Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group.

PURPOSE: The combination of interferon alfa-2a (IFN alpha) and high-dose interleukin-2 (IL-2) is active in metastatic melanoma. The addition of cisplatin (CDDP) has resulted in response rates greater than 50%. This study was performed to determine whether the addition of CDDP to a cytokine treatment regimen with IFN alpha and high-dose IL-2 influences survival of patients with metastatic melanoma. PATIENTS AND METHODS: Patients with advanced metastatic melanoma were randomly assigned to receive treatment with IFN alpha 10 x 10(6) U/m2 subcutaneously on days 1 through 5 and a high-dose intravenous decrescendo regimen of IL-2 on days 3 through 8 (18 mIU/ m2/6 hours, 18 mIU/m2/12 hours, 18 mIU/m2/24 hours, and 4.5 mIU/m2/24 hours x 3) without (arm A) or with (arm B) CDDP 100 mg/m2 on day 1. Treatment cycles were repeated every 28 days to a maximum of four cycles. RESULTS: One hundred thirty-eight patients with advanced metastatic melanoma, of whom 87% had visceral metastases, were accrued for the trial. Both regimens were feasible in a multicenter setting. The objective response rate was 18% without and 33% with CDDP (P = .04). The progression-free survival was 53 days without and 92 days with CDDP (P = .02, Wilcoxon; P = .09, log-rank). There was no statistically significant difference in survival between treatment arms, with a median overall survival duration for all patients of 9 months. CONCLUSION: The addition of CDDP to cytokine treatment with IFN alpha and IL-2 does not influence survival of patients with advanced metastatic melanoma, despite a significant increase in response rate and progression-free survival.

Pharmacological actions of SDZ 218-135, a novel positive inotropic agent.

The effects of the new inotropic agent, SDZ 218-135 [(+)-(S)-4-[3-(4-diphenyl-methyl-1-piperazinyl)-2-hydroxy-propyl]- 6-(2-hydroxyethyl)-5-methyl-1,2,4-triazolo-[1,5-a]pyrimidin-7(4H)-one], were investigated using in vitro and in vivo techniques. In isolated rat atria, SDZ 218-135 elicited a dose-dependent increase in contractile force (+50% at 10 microM), which was paralleled by an increase in functional refractory period. In anesthetized rats SDZ 218-135 enhanced left ventricular (+)dP/dtmax by 100% at 10 mg/kg without influencing heart rate, arterial blood pressure, and cardiac output. In contrast to its predecessor, DPI 201-106, cardiac relaxation remained essentially unimpaired. The positive inotropic action was also maintained in a rabbit model of depressed heart function after myocardial infarction, where SDZ 218-135 increased peak acceleration of blood in the aorta. The prolongation of the effective refractory period in rat atria suggested possible antiarrhythmic effects. Indeed, SDZ 218-135 showed a dose-dependent marked reduction in reperfusion arrhythmias after coronary artery occlusion in rats. This effect was most likely due to a Class III action, since SDZ 218-135 significantly increased action potential duration (+10% at 10 microM/l) of the isolated guinea pig papillary muscle. In conclusion, SDZ 218-135 is a novel positive inotropic agent with an interesting profile of action. It does not impair cardiac relaxation and shows antiarrhythmic effects in a model of reperfusion-induced arrhythmias. The in vivo and in vitro data are consistent with a mechanism of action via sodium channel agonism.

[Cognitive and psychomotor performance following isoflurane, midazolam/alfentanil and propofol anesthesia. A comparative study]. / Kognitive und psychomotorische Leistungsfähigkeit nach Isofluran-, Midazolam/Alfentanil- und Propofol-Anästhesie. Eine vergleichende Untersuchung.

Mental and psychomotor abilities are impaired to varying degrees after general anaesthesia. This has important implications for the time over which patients are monitored in the recovery room and for the discharge of outpatients after day surgery. The present study was undertaken to compare recovery and mental and psychomotor skills in the first 60 min following general anaesthesia with isoflurane, midazolam/alfentanil and propofol. METHODS. A total of 45 patients undergoing microsurgical lumbar nucleotomy were randomized to three study groups. Group 1 (n = 15): anaesthesia was induced with thiopentone and maintained with isoflurane; group 2 (n = 15): anaesthesia was induced with midazolam and maintained with alfentanil; group 3 (n = 15): anaesthesia was induced and maintained with propofol. Vecuronium was used for muscle relaxation and the lungs were ventilated with a mixture of 66% nitrous oxide in oxygen. The following were checked 15, 30, 45, and 60 min after extubation: choice reaction times and critical flicker fusion for psychomotor testing; the maze test and a modification of the ball-bearing test for discrimination of motor and mental activities; and short- and long-term memory. RESULTS. Immediate recovery did not differ in the three different groups. In all patients psychomotor function was impaired compared with baseline for more than 60 min after general anaesthesia. However, impairment was significantly less pronounced after propofol, and recovery to preanaesthesia values was faster following propofol than after midazolam/alfentanil, and slowest after isoflurane-anaesthesia (Figs. 1, 2). The flicker fusion frequency, a very sensitive parameter for the persisting effects of anaesthetics, was significantly higher following propofol anaesthesia and remained so throughout the entire study period (Fig. 3). By 30 min after extubation, short-term memory was already normal in patients who had undergone propofol anaesthesia, and a statistically significant difference from the midazolam/alfentanil and isoflurane anaesthesia groups was obvious throughout the entire study period. However, no differences in long-term memory were found. At 30 min after propofol anaesthesia all patients were able to perform the ball-bearing test, as against 13 patients following midazolam/alfentanil and 10 patients following isoflurane (Table 3). The maze test was mostly impaired after midazolam/alfentanil anaesthesia. Patients who underwent isoflurane anaesthesia needed the same time for the maze test at 60 min afterwards propofol patients needed after 30 min (Table 2). Side effects, e.g., nausea, vomiting, and double vision, were observed significantly more often in groups 1 and 2 (Table 4). DISCUSSION AND CONCLUSION. The results indicate that in operations of approximately 90 min duration the return of motor and mental abilities is faster following propofol anaesthesia. At 30 min after extubation following propofol anaesthesia patients had test results that allow their transfer from the recovery room, while it took 60 min for patients in the two other groups to reach the same levels of motor and mental function. This is important for the duration of monitoring in the recovery room and, especially, for day case anaesthesia.

Interaction of DPI 201-106 with cardiac glycosides.

The interaction of the cardiotonic agent DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl(-2-hydroxypropoxy]-1H-indole -2- carbonitrile) with cardiac glycosides was investigated. In rabbit papillary muscles, all effects were normalized by using potentiating paired stimulation (PPS) as the 100% reference standard. Ouabain 1 microM alone increased the force of contraction (FC) by 66% +/- 6% (SEM) of PPS; 0.1 microM was ineffective. In the presence of 0.1 microM S-(-)-DPI 201-106, the active enantiomer of DPI 201-106, ouabain 0.1 and 1 microM increased FC by 41% +/- 11% and 119% +/- 19% of PPS, respectively. In anesthetized dogs, left ventricular dP/dtmax was increased by racemic DPI 201-106 0.2 mg/kg i.v. (+1987 +/- 660 mm Hg/s) and by ouabain 35 micrograms/kg i.v. (+560 +/- 40 mm Hg/s). The combined effect of DPI 201-106 and ouabain in similar doses was +2827 +/- 942 mm Hg/s. In digoxin-pretreated anesthetized cats, racemic DPI 201-106 was infused up to an accumulated dose of 12.22 mg/kg i.v. No signs of cardiotoxicity were observed in combination. In conclusion, the concomitant administration of DPI 201-106 and cardiac glycosides leads to enhanced positive inotropic effects in vitro and in vivo. The cardiotoxicity of glycosides was not increased by DPI 201-106.

Pharmacological actions of DPN 205-734, a novel cardiotonic agent.

DPN 205-734 [5-(4-cyanophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-3-carbo nitrile] was investigated in vitro in Langendorff rabbit hearts, guinea pig and rabbit papillary muscles, and rat myocardium and in vivo in anesthetized and unanesthetized dogs, pithed open-chest cats, anesthetized rats, and cardiomyopathic hamsters. In vitro, this substance caused a concentration-dependent positive inotropic effect. Left ventricular dP/dtmax was increased in anesthetized dogs after intravenous injection of 0.02 and 0.2 mg/kg (35 +/- 10 and 130 +/- 13%, respectively) and in unanesthetized dogs after oral doses of 0.05-0.5 mg/kg (15 +/- 2 to 71 +/- 14%). DPN 205-734 lowered blood pressure and total peripheral resistance in several experimental models, indicating an afterload-reducing effect. It induced moderate tachycardia. The positive inotropic effect is not explainable by beta-stimulation as shown in pithed open-chest cats pretreated with propranolol. A phosphodiesterase-inhibiting activity (IC50 = 35.5 microM), measured in rat myocardium, may be primarily responsible for the positive inotropic action. In guinea pig papillary muscles partially depolarized with 22 mM K+, DPN 205-734 in a concentration of 1 microM restored slow action potentials, which were then blocked by carbachol. These actions can be explained by the increase in cardiac cyclic AMP level due to a phosphodiesterase-inhibiting effect. In rabbit papillary muscles the positive inotropic effect of DPN 205-734 (100 microM) was only moderately inhibited by carbachol (3 microM), suggesting an additional mechanism.

Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533.

In the present paper, two experimental models of heart failure, namely hereditary cardiomyopathy in hamsters (BIO 14.6) and cardiac insufficiency due to mild (0.06 microM) isoprenaline overload of rabbit isolated perfused hearts, were compared in terms of resulting alterations at the level of the functionally isolated contractile system of detergent/glycerol treated skinned cardiac fibres. As the main features of Ca activation of tension in these models, the following were found: 1. Within the same species (RB hamsters, BIO 14.6 hamsters or rabbits), the Ca sensitivity, measured as pCa for half maximal Ca activation, was invariably higher in left than in right ventricular skinned fibres. 2. During the development of hereditary cardiomyopathy (BIO 14.6), maximum Ca-activated tension, measured per unit cross-sectional area, was reduced in an age-dependent manner, without any significant reduction in Ca sensitivity. This effect appeared to be more pronounced in left than in right ventricles. 3. In skinned fibres from right or left ventricular papillary muscles from in vitro isoprenaline pretreated rabbit hearts, no significant alteration in the maximum Ca-activated tension (per unit area) was observed in comparison to non-pretreated control hearts, whereas the Ca sensitivity was reduced. Treatment of control or failing heart skinned fibres with cAMP showed no additivity to the Ca desensitization induced by isoprenaline pretreatment. 4. Skinned fibres from isoprenaline pretreated left ventricular rabbit hearts showed a higher susceptibility to the Ca sensitizing effect of APP 201-533 than fibres from unpretreated control hearts. Mild isoprenaline overload and hereditary cardiomyopathy both are forms of heart failure which are presumably not associated with a lack of activator Ca. It is concluded that cardiotonic agents increasing the cardiac myofibrillar sensitivity to Ca ions would be beneficial in both cases, representing a phenomenologically causative treatment in hearts failing due to isoprenaline pretreatment. A main advantage over "classical" cardiotonic agents like cardiac glycosides, beta adrenergic stimulants or phosphodiesterase inhibitors would be the absence of the risk of drug-induced Ca overload.

Selective effects of PN 200-110 (isradipine) on the peripheral circulation and the heart.

PN 200-110 (isradipine) is a new dihydropyridine calcium antagonist with selective actions on the heart as well as the peripheral circulation. It selectively inhibits the sinus node but not atrioventricular conduction and its negative inotropic action is minimal, about 20 times weaker than its negative chronotropic effect. This in vitro pattern also expresses itself in vivo: partial suppression of the reflex tachycardia induced by its peripheral vasodilatation and no effect on the P-Q interval on the electrocardiogram even at large doses. The presence of first- or second-degree heart block should therefore not limit its use, whereas the sick sinus syndrome might. PN 200-110 does not decrease myocardial contractile force even in vagotomized animals with full beta blockade. PN 200-110 nevertheless lowers myocardial oxygen consumption mainly by its action on afterload. It should therefore be useful in angina pectoris. PN 200-110 is a powerful peripheral vasodilator. It preferentially dilates coronary, cerebral and skeletal muscle vasculature. Its long lasting (24 to 48 hours) antihypertensive action is not accompanied by tachycardia in spontaneously hypertensive rats and it enhances sodium and water excretion in normotensive rats. It should be useful in the treatment of hypertension, and, considering its pattern of cardiac actions, perhaps also as an after-load-reducing agent for the treatment of heart failure. Antiarteriosclerotic effects in conscious rabbits were found at reasonably small doses, suggesting that such effects might occur in man at therapeutic doses.

Cardiovascular actions of DPI 201-106, a novel cardiotonic agent.

DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole -2- carbonitrile) is characterized by a marked cardiotonic activity. The compound exerted positive inotropic effects in anesthetized and conscious dogs, pithed open-chest cats, and isolated hearts of cardiomyopathic hamsters and vanadate-treated guinea-pig atria. Left ventricular dP/dtmax was increased in anesthetized dogs after i.v. injection of 0.2 and 2 mg/kg DPI 201-106 (34 +/- 6 and 104 +/- 18%, respectively) and in unanesthetized dogs after oral doses of 2-8 mg/kg (22 +/- 3 to 50 +/- 5%, respectively). In most experiments, the compound lowered blood pressure and heart rate. Stroke work and left ventricular work were almost unaffected by DPI 201-106, and oxygen consumption and cardiac efficiency remained unchanged in open-chest dogs. Studies of the mechanism of action of DPI 201-106 lead to the conclusion that its positive inotropic effect is not explainable either by beta-stimulation or by liberation of catecholamines. This was shown in anesthetized dogs and pithed open-chest cats pretreated with propranolol and reserpine.

Sprouting and nerve retraction in frog neuromuscular junction during ontogenesis and environmental changes.

Based on recent evidence for a physiological remodeling of neuromuscular contacts (Wernig et al.), a morphometric study was performed on axon- and cholinesterase-stained cutaneous pectoris muscle of frog. The aim of this investigation was to separate changes due to aging, growth, and environmental conditions. Within a single muscle, fiber diameters, synaptic lengths, number of intraterminal branches, and lengths of abandoned gutters differ considerably (with coefficients of variation from 40 to 56%). On the other hand, these parameters are correlated and correlations hold when muscle fibers grow during ontogenesis: large muscle fibers bear larger and more complex junctions than small fibers. Obviously there exist growth regulating interactions between muscle fiber and the presynaptic nerve. To dissociate between age- and growth-related changes muscle fibers of equal diameters in frogs of different age are compared. With increase in age there is an additional increase in abandoned gutters, synaptic length, and complexity independent of muscle fiber growth. Possibly, abandoned gutters accumulate with time and synaptic length increases with age as the net outcome of continual synapse remodeling. When freshly caught frogs (October) were compared with frogs kept under laboratory conditions for a period of 16 weeks (which in addition included a change in season) the number of sprouts in a junction increased by about 2, the average length of presynaptic nerve terminals with small circumscribed contacts increased by 30-150 microns, and abandoned gutters tended to be shorter on fibers with large junctions. The hypothesis is discussed that remodeling is "inherent" to nerve terminals whereby sprouting is counterbalanced and reversed by nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological actions of APP 201-533, a novel cardiotonic agent.

APP 201-533 [3-amino-6-methyl-5-phenyl-2(1H)-pyridinone] was investigated in vivo in anesthetized and unanesthetized dogs and pithed open-chest cats and in vitro in guinea pig atria and papillary muscles, skinned muscle fibers from pig hearts, and rat myocardium. Left ventricular dP/dt was increased in anesthetized dogs after intravenous injection of 0.2 and 2 mg/kg APP 201-533 (34 +/- 3 and 132 +/- 28%, respectively) and in unanesthetized dogs after oral doses of 1.5-7.5 mg/kg (34 +/- 11-138 +/- 43%). The substance induced moderate tachycardia. Large intraduodenal doses of APP 201-533 reduced afterload in anesthetized dogs. The compound does not seem to act either by stimulation of alpha- or beta-adrenoceptors or histamine receptors or by liberation of catecholamines. APP 201-533 up to 10(-5) M had no electrophysiological effect on normal action potentials in guinea pig papillary muscles. A phosphodiesterase-inhibiting activity (IC50 = 1.6 X 10(-4) M) may be responsible for the positive inotropic action. Another key to the mechanism of action may be based on our observation of a shift of the relationship between cardiac force and intracellular Ca2+ concentration. In contrast to amrinone and ouabain, APP 201-533 increases Ca2+ sensitivity of the myocardial contractile structures.

DPI 201-106, a novel cardioactive agent. Combination of cAMP-independent positive inotropic, negative chronotropic, action potential prolonging and coronary dilatory properties.

The in vitro cardiac effects of DPI 201-106, a novel piperazinyl-indole, were investigated. DPI 201-106 produced concentration-dependent positive inotropic effects in guinea-pig and rat left atria, kitten, rabbit and guinea-pig papillary muscles and Langendorff perfused hearts of rabbits between 10(-7) and 3 X 10(-6) mol/l. During isometric twitches, contraction and relaxation phases were prolonged in guinea-pig left atria and right ventricular papillary muscles from kitten and guinea-pigs. Spontaneous sinus rate was decreased in right atria of guinea-pigs and rats. Coronary flow increased in rabbit isolated hearts. Functional refractory period was increased in left atria from guinea-pigs and rats with EC50 values of 1.7 and 0.24 mumol/l respectively. In electrophysiological measurements, DPI 201-106 prolonged the action potential duration (APD70) in guinea-pig papillary muscles up to 70% and in rabbit atria up to 120% at 3 mumol/l. Other action potential characteristics were not changed in guinea-pig papillary muscles but Vmax was decreased in rabbit left atria. The electrophysiological as well as the positive inotropic effects were stereoselective with the activity residing in the S-enantiomer. DPI 201-106 increased the Ca2+-sensitivity of skinned fibres from porcine trabecula septomarginalis with an EC50 of 0.2 nmol/l. DPI 201-106 dit not change cAMP levels in guinea-pig atria and rabbit papillary muscles. Slow action potentials were not induced by DPI 201-106 in partially depolarized guinea-pig papillary muscles. Phosphodiesterase activity of rat hearts was not inhibited by DPI 201-106 at pharmacologically relevant concentrations. The presence of propranolol did not influence the inotropic potency of DPI 201-106 in guinea-pig atria. In conclusion, DPI 201-106 represents a novel type of positive inotropic agents with a synergistic sarcolemmal and intracellular mechanism of action.

Digoxin-specific antibody fragments and a calcium antagonist for reversal of digoxin-induced mesenteric vasoconstriction.

The effect of digoxin-specific antibody fragments on glycoside-induced mesenteric vasoconstriction were investigated. Digoxin caused a sustained contraction of strips of isolated feline mesenteric artery lasting for several hours, while in anaesthetized cats it produced a significant decrease in blood flow and increase in resistance in the mesenteric artery. In-vitro, digoxin's contractile effect was inhibited by 'prophylactic' addition of antibody to the organ bath, but the clinical use for prophylaxis is not a practical proposition. When the antibodies were added with the contraction of the arterial strip in response to digoxin already established, the tone of the preparation decreased significantly over 3 h, but the effect of the glycoside was not fully reversible. In-vivo, control animals not treated with antibodies developed arrhythmias, mesenteric blood flow fell by more than 50% and resistance increased by more than 80% relative to the initial values. These animals died of ventricular fibrillation before the end of the experiment. Animals treated with digoxin-specific antibody fragments after receiving digoxin injections showed no further decrease in mesenteric blood flow and 90 min after the last dose of digoxin, the flow was recovering and mesenteric resistance decreasing. Furthermore, all the animals that had received antibodies remained in sinus rhythm to the end of the experiment. In view of the latent period to onset of action of the antibodies, valuable time may be lost in impaired mesenteric blood flow. To bridge the gap or, indeed, as primary treatment, calcium antagonists merit consideration; in our experiments mesenteric vasoconstriction was abolished within a few minutes by application of the dihydropyridine calcium antagonist 4-(2,1,3-benzo-oxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic aid, diethyl ester (PY 108-068).

Effects of the vasodilator endralazine given with the antihypertensive agent guanfacine on heart rate and blood pressure of spontaneously hypertensive rats and normotensive dogs.

Endralazine (BQ 22-708, Miretilan) and guanfacine (BS 100-141, Estulic) were tested alone and in combination for their effects on blood pressure and heart rate in conscious spontaneously hypertensive rats and conscious normotensive dogs. During combined administration of endralazine and guanfacine to spontaneously hypertensive rats, guanfacine 1 mg kg-1 i.v. blocked the tachycardia caused by endralazine, 1 mg kg-1 i.v. After oral administration, the tachycardia induced by 0.5 and 1 mg kg-1 of endralazine was inhibited dose-dependently by 0.05, 0.1 and 0.5 mg kg-1 of guanfacine. The antihypertensive efficacy of endralazine was either unchanged or increased by guanfacine at 0.05-1 mg kg-1. In normotensive conscious dogs, 0.2 mg kg-1 i.v. of guanfacine antagonised the tachycardia elicited by 0.3 mg kg-1 i.v. of endralazine. The elimination of the endralazine-induced reflex tachycardia by guanfacine suggests that the combination of both drugs could be useful in antihypertensive therapy.

Trapping and intramyocardial distribution of microspheres with different diameters in cat and rabbit hearts in vitro.

Microsphere trapping was determined in isolated perfused Langendorff hearts of cats and rabbits with 7.9-, 8.6-and 14.6-micrometers microspheres. Only the largest spheres were completely trapped whereas significant and relevant fractions of the smaller spheres were found in the perfusate leaving the heart. These fractions were 8.3 and 3.0% of the total activity for the cat and 6.7 and 2.1% for the rabbit hearts. The density of spheres trapped in the outer layer was similar with all three sizes of microspheres, whereas the density in the subendocardial layer increased with increasing microsphere size and paralleled overall trapping in both species. The complete trapping of 14.4-micrometer microspheres proves that there were no leaks and no arterio-venous shunts. The results obtained with the two smaller sphere sizes suggest regional differences in trapping and therefore regional differences in capillary size. Only selected batches of commercially available 7-10 micrometer spheres should be used. The mean diameter should be 10 micrometer with a standard deviation no larger than 1 micrometer. 15-micrometer spheres may not be ideal but, nevertheless, give reasonable values, for intramyocardial distribution of blood flow in cats and rabbits.

The effects of treatment and of withdrawal of treatment with guanfacine and clonidine on blood pressure and heart rate in normotensive and renal hypertensive rats.

Disagreement in the literature about the occurrence of rebound hypertension (hypertensive overshoot) in animal models initiated this investigation. Oral doses of clonidine (0.03 mg kg-1) or guanfacine (0.3 mg kg-1) were administered twice daily during three weeks to groups of normotensive and renal hypertensive rats. Blood pressure and heart rate were measured immediately before and 3 h after the first daily dose, and compared with values obtained from placebo-treated control rats. Treatment with either drug induced large daily fluctuations rather than sustained falls in blood pressure. In the normotensive, but not in the hypertensive groups, the morning blood pressures measured before the first daily dose were significantly elevated over those of the control groups after 9 and 5 days of treatment with clonidine or guanfacine. This elevation persisted for 3 days after drug withdrawal. It is concluded that in the rat the duration of action of both drugs was short, so that twice daily administration of both drugs similarly produced large daily fluctuations rather than sustained falls in blood pressure. Blood pressure rises developed during treatment rather than after withdrawal in normotensive rats only. Therefore, this type of study does not relate well to the human situation and different experimental approaches to this problem are needed.

[Bicyclic 3-hydrazinopyridazines with antihypertensive action (author's transl)]. / Antihypertensiv wirksame bizyklische 3-Hydrazinopyridazine.

The synthesis of a series of 3-hydrazinopyridazines is described. Several of these compounds exhibited high antihypertensive activity in the rat. The most potent member of the series is l-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido-[4,3-c]pyridazine, compound 28 [1], which is now under clinical trial [2] under the clinical code number BQ 22-708 (endrazaline, Miretilan). It was possible to discover certain structure-activity relationships.

The effects of the beta-adrenoceptor blocking agent LL 21-945 on renal hypertensive (Grollman) rats.

Prophylactic administration of LL 21-945 [4-(3-tert. butyl-amino-2-pivaloyloxypropoxy)-9-fluorenone] during 15 weeks to Grollman rats depressed the development of hypertension, tachycardia and myocardial pathogical changes. The tachycardia was eliminated and the degree of the myocardial pathological changes and coronary sclerosis was less severe than in the untreated Grollman rats. The survival rate was slightly improved with LL 21-945. With respect to the biochemical parameters studied, only a tendency of LL 21-945 to moderate the rises in blood cholesterol, total glycerides and urea was observed towards the end of the experiment.

Pharmacological actions of the antihypertensive agent N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride (BS 100-141).

Pharmacological properties characterizing N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride (BS 100-141) as a centrally acting antihypertensive agent are described. Its action resembles that of clonidine in many respects but with important differences which are discussed. In DOCA-NaCl--hypertensive conscious rats, BS 100-141 lowers systemic blood pressure with oral doses of 0.3-5 mg/kg. Evidence for a central site of action is provided by the following findings. Infusion of BS 100-141 into the vertebral artery of anaesthetized dogs reduces blood pressure, the same dose being ineffective by i.v. route. Injection into the lateral cerebral ventricle of anaesthetized cats causes a marked reduction in blood pressure and heart rate, the same dose being ineffective when given i.v. The effects of intraventricular injection are inhibited by phentolamine administered by the same route. Intravenous administration of BS 100-141 induces dose-dependent reductions in the splanchnic (sympathetic) nerve activity in the cat. BS 100-141 reduces noradrenaline turnover in the brain stem of the rat as a result of central alpha-adrenoceptor stimulation. Doses which are effective in the hypertensive rat do not reduce dopamine turnover in the corpus striatum. The peripheral, direct alpha-sympathomimetic action of BS 100-141 was demonstrated by the transient increases in blood pressure observed in rats. These increases were unaffected by pretreatment with reserpine, but were antagonized by phentolamine. BS 100-141 was shown to induce contractions of isolated veins and arteries which were competitively inhibited by phentolamine. It stimulates presynaptic cardiac sympathetic alpha-adrenoceptors, thus inhibiting transmitter release to the heart. The sedative effects of BS 100-141 observed in dogs were slight compared to those of clonidine.