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Twenty-three new phosphonic ester derivatives of stilbene exhibiting structural analogies with fostedil are described. Examination of calcium antagonism showed that this activity could not be increased by introducing electron-withdrawing, electron-releasing or lipophilic substituents. Only compounds containing fluorine at the 2 or 4 positions exhibited similar activity to the model.

Four aryl vinyl diethyl benzylphosphonates related to Fostedil were synthesized and evaluated for their in vitro calcium-inhibitory activity. None of these compounds exhibited any calcium antagonistic profile. Unlike a series of diethyl-styryl benzylphosphonates, previously described, the presence of two aromatic rings linked by a vinyl group did not improve the calcium antagonistic activity.

Several phosphonic diethyl esters were synthesized and their calcium antagonistic activity evaluated in vitro. The diethyl phosphonate group was condensed on substituted [diphenylmethyl], [(2-benzofuranyl)phenylmethyl], [(4-(diphenylmethyl-1-piperazinyl) methyl], [4 (4-diphenylmethyl-1-piperazinyl methyl) phenylmethyl], and [4-(3-phenyl-2-propenyl)-1-piperazinyl methyl] groups. Despite the presence of the diethyl phosphonate moiety and the benzhydrylpiperazinyl group, both present in potent calcium antagonist structures, only 1 of the 19 synthesized compounds exhibited a calcium antagonistic profile.

A series of 2,3-dihydro-4 H -1,3-benzoxazin-4-ones substituted at the 3-position with an arylalkyaminoalkyl group have been synthesized and their specific bradycardic and antiarrythmic activities evaluated. Bradycardia is optimal when the aromatic rings are substituted with methoxy groups and the side-chain amine is N -methylated. N -Demethylated and 2-alkylated derivatives show the highest antiarrhythmic activity but have little bradycardic action. Most of the compounds described are more potent than Falipamil. Compound 1m (F 3226) has been selected for further pharmacological tests and the bradycardic activity has been confirmed when administered orally to anesthetized rats without notable side effects.

In this work we present about 15 original heterocyclic diethyl benzylphosphonate analogues of fostedil, in which we have varied the nature of the heterocycle, the substituents or the phosphonic group, or even the position of this latter. Three diethyl 4-(2-benzofuryl) benzyl phosphonates exhibited slightly higher calcium antagonism than the control. Solely substitution with a fluorine atom was able to maintain activity, whereas the other modifications always decreased it.

A series of 2,3-dihydro-4 H -1,3-benzoxazin-4-ones substituted at the 3-position with an arylalkyaminoalkyl group have been synthesized and their specific bradycardic and antiarrythmic activities evaluated. Bradycardia is optimal when the aromatic rings are substituted with methoxy groups and the side-chain amine is N -methylated. N -Demethylated and 2-alkylated derivatives show the highest antiarrhythmic activity but have little bradycardic action. Most of the compounds described are more potent than Falipamil. Compound 1m (F 3226) has been selected for further pharmacological tests and the bradycardic activity has been confirmed when administered orally to anesthetized rats without notable side effects.

Resume Les proprietes inhibitrices calciques d'une serie de 39 benzylphosphonates de diethyle diversement substitues, analogues du Fostedil, ont eteevaluees. Seuls 6 composes presentent une certaine activite, celle-ci reste cependant beaucoup plus faible que celle du temoin. Le criblage sur l'aorte de lapin s'avere plus selectif que celui pratique sur le muscle atrial gauche de cobaye. Une approche de relations structure-activite met en evidence une certaine influence de la lipophilie et de la presence de deux cycles aromatiques conjugues et separes par une distance optimale. Aucun effet electronique du aux substituants n'a pu etre demontre.

Tioxamast (F 1865) is an antiallergic drug that, administered systemically, reduces anaphylaxis in various models in rats. This action is due mainly to the inhibition ofthe synthesis and release of certain mediators. Orally or intraduodenally administered tioxamast inhibits IgE-dependent passive cutaneous anaphylaxis (ED50 = 0.8 mg/kg), IgE-dependent passive pulmonary anaphylaxis (ED50 = 0.5 mg/kg), and IgG-dependent passive cutaneous anaphylaxis (ED50 = 0.6 mg/kg). It has little or no effect on the increase of cutaneous capillary permeability induced by various mediators. In IgE-dependent passive peritoneal anaphylaxis in rats, tioxamast reduces the release of histamine (IC50 = 0.024 µg/ml) and of β-glucuronidase (IC50 = 0.102 µg/ml). Also, histamine release is inhibited in IgG-dependent peritoneal anaphylaxis (IC50 = 0.103 µg/ml). The antiallergic compound has less effect on the release of histamine induced by the compound 48/80 in the peritoneal cavity of rats (IC50 = 1.67 µg/ml). Tioxamast inhibits the synthesis in vitro of leukotriene B4 (LTB4) by peritoneal neutrophils from rats stimulated by A23187 (IC50 = 8.88 µg/ml). At higher tioxamast concentrations, metabolites ofthe cyclo-oxygenase pathway are inhibited at concentrations ofthe same order of magnitude as those that inhibit Naja naja phospholipase A2 (IC50 = 144 µg/ml). Tioxamast also reduces the production of free radicals by leukocytes from the pleural cavity of rats which had phagocytosed opsonized zymosan (IC50 = 5.21 µg/ml).

Background: Retinaldehyde is a key molecule in the metabolism of vitamin A by keratinocytes. In order to evaluate its range of topical activity in acne, its comedolytic effect was compared to that of retinoic acid in the same vehicle, in the rhino mouse model. Methods: The animals were treated on the back daily for 5 consecutive days per week for 3 weeks. At the end of this period, histological slides were analyzed in order to quantify the features of comedones and epidermal thickness. Results: Topical treatment with a retinaldehyde (0.05% w/w) and a retinoic acid formulation (0.025% w/w) induced comedolysis and increased the epidermal thickness with the same intensity. Conclusion: These data indicate that retinaldehyde exerts a significant comedolytic activity.

Two sets of phosphonic diethylester including a substituted benzylpiperazine moiety are synthesized. In spite of the spasmolytic or the calcium antagonistic potentialities of benzylpiperazine and phosphonic moieties, none of the six compounds, tested in vitro, exhibit any calcium antagonistic profile.

A series of arylmethyloxypropanolamines structurally related to Dioxadilol has been synthesized and tested for their beta adrenolytic activity. Only one compound, the benzofuranic derivative 3c, exhibited a similar activity as Dioxadilol but was less potent than propranolol.

The action of theophylline was studied on the inflammatory reaction obtained in bronchoalveolar lavage fluid 24 h after an active anaphylactic shock had been induced by ovalbumin inhalation in conscious sensitized guinea-pigs. The compound was administered twice by intraperitoneal administration after the anaphylactic reaction at a dose of 50 mg kg−1. When the guinea-pigs were sensitized by intramuscular injection of 30 mg kg−1 ovalbumin or by ovalbumin aerosol, theophylline reduced the number of eosinophils and mononuclear cells in the fluid. When animals were sensitized by intramuscular injection of 30 mg kg−1 ovalbumin mixed with Freund's complete adjuvant, treatment with the xanthine derivative decreased only the number of eosinophils. In the three models theophylline did not modify significantly the number of neutrophils. Thus theophylline always reduced pulmonary eosinophilia irrespective of the mode of sensitization used to induce anaphylactic shock.

Twenty-four hours after an active anaphylactic shock induced by inhalation of antigen in conscious guinea pigs sensitized by a large dose of ovalbumin in complete Freund's adjuvant, a noteworthy bronchial inflammation, characterized by increased numbers of neutrophils, mononuclear cells and eosinophils in the bronchoalveolar lavage fluid, was observed. Some drugs administered after the anaphylactic shock were investigated using this model. Disodium cromoglycate primarily reduced the number of mononuclear cells and eosinophils. Dexamethasone and theophylline decreased the number of eosinophils. Salbutamol and mepyramine increased neutrophils. Indomethacin did not give rise to any significant effect. This test appears to be of use for the investigation of anti-inflammatory compounds in the prophylactic treatment of asthma.

Various models of delayed hypersensitivity (DH) were used in mice: contact hypersensitivity reactions to picryl chloride and oxazolone and reactions to methylated bovine serum albumin (MBSA) and sheep red blood cells (SRBC). Drugs of different classes were tested in these models by systemic treatment around the challenge period: non-steroidal anti-inflammatory drugs (cyclooxygenase inhibitors, and inhibitors of both cyclooxygenase and lipoxygenase); glucocorticoids and immunosuppressants (cyclosporin A. CsA; cyclophosphamide, Cy; methotrexate, Mtx; azathioprine, Aza). These compounds were also studied and compared for their effects on the 3-h and 24-h phase of the carrageenin mouse-paw edema (in which inflammation is maximal after 24 h). Non-steroidal anti-inflammatory drugs (including double inhibitors of cyclooxygenase and lipoxygenase) had little or no effect on DH models, except indometacin. Glucocorticoids inhibited all immune reactions except that to MBSA. Of the immunosuppressants, CsA reduced all the DH reactions while Aza mainly reduced the reaction to SRBC; Cy and Mtx were mainly active on SBRC and MBSA inflammations. On another hand CsA, Cy and Mtx were inactive on the 3-h phase but decreased the 24-h phase of carrageenin edema. At doses active on the DH models and on carrageenin inflammation, Cy induced a lasting blood leukopenia, but CsA and Mtx did not. This combination of tests in the mouse seems to be of interest to demonstrate any action on DH and any anti-inflammatory effect and to suggest whether these activities are related to a possible leukopenic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Eighteen substituted 2-phenyl benzothiazoles, nine of which are new, are described. Pharmacological investigation of these Fostedil analogues did not demonstrate the same calcium inhibitory properties shown by Fostedil. The enhancement induced by the diethyl phosphonate group is confirmed.

The reaction of various 2-cyano chromones with diazomethane generated a series of 21 N-methyl triazoles, with a benzopyrone moiety and divided into three isomeric groups. The anti-inflammatory, psychotropic and anti-allergic effects of these new compounds were evaluated. The results obtained did not confirm their expected potentialities.

A model of bronchial hyperreactivity at various times after an active anaphylactic shock in conscious guinea pigs is described. The bronchial inflammation was quantified in parallel by determination of the number of mononuclear cells, neutrophils, and eosinophils in bronchoalveolar lavage (BAL) fluids. The guinea pigs were sensitized by an intramuscular (i.m.) injection of a large dose of ovalbumin in Freund's complete adjuvant. The administration of ovalbumin (to induce anaphylactic shock) and of histamine to investigate bronchial hyperreactivity was by aerosol. The bronchial hyperreactivity to histamine was observed 3-6 hr after the anaphylactic shock. In the BAL fluid a decrease (1-3 hr) and then an increase (24-48 hr) in the number of mononuclear cells was found as well as an increase in neutrophils (3-48 hr) and in eosinophils (6-48 hr). The hyperreactivity was not correlated with changes in one category of cell in the BAL fluid. This model constitutes one simple test for investigating bronchial hyperreactivity in conscious guinea pigs. Further work is needed to try to determine the possible inflammatory parameters responsible for the hyperreactivity.

Injection of zymosan in rat pleural cavity provokes an exudate which is already detectable at 15 min and which is maximum at 24 h. The leucocyte count (mostly neutrophils) increases at 2-4 h and is maximum at 48 h. In this paper the reaction has been studied up to 6 h. Evidence of histamine release, of mast cell degranulation and of reduction of the exudate by anti-H1 compounds, as well as by sodium cromoglycate, proves the active role played by histamine in the early stage of pleurisy. Serotonin (whose role was studied exclusively using antagonists) seems to have only a minor part in the early phase of the reaction. Some metabolites of arachidonic acid were determined in the pleural exudate at 1 h and 6 h. The concentration of leukotriene B4 was high at 1 h and decreased at 6 h. The thromboxane B2 level was already high at 1 h and was neatly augmented at 6 h while the amount of prostaglandin F1 alpha was high at both times. The non-steroidal anti-inflammatory substances studied all reduced the pleural exudate at 1 h but their activity then varied from each other at 6 h. Cyclooxygenase and lipoxygenase inhibitors (phenidone, BW755C) induced a reduction of the exudate at both times. Zymosan-induced pleurisy seemed thus to be an excellent model for the investigation of antiallergic and anti-inflammatory compounds active on histamine and cyclooxygenase and lipoxygenase pathways.

Injections of zymosan in mouse and rat paws provoke inflammatory reactions, the kinetics of which are different. In both models, inflammation occurs at an early stage but oedema is maximal at 30 min in rat paw and 6 h in mouse paw. In this study the two reactions have been studied up to 6 h. The reduction of oedema by anti-H 1 compounds, as well as by disodium cromoglycate, proves the active role played by histamine in rat paw oedema. In mouse its role appears to be minor or non-existent. Serotonin seems to be clearly implicated in the early stages of the oedema in mouse, somewhat less in rat. In the two species, non-steroidal anti-inflammatory compounds only reduce the 4–6 h phase. BW755C and phenidone reduce the early and late phase of paw oedema in both species, with the exception of phenidone which is inactive on the 4–6 h phase in the mouse. We can hypothesize that in the two species some leukotrienes seem to be implicated principally in the early phases, while derivatives of cyclooxygenase play a more important role in the late phases. Theophylline reduces inflammation in the two models, hydrocortisone acetate, however, is only active on the late phases. These results indicate that there are important differences in the participation of the various mediators studied in the two models.

Injection of platelet-activating factor (PAF-acether) into the pleural cavity of rats induced the accumulation of a moderately intense exudate within 30 to 60 minutes. By comparison with animals given injections of the vehicle alone, the animals given this mediator had elevated levels of leukotriene C 4 -immunoreactive material (LTC 4 im) in the exudate and decreased quantities of thromboxane B 2 (TxB 2 ) and of 6-KetoF 1α -prostaglandin (6-Keto PGF 1α ). Nifedipine, verapamil, and diltiazem reduced the pleural exudate with no major effect on the mediators. Both salbutamol and theophylline reduced the exudate and the levels of LTC 4 im. Acetylsalicylic acid, phenylbutazone and indomethacin significantly inhibited the exudate, greatly lowered the quantities of cyclooxygenase derivatives and tended to increase LTC 4 im. Phenidone, which inhibits the cyclooxygenase and lipoxygenase pathways, decreased the exudate and the three mediators. The phospholipase A 2 inhibitor, chloroquine, decreased both the amount of exudate and moderately the concentration of LTC 4 im. The glucocorticoids studied had no effect on the exudate or on the mediators. These results suggest that the role of the increased LTC 4 im in the induction of the pleurisy is not clear

Reaction of various amines on 6-(2-bromoethyl)benzoxazolinone or its N-methylated derivative provided eleven new 6-substituted aminoalkyl analogues. In a pharmacological evaluation, several compounds bearing an arylpiperazinic moiety were found to possess significant effects on arterial blood pressure and on the central nervous system; two of them showed interesting analgesic activity.

Summary— Midalcipran is a new antidepressant drug inhibiting both noradrenaline and serotonin uptake without any postsynaptic and anticholinergic activities. Its cardiac effects were compared with those of imipramine, a tricyclic antidepressant drug. In anaesthetised guinea-pigs intravenous perfusion of imipramine and midalcipran (1 ml/min from a solution at 0.66 mg/ml) brought about ventricular arrhythmias, respectively at 16.5 and 26.4 mg/kg and cardiac arrest at 58 and 97 mg/kg. The safety index (ratio of i.v. lethal dose and ED50 evaluated by the yohimbine test) is 22 times wider for midalcipran than imipramine. In in vitro studies on guinea-pig ventricular myocardium, imipramine exerted a greater class 1 antiarrhythmic effect than midalcipran. The reduction of Vmax was significant at 3times10−6 M for imipramine and 1times10−5 M for midalcipran in normal (4 mM K+) and hyperpolarizing (2.7 mM K+) conditions. At the concentration of 1times10−5 M midalcipran significantly lengthened, whereas imipramine non significantly shortened the action potential durations (APD50, APD90). The results provide confirmation of a lesser depression in sodium conductance with midalcipran as compared to imipramine. Therefore it is proposed that less adverse cardiac effects may be observed at therapeutic doses.

Subtotal reduction (60%-70%) of blood flow in the circumflex artery in anaesthetized open-chest dogs caused a long-lasting increase (222%) in coronary vascular resistance and stable changes in myocardial segmental contractility (% delta L), as measured by the method of piezoelectric crystals. % delta L increased by 31.2% in the healthy zone while hypokinesia occurred in the moderately ischaemic zone (-50.8%). In the severely ischaemic zone there was a paradoxical lengthening (bulge or dyskinesia) of 7.3% during systole. Bepridil (2.5 mg.kg-1, IV) decreased heart rate (-15.6%) and systolic (-20.8%) and diastolic (-31.6%) blood pressure, and increased total coronary blood flow (+40.7%). % delta L was increased in the healthy zone (+20.4%) and in the moderately ischaemic zone (+48.2%). Bepridil completely inhibited the bulge in the severely ischaemic zone. Nifedipine (0.02 mg.kg-1, IV) greatly reduced systolic (-31.3%) and diastolic (-40.7%) blood pressure as well as coronary blood flow (-30.4%), without changing heart rate. A delayed increase in % delta L occurred in the healthy zone (+8.4%) and in the moderately ischaemic zone (+38.5%). In the severely ischaemic zone, there was no improvement of the bulge. The observed differences in contractility between the two calcium antagonists are discussed in terms of their haemodynamic differences. Improvement of myocardial segmental contractility, if it occurred, may have been due to bradycardia, slight decrease in contractility, as measured by LV dP/dt max/P, increased total coronary blood flow, decreased afterload, so long as it was not too great, and anti-ischaemic properties of the compound.

1. A comparative study between the effects of ischemia and reperfusion on the hypertrophied heart of spontaneously hypertensive rat (SHR) and on the heart of Wistar-Kyoto (WKY) was carried out in working heart conditions. 2. The decrease of coronary flow induced by a coronary occlusion had an equal magnitude in the two groups. In the SHR group, the aortic output became null in 40% of the cases, whereas this effect was never seen in WKY group. 3. In reperfusion conditions, the recovery of haemodynamic values was slower in SHR group. The release of LDH and the rhythmic disturbances were also increased. 4. The perfusion of SHR hearts by lidocaine (4.3 10(-5) M), propranolol (7.7 10(-6) M) and verapamil (1.1 10(-7) M) decreased significantly the heart rate and the aortic output. 5. When these substances were added to the perfusion medium, the deleterious effects of reperfusion were greatly reduced. Aortic output recovered more quickly than his basal values and the enzymatic leakage was decreased. None of the hearts fibrillated after lidocaine and propranolol. Ventricular fibrillation continued in 14% of cases after verapamil compared to 80% of cases in the control group.

The haemodynamic effects of 4 calcium antagonists, bepridil (1.25 to 5 mg/kg i.v.), diltiazem (0.1 to 0.3 mg/kg i.v.), nifedipine (0.01 to 0.03 mg/kg i.v.) and verapamil (0.1 to 0.3 mg/kg i.v.) were compared in anaesthetized open-chest dogs. The following parameters were measured: sinusal coronary blood flow (SCBF), total coronary vascular resistance (TCVR), aortic blood pressure, heart rate, left dP/dt max, amplitude of right ventricular contraction, double product, myocardial oxygen consumption (MVO2) and arterial and coronary venous blood gases (pO2 and pCO2) and pH. All 4 substances increased SCBF and decreased TCVR. The greatest effects, taking into account relative dose size, were obtained with nifedipine and verapamil. These 2 substances also had the greatest effect on systemic vasodilatation, as reflected by hypotension. The 4 substances had a direct negative chronotropic effect on the myocardium, an effect which was masked by reflex sympathetic stimulation and decreased vagal tone secondary to a drop in blood pressure. The most marked negative chronotropic effects were seen with diltiazem, verapamil and bepridil in that order. Nifedipine and verapamil produced the greatest negative inotropic effects, whereas diltiazem had very little effect on this parameter. The direct consequence of these haemodynamic effects of the 4 substances was to improve oxygenation of the myocardium. The most durable effect on PvO2 was seen with nifedipine and verapamil. The findings demonstrate not only the heterogeneous action of the 4 calcium antagonists, but also the influence of the experimental conditions on the effects obtained with these substances.

The synthesis of various 6-(4-arylpiperazino-butyryl)-3-methyl-benzoxazolinones and their reduction products, 6-(4-arylpiperazino-1-hydroxy-butyl)-3-methyl-benzoxazolinones and 6-(4-arylpiperazino-butyl)-3 methyl-benzoxzolinones, is described. These compounds were tested for psychotropic and analgesic activities.

The injection of PAF-acether into the pleural cavity of the rat induced a maximal exudate after 30-60 min which then decreased and disappeared after 24 hours. In addition, the mediator produced a decrease in the number of leukocytes in the pleural cavity 30 min after injection and an increase in the number of cells after 6 hours.