Cross-cultural adaptation of the disabilities of the arm, shoulder, and hand (DASH) questionnaire into Hungarian and investigation of its validity in patients with systemic sclerosis.

OBJECTIVE: To adapt and validate the Hungarian version of the DASH and the shorter QuickDASH Outcome Measures and to establish their validity in patients with systemic sclerosis (SSc). METHODS: The Hungarian adaptation of the questionnaires was performed using forward/backward translations, expert and lay reviews. 128 patients completed the DASH, the Health Assessment Questionnaire (HAQ-DI), the Modified HAQ-DI for patients with SSc (SSc-HAQ), and the Short Form Health Survey (SF-36) questionnaire. 76 patients participated in a 12-month follow-up examination. Sensitivity to change was estimated using the standardized response mean (SRM). RESULTS: Cronbach alpha in the DASH sections were between 0.94-0.97. The intraclass correlation coefficient for the test-retest reliability of DASH was 0.89. DASH scores showed a correlation with both SSc-HAQ and the physical dimensions of the SF-36 (Spearman's rho: 0.89, -0.77 and -0.42, respectively). The SRM of DASH was 0.64 among the scleroderma patients with worsening HAQ-DI status. CONCLUSIONS: The Hungarian version of the DASH and QuickDASH demonstrated equivalent reproducibility, internal consistency and validity to the originals. The strong correlations of the DASH and QuickDASH with the HAQ-DI, and with the physical dimensions of the SF-36 show that the disability of the patient with SSc is predominantly caused by the functional impairment of the upper limb. Because both questionnaires were valuable tools for measuring upper extremity function and joint damage in SSc patients, we recommend the shorter and simpler QuickDASH for everyday clinical use.

PET studies on the brain uptake and regional distribution of [11C]vinpocetine in human subjects.

OBJECTIVES: Vinpocetine is a compound widely used in the prevention and treatment of cerebrovascular diseases. It is still not clear whether the drug has a direct and specific effect on neurotransmission or its effects are due to extracerebral actions, such as changes in cerebral blood flow. The main objective of the present investigation was to determine the global uptake and regional distribution of radiolabelled vinpocetine in the human brain in order to explore whether it may have direct central nervous system effects. MATERIAL AND METHODS: Three healthy subjects were examined with positron emission tomography and [11C]vinpocetine. The regional uptake was determined in anatomically defined volumes-of-interest. The fractions of [11C]vinpocetine and labelled metabolites in plasma were determined using high pressure liquid chromatography. RESULTS: The uptake of [11C]vinpocetine in brain was rapid and 3.7% (mean; n = 4) of the total radioactivity injected was in brain 2 min after radioligand administration. The uptake was heterogeneously distributed among brain regions. When compared with the cerebellum, an a priori reference region, the highest regional uptake was in the thalamus, upper brain stem, striatum and cortex. Following an initial peak, the total concentration of radioactivity in blood was relatively stable with time, whereas the concentration of the unchanged compound decreased with time in an exponential manner. CONCLUSION: Vinpocetine, administered intravenously in humans, readily passes the blood-brain barrier and enters the brain. Its regional uptake and distribution in the brain is heterogeneous, indicating binding to specific sites. The brain regions showing increased uptake in the human brain correspond to those in which vinpocetine has been shown to induce elevated metabolism and blood flow. These observations support the hypothesis that vinpocetine has direct neuronal actions in the human brain.

Autoradiographic evaluation of [11C]vinpocetine binding in the human postmortem brain.

The main objective ofthe study was to evaluate with autoradiographic technique whether or not [11C]vinpocetine, a compound widely used in the prevention and treatment of cerebrovascular diseases (Cavinton, Gedeon Richter Ltd., Budapest), binds to specific sites in the human brain in post mortem human brain sections. Binding was assessed under four conditions: the incubation was performed using Tris-HCl buffer with or without the addition of salts (0.1% (weight/vol) ascorbic acid, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 mM MgCl2), with or without the addition of excess (10 microM) unlabelled vinpocetine. Measurements on digitized autoradiograms indicated that [11C]vinpocetine labelled all grey matter areas in the human brain to a similar extent and no significantly heterogeneous binding could be demonstrated among cortical or subcortical regions. The addition of excess unlabelled vinpocetine lowered the binding slightly in all regions. Although these results indicate that [11C]vinpocetine does not bind to human brain transmitter receptors or transporters with a high affinity (Ki < 10 nM), it cannot be ruled out that the compound binds to receptors and/or transporters with lower affinity.

Role of sodium channel inhibition in neuroprotection: effect of vinpocetine.

Vinpocetine (ethyl apovincaminate) discovered during the late 1960s has successfully been used in the treatment of central nervous system disorders of cerebrovascular origin for decades. The increase in the regional cerebral blood flow in response to vinpocetine administration is well established and strengthened by new diagnostical techniques (transcranial Doppler, near infrared spectroscopy, positron emission tomography). The latest in vitro studies have revealed the effect of the compound on Ca(2+)/calmodulin dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage-operated Ca(2+) channels, glutamate receptors and voltage dependent Na(+)-channels; the latest being especially relevant to the neuroprotective action of vinpocetine. The good brain penetration profile and heterogenous brain distribution pattern (mainly in the thalamus, basal ganglia and visual cortex) of labelled vinpocetin were demonstrated by positron emission tomography in primates and man. Multicentric, randomized, placebo-controlled clinical studies proved the efficacy of orally administered vinpocetin in patients with organic psychosyndrome. Recently positron emission tomography studies have proved that vinpocetine is able to redistribute regional cerebral blood flow and enhance glucose supply of brain tissue in ischemic post-stroke patients.

Interaction of Azospirillum lipoferum with wheat germ agglutinin stimulates nitrogen fixation.

In vitro, the nitrogen fixation capability of A. lipoferum is efficiently increased in the presence of wheat germ agglutinin (WGA). A putative WGA-binding receptor, a 32-kDa protein, was detected in the cell capsule. The stimulatory effect required N-acetyl-D-glucosamine dimer (GlcNAcdi) terminated sugar side chains of the receptor and was dependent on the number of GlcNAcdi links involved in receptor-WGA interface. Binding to the primary sugar binding sites on WGA had a larger stimulatory effect than binding to the secondary sites. The WGA-receptor complex generated stimulus led to elevated transcription of the nifH and nifA genes and of the glnBA gene cluster but not of the glnA gene from its own promoter. There may well be a signalling cascade contributing to the regulation of nitrogen fixation.

Effect of RGH-2716 on learning and memory deficits of young and aged rats in water-labyrinth.

RGH-2716 is a novel 1-oxa-3,8-diazaspiro[4.5] decan 2-one, which was published to have potent inhibitory effect on neuronal Na and Ca movement and stimulatory action on nerve growth factor (NGF)-production, as well as to show significant antiamnesic activity in experimental amnesia models. The aim of the present experiments was to study the effect of the compound on the learning process and on the different stages of memory using water-labyrinth in normal and memory impaired young animals, as well as to study cognitive effect of RGH-2716 on aged animals. At the doses of 0.5 mg/kg i.p. or 3 mg/kg p.o. given before daily swimming, this compound improved the learning process of young animals impaired by either diazepam (DIA) or scopolamine (SCOP). In retrograde amnesia model RGH-2716 (3 mg/kg p.o.) significantly ameliorated consolidation process and retrieval of information impaired by SCOP or DIA. Nimodipine and vinpocetine (10 mg/kg p.o.) showed moderate effect compared to RGH-2716. Aged rats pretreated with daily i.p. RGH-2716 performed the tasks with significantly fewer errors and shorter swimming time than untreated aged rats. When aged animals had to solve a new labyrinth problem, treated aged rats showed significantly better learning ability than aged controls. One month of oral treatment of aged rats with 3 mg/kg dose of RGH-2716 two times daily resulted in a "tendency-like" improvement in learning of aged Fischer 344 and spontaneously hypertensive (SH) rats. The present results make RGH-2716 an interesting compound for the treatment of cognitive disorders.

Synthesis of vinca alkaloids and related compounds. Part 84. Sulfonamide derivatives of some vinca alkaloids with cardiovascular activity.

(+)-Vincamine (1) and (+)-vinpocetine (2) were chlorosulfonylated and the resulting sulfonyl chloride isomers (3-6) were transformed into sulfonamides (7-10). The ester group of sulfonamides was modified by selective hydrolysis and transesterification. Apovincaminol derivatives (14-16) were also prepared by reduction. In addition to the known cerebrovascular effects of the unsubstituted compounds (1,2) sulfonamides also show a significant peripheral vasodilator effect.

Bisaramil and antiarrhythmics as inhibitors of free radical generation.

The aim of this study was to investigate the effect of bisaramil--an antiarrhythmic drug under clinical trials-on free radical generation of isolated polymorph neutrophil granulocytes (PMN) and furthermore to compare its activity to that of well-known antiarrhythmics which have different modes of action. PMNs were isolated from healthy beagle dogs, and superoxide radical generation was induced by phorbol-myristate-acetate. Stimulated free radical generation capacity of PMNs and the time lag necessary for the initiation of free radical production were measured. All compounds were used at the concentrations of 10, 25, 50, 75, 100 micrograms ml-1. None of the antiarrhythmics stimulated by itself the free radical generation. Bisaramil exerted concentration dependent inhibitory effect on PMA-stimulated free radical generation and prolonged the time lag concentration dependently. At the investigated concentration range of antiarrhythmics only propafenon, mexiletine and diltiazem showed similar activity to bisaramil, but clear concentration dependency could not be seen in any of the cases. According to the results of this study inhibition of the stimulated free radical production of isolated PMNs cannot be closely connected merely to either membrane stabilizing or Ca-antagonistic activity of drugs. In vitro and earlier measured in vivo inhibitory action of bisaramil on free radical generation indicate a possible cardioprotective effect existing independently from its antiarrhythmic one. This observation may be important in outlining of the clinical indication field of bisaramil, and may be useful in the treatment of reperfusional damage.

The effects of bisaramil and antiarrhythmics on free radical generation of isolated neutrophil granulocytes.

The aim of this study was to investigate the effect of bisaramil--an antiarrhythmic drug under clinical trials--on free radical generation of isolated polymorph neutrophil granulocytes (PMN) and to compare its activity with well-known antiarrhythmics. PMNs were isolated from healthy beagle dogs, and superoxide radical generation was induced by phorbol-myristate-acetate. Free radical generation capacity of stimulated PMNs were measured. Bisaramil exerted a concentration dependent inhibitory effect on stimulated free radical generation. At the investigated concentration range of the antiarrhythmics only propafenon, mexiletine and diltiazem showed similar activity as bisaramil, but clear concentration dependency could not be seen in any of the cases. According to the results of this study inhibition of stimulated free radical production by isolated PMNs can not be closely related merely to either membrane stabilizing or Ca-antagonistic activity of drugs. In vitro inhibitory action of bisaramil on free radical generation indicates a possible cardioprotective effect existing independently of its antiarrhythmic one. This observation may be important in outlining the range of clinical indications of bisaramil as it may also be useful in the treatment of reperfusion injury.

Cardioprotection during heart ischemia-reperfusion.

Oxygen reactive species play a significant role in reperfusion tissue damages. In this study we aimed to investigate the mechanisms of injury regarding changes of neutrophil function. In our experiments the left descending coronary artery (LAD) was ligated in Beagle dogs for 1 hour followed by one hour reperfusion. Animals were divided into two groups: Group I. dogs (n = 10) served as control: Group II. the animals (n = 10) were treated by cardioprotective drug Bisaramil. Peripheral blood samples were taken for neutrophil isolation before operation and subsequent reperfusion (5 min, 1 hour). The stimulated superoxide radical generating capacity of polymorphonuclear leukocytes (PMN) was measured. The lipid peroxidation (MDA), amount of reduced glutathione (GSH) and activity of superoxide dismutase (SOD) were measured in non-ischemic and ischemic parts of left ventricle. There was no significant changes either in control or in treated animals in respect to changes of neutrophil radical production after one hour LAD ligature, however there was a significant discrepancy (p < 0.001) between control and treated animals following a 1 hour reperfusion. The values of MDA in the ischemic-area increased characteristically in the Group I. parallel with decrease of scavenger GSH and SOD. In contrast in Group II., where depleted PMN radical production was observed endogenous scavengers were preserved on a higher level. In summary we can conclude that diminished superoxide radical production of circulating neutrophils during reperfusion has beneficial effects on tissue injury caused especially by free radicals.

[Mechanism of action of vinpocetine]. / Vinpocetin hatásai, hatásmechanizmusa.

Cavinton was introduced into the clinical practice some twenty years ago in Hungary for the treatment of cerebrovascular disorders and related symptoms. Since then, its active ingredient, vinpocetine, beside its therapeutical utilization, has become a reference compound in the pharmacological research of cognitive deficits caused by hypoxia and ischaemia as well as in the cellular and biochemical investigations related to cyclic nucleotides. In this review a survey is given on the experimental data obtained with vinpocetine and an attempt is made to outline the drug's mechanism of action. Early experiments with vinpocetine indicated five main pharmacological and biochemical actions: (1) selective enhancement of the brain circulation and oxygen utilization without significant alteration in parameters of systemic circulation, (2) increased tolerance of the brain toward hypoxia and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase (PDE) enzyme and (5) improvement of rheological properties of the blood and inhibition of aggregation of thrombocytes. Later studies in various laboratories confirmed the above effects and clearly demonstrated that vinpocetine offers significant and direct neuroprotection both under in vitro and in vivo conditions. Evidence has been obtained that neuroprotective action vinpocetine is related to the inhibition of operation of voltage dependent neuronal Na(+)-channels, indirect inhibition of some molecular cascades initiated by the rise of intracellular Ca(2+)-levels and, to a lesser extent, inhibition of adenosine reuptake. Vinpocetine has been shown to be selective inhibitor of Ca(2+)-calmodulin dependent cGMP-PDE. It is assumed that this inhibition enhances intracellular a GMP levels in the vascular smooth muscle leading to reduced resistance of cerebral vessels and increase of cerebral flow. This effect might also beneficially contribute to the neuroprotective action.

Effects of bisaramil on coronary-occlusion-reperfusion injury and free-radical-induced reactions.

The aim of this study was to determine whether bisaramil-an antiarrhythmic compound under clinical investigation-influences the reperfusion-induced arrhythmias and biochemical parameters characterizing occlusion-reperfusion-induced free-radical reactions. The left descending coronary artery (LAD) was occluded for 60 min in anaesthetized dogs followed by one hour of reperfusion. Blood samples were taken at different times of the occlusion and reperfusion for the determination of plasma concentration of malondialdehyde (MDA), reduced (GSH) and oxidized glutathione (GSSG); furthermore of the activity of catalase and superoxide dismutase (SOD). Free-radical generating capacity of polymorph neutrophil granulocytes (PMN) was also measured. At the end of the experiments heart tissue samples were excised from the injured areas and from the intact part of the left ventricular muscle. In tissues samples the concentrations of MDA and GSH and the activity of SOD were determined. Bisaramil was given as an i.v. bolus injection at a dose of 2 mg kg-1 several minutes prior to the end of LAD-occlusion; then the administration was repeated in the 30th minute of reperfusion. In the control group (10 dogs) ventricular fibrillation (VF) occurred in seven cases which resulted in death in three. In the bisaramil-treated group, however. VF was seen in three cases and no death was recorded. Bisaramil inhibited the elevation of the plasma concentration of MDA and GSSG during the reperfusion and abolished the decrease in the plasma concentration of GSH during the occlusion and reperfusion. The activity of SOD and catalase in plasma was much better preserved in the bisaramil-treated group then in the controls. Bisaramil significantly inhibited the increase of the superoxide-radical generating capacity of PMNs during the reperfusion. The data obtained from myocardial tissue samples supported the cardioprotective effect of bisaramil. The biochemical investigation of ischemic-reperfused myocardium showed that bisaramil promoted preservation of SOD-activity and of tissue glutathione. Results of this study clearly showed that bisaramil has a significant effect on ischemiareperfusion injury. Besides its inhibitory effects on ischaemia-reperfusion induced arrhythmias it has a special benefit in influencing free-radical mediated damage leading to better preservation of membranes and to limitations of irreversible cell injuries.

Inhibitors of lipid peroxidation among new pyrimido[1',6':1,2]pyrido[3,4-b]indoles.

A series of potent inhibitors of NADPH- and Fe(2+)-dependent lipid peroxidation has been found among new pyrimido[1'6':1,2]pyrido[3,4-b]indole derivatives. According to preliminary structure-activity relationship analysis the saturated pyrimidine moiety was responsible for this effect. Some members of this family were effective in a bilateral carotid occlusion model in mice, and some derivatives showed protective effect in a mouse head injury model.

Blood coagulation is inhibited by sulphated copolymers of vinyl alcohol and acrylic acid under in vitro as well as in vivo conditions.

Biological effects of the modification of the sulphate ester and carboxyl group content of poly(vinyl alcohol-acrylic acid) copolymers (PAVAS) and sulphated polyvinyl alcohol copolymers (PVAS) with mol. weight of 5,000 to 20,000 D were studied. The in vitro anticoagulant potency of PAVAS assessed by activated partial thromboplastin time (APTT) increased with increasing the overall anionic charge, while differences in mol. weight yielded few obvious effect. The degree of sulphation played an essential part, but the carboxyl group content also contributed to the in vitro anticoagulant activity of PAVAS. On i.v. administration to rats (40 mg/kg), the anticoagulant potency of PAVAS was found to be comparable to that observed in vitro. The ability of PAVAS to induce a state of leukocytosis and decrease serum triglyceride level in rats was also dependent on charge density, and both these effects were increased with elevation of charged groups content irrespectively of mol. weight. Sulphated polyvinyl alcohol copolymers (PVAS) showed similarity to PAVAS charge-dependent biological activities.

Effect of vintoperol on platelet aggregation and experimental thrombosis.

The platelet aggregation inhibitory and antithrombotic effect of the new peripheral circulation enhancing compound vintoperol (RGH-2981, CAS 106498-99-1) was studied. In vitro, vintoperol inhibited the aggregation response to collagen in platelet-rich plasma from mice, rats, rabbits and dogs. It was found to be highly effective in preventing mice from acute pulmonary thromboembolic death induced by adenosine diphosphate (ADP) or collagen. After the oral dose of 10 mg/kg the percentage of survivors increased from 9 to 60% and from 13 to 73%, respectively. In the "mouse antithrombotic assay" it was protective only at the 3 mg/kg dose. Sudden death of mice evoked by hardened red blood cell suspension was not protected by vintoperol. In mice receiving 30 mg/kg vintoperol orally, the inhibition of aggregation response to collagen, ADP and ADP/epinephrine by 15, 33 and 37%, respectively, was associated with a substantial increase in bleeding time. In a rat multifactorial thrombosis model the 10 mg/kg p.o. dose was also sufficient to obtain significant antithrombotic effect (p < 0.01). Results of these experiments indicate that vintoperol interferes with platelet aggregation both in vitro and in vivo and possesses potent antithrombotic effects in thrombosis models in which platelet activation is mainly involved.

[Relation of angiographic changes to clinical data and risk factors in patients with arteriosclerosis obliterans]. / Arteriosclerosis obliteransos betegek angiográfiás eltéréseinek összefüggése klinikai adatokkal és kockázati tényezökkel.

The arteriographical changes of 66 patients with peripheral arterial obliterative disease and the relationship between the observed alterations and certain clinical and laboratory data as well as some risk factors were analysed. A score system was used to quantify the arteriosclerotic lesions. The arterial alterations of the examined 90 extremities were studied in the pelvic (common and external iliac arteries), femoral (common, superficial, deep femoral and popliteal arteries) and crural (anterior and posterior tibial arteries) regions. Pathomorphological changes in 433 of the investigated 720 arteries were shown, from among them plaque in 11.8%, stenosis in 22.3%, total occlusion in 26% were proved. Most frequently (89%) the superficial femoral artery was affected. As to the single vessels, the superficial femoral and posterior tibial arteries, while among the zones the femoral region proved to be most serious radiologically. The degree and extent of vessel lesions were related to age. The morphological severity was basically concordant with the results of clinical investigations (walking distance, ergometry, Doppler index). The separately examined risk factors (smoking, hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia) were not related consequently to the radiological changes, but in certain combinations, as heavy smoking with hypertension and heavy smoking with diabetes, the relationship proved to be statistically significant.

[Pharmacologic effects of pipecuronium bromide (Arduan)]. / A pipecuronium bromid (Arduan) farmakológiai hatásai.

The experimental results in animals suggest that pipecuronium bromide offers the possibility of a neuromuscular blocking agent without side effects for surgical procedures of long duration. Its mechanism of action is twofold: 1. antagonism of acetylcholine effect at neuromuscular junction (postsynaptic nicotine receptors), 2. inhibition of acetylcholine release (presynaptic nicotine receptors). Its neuromuscular blocking potency is somewhat greater (2.0-3.0) than that of pancuronium in all species studied, and the duration of action is twice of that. It has no remarkable cumulative effect. Neostigmine rapidly and completely antagonises the neuromuscular blockade caused by pipecuronium. Certain structural properties (e.g. pipecuronium has no acetylcholine-like fragments in contrast with pancuronium and the interonium distance is also considerably larger than in pancuronium) may predict advantages. This has been proved by low vagal blocking--and ganglion--blocking potencies. On the basis of these a wide margin of safety can be expected in humans as well in preventing cardiovascular side effects. Pipecuronium is also characterized by interactions--only slight interactions--with other drugs used mainly in perioperative period.

Electrophysiological actions of a new antiarrhythmic drug, bisaramil, on isolated heart preparations.

Electrophysiological effects of bisaramil--a new antiarrhythmic drug under clinical trial--were investigated on isolated heart preparations, at a concentration range of 2.3-23 x 10(-6) M. Bisaramil dose dependently decreased the maximum rate of depolarization (Vmax), action potential amplitude (APA) and overshoot (OS) both in auricle and in papillary muscle of guinea-pig heart. There was no significant and obvious effect on the duration of the action potential and the resting membrane potential was also unchanged. Bisaramil slowed the spontaneous frequency of pacemaker cells in rabbit sinus node preparation due to its inhibitory effect on slow diastolic depolarization (SDD). Bisaramil was able to inhibit slow Ca(2+)-action potentials induced by isoprenaline on K(+)-depolarized papillary muscle. Results obtained with transmembrane current measurements revealed that bisaramil inhibited both fast Na(+)-current and slow Ca(2+)-current in frog sinoauricular fibres at the same concentration. Bisaramil with a mixed mode of the action seems to be a very promising drug.

Investigations to characterize a new antiarrhythmic drug bisaramil.

Bisaramil is a new, orally active antiarrhythmic agent. We investigated and classified its mechanism of action according to Vaughan Williams [1]. We have found that bisaramil at the concentration range of 2-20 microM decreased the frequency and the force of the contraction in spontaneously beating guinea-pig's right auricle in a dose-dependent manner. Furthermore, bisaramil significantly prolonged the conduction time and effective refractory period both in the auricle and in the ventricle which were driven electrically. The atrioventricular conduction time, as measured on isolated rabbit heart preparation containing both auricles and the left ventricule, was also lengthened in the presence of bisaramil in a concentration-dependent manner. Bisaramil did not inhibit isoprenaline-induced tachycardia in anaesthetized cats, indicating that it has no beta-blocking activity. When tested on frog sciatic nerve, bisaramil showed a significant local-anaesthetic property well comparable to lignocaine (lidocaine). The drug caused a parallel shift of the dose-response curve to CaCl2 similar to that of the verapamil on isolated guinea-pig left auricle, indicating a possible Ca-antagonistic activity. The prolongation of the atrial, ventricular and atrioventricular conduction time as well as the lengthening of the effective refractory periods were also observed in anaesthetized dogs after an i.v. dose of 0.5 mg/kg bisaramil. On the other hand, this dose of bisaramil did not exert significant negative inotropic and unfavourable haemodynamic effect on anaesthetized dogs. In conclusion, bisaramil seems to be an effective antiarrhythmic drug having both class I (membrane stabilizer) and class IV (inhibitor of calcium transport) type activity.

Vasodilator and angioprotective activity of 1-ethyl-1-hydroxyalkyl-octahydroindolo[2,3a]quinolizine derivates.

The blood flow enhancing activity of the homologue series of "trans" racemic 1-ethyl-1-hydroxyalkyl-1,2,3,4,6,7,12,12b-octahydroindolo[2, 3a]quinolizine (1) was studied in anesthetized dogs. It was found that the femoral vasodilator activity is the strongest for 1b, and decreases if the carbon chain is shortened (1a) or lengthened (1c). Also, a breakdown of vasodilation was observed with the racemic "cis" derivative (2). After resolution of 1b the optically active compound 3 retained the dilator capacity while 4 isomer lost it. Hence 3 (RHG-2981, vintoperol, CAS 106498-99-1) was selected for detailed pharmacological study. Dose-response studies performed in anesthetized dogs showed that vintoperol 0.03 mg/kg (i.v.) was more potent as peripheral vasodilator than buflomedil or pentoxifylline at doses ranging from 1 to 15 mg/kg. Similar results were observed during a 4-week cross-over test of maximal running distance of femoral ligated mice. The running performance, as measured by the rotating drum, showed a linear increase in the untreated control group (UCG) as a consequence of every day testing (= intensive endurance training). After bilateral femoral occlusion the maximal running distance of the mice fell off, and despite daily training it stagnated. If 0.3 or 1 mg/kg/d vintoperol or 10 mg/kg/d pentoxifylline was administered orally 4 days after the bilateral femoral occlusion, the maximal running distance increased. In the case of 1.0 mg/kg of vintoperol applied daily, the rate of enhancement approached, or even overtook, that of the UCG. 0.3 mg/kg/d of vintoperol showed less activity, however, this result is still about twice better than the effect of 10 mg/kg/d pentoxifylline.