrera and haematoxylin-eosin staining. 2. After 2 days, rCBF was significantly reduced to 33-58% in the cortex, white matter and amygdala and similar reductions were observed after 1 week. 3. After 4 weeks, rCBF recovered; however, rCBF remained significantly reduced in the occipital cortex, white matter, globus pallidus and substantia nigra. 4. After 2 days, rCGU was mostly maintained but, after 1 week, rCGU was reduced significantly to 40-70% in the cortex, white matter, basal ganglia and thalamus. Four weeks later, these reductions were no longer seen. 5. Rarefaction of the white matter was observed from 1 week. 6. These results showed that the BCAO in rats is an appropriate model for chronic cerebral hypoperfusion and that uncoupling of rCBF and rCGU was observed from 2 days until 4 weeks in the white matter.     

Effects of morphine,fentanyl, sufentanil,and the short-acting morphine-like analgesic alfentanil on the EEG in dogs

Visual and computerized methods were used to analyze the effects of intravenously injected narcotic analgesics on the EEG of dogs implanted with cortical and subcortical electrodes. The drugs were morphine (1.6 mg/kg), fentanyl (0.004 mg/kg), sufentanil (0.0004 mg/kg), and a new potent and very short-acting compound under clinical trial in anaesthesia, alfentanil (0.04, 0.16 and 0.63 mg/kg). All compounds increased the amplitude of the EEG, decreased the frequency of the EEG, and produced spindle-like bursts of biphasic waves. These bursts were more frequent and of a higher amplitude following alfentanil than after the other compounds. A computerized on-line power spectral analysis was applied to three derivations (frontal-occipital cortex, dorsal hippocampus, amygdala). The power of the total band width (0–40 Hz) increased following all narcotic analgesics. The duration of this increase was coincident with the period of loss of righting. Spectral analysis of various frequency bands revealed significant differences between the compounds, specifically with regard to fentanyl and alfentanil as compared to morphine and sufentanil. Sleep-wake patterns of the night following injection of alfentanil were studied. This compound did not produce significant post-drug effects.     

Tissue distribution kinetics as determinant of transit time dispersion of drugs in organs: Application of a stochastic model to the rat hindlimb

A stochastic theory of drug transport in a random capillary network with permeation across the endothelial barrier is coupled with a model of tissue residence time of drugs assuming radial intratissue diffusion. Axial diffusion is neglected both in tissue as well as in the radially well-mixed vascular phase. The convective transport through the microcirculatory network is characterized by an experimentally determined transit time distribution of a nonpermeating vascular indicator. This information is used to identify three adjustable model parameters characterizing permeation, diffusion, and steady-state distribution into tissue. Predictions are made for the influence of distribution volume, capillary permeability, and tissue diffusion on transit time distributions. The role of convection (through the random capillary network), permeation, and diffusion as determinants of the relative dispersion of organ transit times has been examined. The relationship to previously proposed models of capillary exchange is discussed. Results obtained for lidocaine in the isolated perfused hindleg in rats indicate that although the contribution of intratissue diffusion to the dispersion process is relatively small in quantitative terms, it has a pronounced influence on the shape of the impulse response curve. The theory suggests that the rate of diffusion in muscle tissue is about two orders of magnitude slower than in water. We acknowledge the support by a University of Queensland Travel Grant, the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (M.W.), the Australian National Health and Medical Research Council and the Queensland and Northern New South Wales Lions Kidney and Medical Research Foundation (M.S.R.)     

Effects of propranolol and tertatolol on cardiac output and regional blood flows in the rat

Tertatolol (±)-1-(tert-butylamino)-3(thiochroman-8-yloxy)-2-propanol, hydrochloride is a noncardioselective beta-adrenoceptor antagonist that is devoid of partial agonist activity. The effects of this substance on regional blood flows (RBF) in the rat were studied in comparison with those of propranolol. Rats were artificially ventilated with a mixture of 70% nitrous oxide and 30% oxygen. RBFs were assessed using radioactive microspheres of 15 ± 5 μm diameter, injected into the left ventricle. An initial injection of microspheres (⁵⁷Co) was carried out 5 min before intravenous administration of propranolol (500 μg·kg^?1), tertatolol (50 μg·kg^?1) or physiological serum. A second microsphere administration (¹¹³Tin) was performed 10 min after injection of the test substances. The animals were sacrificed 3 min after the second injection of microspheres. Neither modifications in arterial pH, pO₂, pCO₂, nor in the arterial blood pressure were observed with either propranolol or tertatolol. In contrast, a decrease in heart rate was observed (?22% with propranolol and ?14% with tertatolol). The reduction in cardiac output was 33% with propranolol and 29% with tertatolol. Propranolol reduced blood flow to the majority of structures and organs examined; such a reduction was 39% in the cerebral hemispheres, 31% in the brainstems and of greater than 20% in all the renal zones studied. With tertatolol, no significant modifications of RBF were observed in any of the cortical or medullary renal zones investigated, nor in any of the cerebral areas studied; only in several colonic areas and in the skin of the abdomen and back, were reductions in RBF observed. These results demonstrate a difference in the effects of these two substances on renal and cerebral haemodynamics.     

Tissue blood flow and cephalic arteriovenous shunting in cats following administration of indalpine,a selective inhibitor of 5-hydroxytryptamine uptake

A number of observations indicate that a decrease in plasma 5-hydroxytryptamine (5-HT) level may lead to a diminished tissue perfusion and an opening of arteriovenous (AV) anastomoses in the head during migraine headaches. Indeed, some antimigraine drugs and the amine itself decrease the shunting of radioactive microspheres over the cephalic circulation in the experimental animals. Since indalpine selectively inhibits 5-HT uptake mechanisms and increases plasma 5-HT level, we have investigated the effects of the drug (1, 2, and 4 mg·kg^?1) on tissue blood flow and on AV shunting using the radioactive microsphere method in anesthetized cats. Indalpine caused minimal systemic hemodynamic effects; only a moderate (14%) hypotension resulted with the highest dose. Regionally, the drug increased blood flow to brain, intestines, mesentery + pancreas, and skeletal muscles. Both total peripheral AV-shunting (as indicated by the microsphere content of the lungs) and jugular venous AV-shunting (as measured by microspheres in the jugular venous blood) were decreased by the drug. These hemodynamic changes resemble those occurring during 5-Ht infusions. It is suggested that indalpine may be of therapeutic value in migraine since it decreased AV-shunting across the cephalic circulation.     

Uncoupling of cerebral blood flow and glucose utilization by dihydroergocristine in the conscious rat

Summary Dose-dependent effects of the dihydrogenated ergot alkaloid dihydroergocristine on physiological variables, local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) were evaluated in the conscious rat after intravenous injection. Heart rate was reduced with 2.5 mg/kg and 20 mg/kg dihydroergocristine. LCBF and LCGU were determined autoradiographically by employing the ¹⁴C-iodoantipyrine or ¹⁴C-2-deoxyglucose technique, respectively. At a dose of 0.5 mg/kg, dihydroergocristine neither changed LCGU nor LCBF, while at 2.5 mg/kg a slight decrease in LCGU was measured, which was more pronounced at 20 mg/kg. LCBF was significantly increased in several structures at 2.5 mg/kg, but it was markedly reduced at 20 mg/kg. The divergent effects on LCBF and LCGU at a dose of 2.5 mg/kg suggest a potential capacity of dihydroergocristine to uncouple the close interrelation of cerebral blood flow and cerebral energy metabolism.Send offprint requests to T. Beck at the above address     

冠状动脉造影正常的心绞痛患者心肌血流分布特征的研究

目的　研究X综合征患者心房起搏状态下心肌血流分布特征和微血管功能的变化。方法　采用定量心肌超声显像（MCE）测定25例X综合征患者在心房起搏状态下心肌血流分布特征和微血管功能状态的变化。测定前对所有患者进行活动平板运动实验（Bruce方案），将运动中出现前壁ST水平或下斜型压低患者分配在X综合征组（X组，男5例，女6例，平均年龄52岁），而无ST段变化的患者为对照组（男7例，女7例，平均年龄46岁）。基础及心房起搏（150　bpm,共3　min）后即刻测定前降支区域心内膜和心外膜下心肌灰阶比值（ED/EP）。结果　心房起搏可诱发所有X综合征患者出现胸痛及ST段压低，而对照组则阴性。起搏后即刻X综合征患者ED/EP比值显著降低（0.98±0.10～　0.76±0.17,P<0.01）,而对照组则无变化。结论　运动负荷状态下心肌血流分布异常是导致X综合征患者出现胸痛和ST段压低的主要原因。     

Analysis of methadone disposition in the pregnant rat by means of a physiological flow model

A physiological flow model simulating the pregnant rat is constructed for methadone. The model includes brain, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. Since methadone kinetics may provide valuable information for optimal therapy, an attempt is made to describe methadone kinetics in brain and other tissues simultaneously. The concentration-time profiles of methadone in various tissues after an i.v. bolus dose of 2 rng/kg are reasonably described by the model. The role of the different organs in the disposition of methadone is further explored by simulations. It is found that methadone is initially sequestered in lung tissues immediately after intravenous administration. Therefore, both venous and arterial blood pools are included in the model. Rapid uptake then takes place into vascular-rich organs, including kidneys, liver, and muscle, followed by redistribution into less penetrable organs, such as brain, fetal, and intestinal tissues. Data indicate that diffusional resistance governs the transfer of drug into brain, fetal, and intestinal tissues. Simulations suggest that muscular tissues play an important role in the rat and in man, becoming the major methadone reservoir. The tissue-to-blood partition coefficients derived from equilibrium conditions in this study are generally higher than those reported hitherto. The model is scaled up to a human to investigate whether it can be used to predict the concentration of methadone in different organs after a certain dose. Volume of distribution (Vd_ss) and biological half-life are consistent with earlier findings in man. The study is done by means of the GC-MS method with selected ion-monitoring where deuterated methadone is used as an internal standard.     

Comparative scoring of micronucleated reticulocytes in rat peripheral blood by flow cytometry and microscopy.

A flow cytometric technique for scoring the incidence of micronucleated reticulocytes in rat peripheral blood was compared to a standard microscopy-based procedure. For these studies, groups of five male Sprague-Dawley rats were treated with vehicle or a broad range of chemical genotoxicants: 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, vincristine, methylaziridine, acetaldehyde, methyl methanesulfonate, benzene, monocrotaline, and azathioprine. Animals were treated once a day for up to 2 days, and peripheral blood was collected between 24 and 48 h after the final administration. These samples were processed for flow cytometric scoring and microscopy-based analysis using supravital acridine orange staining, and the percentage of reticulocytes and micronucleated reticulocytes was determined for each sample. The resulting data demonstrate good agreement between these scoring methodologies, although careful execution of the flow cytometric method was found to enhance the micronucleus assay by reducing both scoring time and scoring error. These data add further support to the premise that the peripheral blood compartment of rats can be used effectively to detect genotoxicant-induced micronuclei.     

Analysis of pethidine disposition in the pregnant rat by means of a physiological flow model

The disposition of pethidine (meperidine) in the pregnant rat is described by means of a physiological flow model. The model includes arterial and venous blood, brain, fat, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. The concentration-time profiles of pethidine calculated by the model are consistent with experimental data, except for the brain and renal tissues, where the model predicts initially higher concentrations. Simulations are carried out to further explore the contribution from different organs on the kinetics in blood and tissues. The tissue-to-blood partition coefficients vary over a range from 5 to 316, where fat has the lowest and liver the highest after a correction is made due to hepatic extraction. Rapid uptake occurs into highly perfused organs such as brain, kidneys, liver, and lungs, followed by fetus, intestines, muscle, and fat. Data indicate no marked membrane resistance to pethidine of the investigated organs, except for fetal tissues, but rather a perfusion-limited uptake. Simulations suggest that muscles and adipose tissue play an important role in the rat, becoming the major reservoir of drug during the intermediate and terminal elimination phase, respectively. Volume of distribution and the biological half-life agree with reported findings. Pethidine is subject to a high systemic blood clearance, which exceeds the total hepatic blood flow in the rat. No degradation of pethidine is found in blood, and therefore a pulmonary expression for pethidine clearance is added as a potential source of pethidine elimination. The elimination of pethidine after a single i.v. bolus dose is found to be dependent on simulated changes in cardiac output and hepatic blood flow. A simulation is performed with the scaled model to mimic the human concentration-time profiles in maternal blood and brain tissues and fetal tissue during repetitive doses of pethidine.     

牛磺酸对急性局部脑缺血大鼠脑血流和脑梗死体积的影响

目的 :研究牛磺酸对脑缺血再灌注模型大鼠的局部脑血流和脑梗死体积的影响。方法 :用大脑中动脉栓塞 (MCAO)法制作大鼠急性局部脑缺血再灌注模型 ,分别用 10 ,4 0和 80mg·kg- 1牛磺酸经腹腔注射给药 ,检测缺血 1h和灌注 30min内脑血流 ,再灌注 2 4h后进行神经功能缺损评分并计算脑梗死体积的大小。结果 :MCAO引起大脑中动脉供血区脑血流显著下降 ,牛磺酸可减少脑血流量下降的幅度 ;缺血 1h再灌注 2 4h后 ,模型组脑梗死体积为 (33±s 9) % ,而牛磺酸治疗组脑梗死体积明显缩小 ,各组分别为 (17± 5 ) % ,(12± 5 ) %和 (11± 3) % ;牛磺酸治疗组神经缺损评分比模型组小。结论 :牛磺酸可以增加缺血局部的脑血流量 ,缩小脑梗死体积 ,对急性脑缺血具有脑保护作用。     

氢氯噻嗪在小鼠体内的组织分布及药动学研究

目的建立小鼠血浆及组织中氢氯噻嗪浓度测定的HPLC—MS／MS方法,研究氢氯噻嗪在小鼠体内的组织分布及药动学。方法在血浆样品及组织样品中加入内标布洛芬,分别采用乙醚和乙酸乙酯提取处理,以甲醇-水-氨水（90：10：1）为流动相,用C18柱分离,采用电喷雾电离源（Turbo Ionspray）,负离子方式检测,扫描方式为多反应监测（MRM）。以此方法测定72只雄性健康小鼠给予氢氯噻嗪后10个时间点的血浆及组织样品,并采用DAS2．0药动学程序计算主要药动学参数。结果氢氯噻嗪在血浆中线性范围为5．0～1000μg·L^-1,在组织中线性范围为0．05～50．0μg·g^-1,日内、日间RSD均〈15％。小鼠灌胃给予氢氯噻嗪后快速分布在各组织中,其中胃、肠、肝分布最多,心分布最少。结论本法快速、准确、专属、灵敏。氢氯噻嗪灌胃给药后吸收快,消除半衰期长,组织分布广泛。     

Comparison of the effects of intravenous and intrasplenic infusions of glucagon on cardiac output and its distribution in the rat

Summary In order to determine whether or not glucagon released from the pancreas might have local vascular effects, the actions upon regional haemodynamics in the anaesthetised rat of two doses of glucagon (2 and 10 g kg^–1 min^–1) infused intrasplenically (and thus into the portal vein) were compared with those of a single dose (2 g kg^–1 min^–1) infused i. v. Infusion of glucagon i. v. produced a significantly increased heart rate (by 6%) and cardiac output (by 23%) in the experimental animals compared to those receiving saline by the same route. Total peripheral resistance fell by 24%. A greater proportion of the cardiac output passed to the coronary and renal vascular beds and blood flow was increased in the spleen, testes, pectoral skeletal muscle, stomach and small intestine as well as the heart and kidneys.The lower dose infused intrasplenically had no significant effect on cardiac output or total peripheral resistance but significantly increased the proportion of cardiac output passing both to the stomach and the small intestine such that the percentage of cardiac output flowing through the portal vein increased from 19.1 ± 1.1% to 23.8 ± 1.7%.Intrasplenic infusion of 10 g kg^–1 min^–1 significantly increased cardiac output (by 29%) but reduced total peripheral resistance by 37%. Greater fractions of the cardiac output were received by the spleen, small intestine and epididymides. Blood flow was increased in these organs and the skin, kidneys, stomach, large intestine and the mesentery.It is concluded that pharmacologically effective amounts of glucagon only passed into the systemic circulation with the higher dose infused intrasplenically. Thus the redistribution of cardiac output in favour of the splanchnic bed with the lower dose of glucagon infused into the portal region is most likely the result of local mechanisms rather than a direct effect of the hormone on the inflow vasculature resulting from recirculation. Send offprint requests to C. R. Hiley at the above address     

Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow,plasma and blood cell binding,and the hepatocellular enzymatic activity on hepatic drug clearance

Two commonly used models of hepatic drug clearance are examined. The “well-stirred” model (model I) views the liver as a well-stirred compartment with concentration of drug in the liver in equilibrium with that in the emergent blood. The “parallel tube” model (model II) regards the liver as a series of parallel tubes with enzymes distributed evenly around the tubes and the concentration of drug declines along the length of the tube. Both models are examined under steady-state considerations in the absence of diffusional limitations (cell membranes do not limit the movement of drug molecules). Equations involving the determinants of hepatic drug clearance (hepatic blood flow, fraction of drug in blood unbound, and the hepatocellular enzymatic activity) and various pharmacokinetic parameters are derived. Similarities and differences between the models are explored. Although both models predict similar hepatic drug clearances under a variety of conditions, marked differences between them become apparent in their predictions of the influence of changes in the determinants of drug clearance on various pharmacokinetic parameters.     

Pharmacokinetic analysis and tissue distribution of andrographolide in rat by a validated LC-MS/MS method

Context: Andrographis paniculata (Burm.f.) Nees (Acanthaceae) is widely used in tribal medicine in India and some other countries for multiple clinical applications. It contains andrographolide (AG) (diterpenoid lactone), a major phytomarker which probably accounts for its medicinal properties.

Objective: This study investigates the site-specific distribution of AG in different tissues of rats and its pharmacokinetic parameter evaluation by using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method.

Materials and methods: A simple and sensitive LC-MS/MS method has been developed and validated to quantify the presence of AG in plasma and various tissues of rat following oral administration of A. paniculata extract and AG in a dose of 133.33 and 100?mg/kg/day, respectively, for four weeks.

Results: The present study showed that the highest concentration of AG was in kidney (156.12?ng/g) followed by liver, spleen and brain while almost same concentration was found in heart and lung. The apparent C_max, T_max, elimination half-life and total exposure (AUC_0–α) were 115.81?ng/ml, 0.75, 2.45 and 278.44?ngh/ml, respectively.

Conclusion: This was an attempt to determine the presence of AG (a known biomarker) in tissues such as kidney, heart, lungs, brain and plasma of rats using a validated LC-MS/MS method. Furthermore, the observed reduced concentration in plasma and various tissues from 1 to 8?h might be attributed to relatively rapid elimination or distribution of AG from the central compartment.     

Effects of emopamil on postischemic blood flow and neuronal damage in rat brain

Summary The effects of the calcium entry blocker emopamil on physiological variables, local cerebral blood flow (LCBF) and on hippocampal cell damage were evaluated after 10 min of forebrain ischemia in the rat. LCBF was determined with the ¹⁴C-iodoantipyrine technique after 2, 10, and 60 min of postischemic recirculation. Histological evaluation was performed 7 days after ischemia in cortical and hippocampal tissue by determination of the percentage of necrotic neurons. Preischemic application of emopamil [4 mg/kg racemate or 2 mg/kg (S)-emopamil; i.v.] caused increases in LCBF in cortical areas but did not alter blood flow in the hippocampus at 2 min of recirculation. After 10 and 30 min of flow resumption no differences in LCBF between drug-treated and control animals were observed. In the histological series (S)-emopamil was applied at doses of 2, 4 or 6 mg/kg before the induction of ischemia. After 7 days of postischemic recovery, neuronal damage was significantly reduced by the calcium antagonist in hippocampal CA 1 sector at all doses tested, the most prominent effects being observed with the lowest dose. At this dose cell loss in the Ca3 sector was also reduced. In cortical tissue the number of necrotic cells remained unchanged by emopamil treatment. It is concluded that the calcium antagonist emopamil can reduce ischemia-induced neuronal cell damage. The compound improves circulation in cortical tissue only during early recovery but not at later phases of reflow, i.e. the period of delayed hypoperfusion. These increases in blood flow are not of crucial importance for ultimate neuronal death in this area. The ameliorative action of emopamil on the survival of hippocampal neurons is not associated with blood flow changes and therefore seems to reflect a direct effect on cerebral parenchyma. Send offprint requests to G. W. Bielenberg at the above address     

Differential effects of methylxanthines on local cerebral blood flow and glucose utilization in the conscious rat

Summary The aim of this study was to test the effects of the three classical methylxanthines, theophylline, caffeine and theobromine, on local cerebral blood flow and glucose utilization. Equimolar doses (1.6 mol/kg/min i.v.) of theophylline and caffeine produced increases in local cerebral glucose utilization and decreases in local cerebral blood flow. These compounds, therefore, re-set the ratio of cerebral blood flow per unit of glucose utilization at a lower level. These results are interpreted with respect to the known adenosine antagonist properties of caffeine and theophylline. Theobromine, a substance with less significant adenosine antagonist properties, had minimal effects on local cerebral blood flow and glucose utilization at a dose of 1.6 mol/kg/min i.v. These data may provide supportive evidence for the hypothesis that adenosine plays an important role in cerebral blood flow-metabolism coupling.Part of this work has previously been presented at the Deutsche Pharmakologische Gesellschaft March 13–16, 1984 on Mainz