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Rationale: Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man)., Objectives: The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit., Materials and Methods: In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine. The clinical study examined the effect of DMAE p-Glu on cognitive deficits induced by an intravenous injection of scopolamine in healthy young male subjects., Results: In rat experiments, DMAE p-Glu increased the extracellular levels of choline and acetylcholine in the medial prefrontal cortex, as assessed by intracerebral microdialysis, improved performance in a test of spatial memory, and reduced scopolamine-induced memory deficit in passive avoidance behavior. Clinical study results show that scopolamine induced a memory deficit and that DMAE p-Glu produced a significant positive effect on scores in the Buschke test, as well as a slight but significant difference on choice reaction time., Conclusion: These results indicate that DMAE p-Glu reduces the deleterious effect of scopolamine on long-term memory in healthy volunteers and suggest that DMAE p-Glu might be effective in reducing memory deficits in patients with cognitive impairment.

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.

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.

Exposure of non-sensitized Brown Norway (BN) rats to a 10%-ovalbumin aerosol induced an increase in the number of neutrophils in the broncho-alveolar lavage (BAL) fluid 3 and 6 h later but with no change in number of cells at 24 h. When the BN rats were actively sensitized (i.m. injection of 10 mg/kg ovalbumin and i.p. injection of killed Bordetella pertussis) and exposed 12-14 days later to a 10%-ovalbumin aerosol there was an increase in the number of eosinophils in the BAL fluid, maximal 24-48 h after the anaphylactic reaction. The increase in the number of neutrophils in the bronchial lumen 3 and 6 h after the anaphylactic reaction was larger than that obtained in non-specific inflammation and in contrast to this was still present 24-48 h after ovalbumin exposure. In passively sensitized BN rats exposed to ovalbumin aerosol, no inflammation appeared in the BAL fluid 24 h after the anaphylactic reaction. Various drugs, administered twice, 5 min and 5 h after the anaphylactic reaction, have been evaluated for their effects on the 24-h inflammation obtained in actively sensitized rats. Dexamethasone acetate (0.08 mg/kg i.p.) and theophylline (50 mg/kg i.p.) decreased the number of eosinophils and neutrophils. Ketotifen fumarate (12.5 mg/kg), cetirizine dihydrochloride (12.5 mg/kg), salbutamol (2 mg/kg), disodium cromoglycate (50 mg/kg) all given intraperitoneally, reduced the number of eosinophils. Tioxamast decreased the number of eosinophils at 12.5 mg/kg i.p. and by the oral route.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The reactions to platelet-activating factor (PAF-acether) injected into the pleural cavity of rats were compared with the reactions in animals injected with 0.9% NaCl. PAF-acether induced a maximum exudate after 30-60 min, which then decreased and disappeared after 24 h. The number of pleural leukocytes in the exudate was clearly decreased 30 min after the injection, was slightly increased after 6 h and was unchanged at other times. The estimation of lipid mediators in the pleural exudate obtained 30 and 60 min after the injection of PAF-acether revealed an increase in type-C4 leukotriene (LTC4) and a decrease in thromboxane B2 (TxB2) and in 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha). In addition, the amount of histamine was found to be lower after 30 min. These results confirm in vivo that some biological effects of PAF-acether seem to involve the participation of other mediators.

Various 5-aminobenzofuran derivatives were prepared from khellin and screened intravenously in the dog for their potential antiarrhythmic activity against ouabain-induced ventricular arrhythmia and in the Harris test. From systematic structural variations it was found that two methoxy groups in positions 4 and 7 on the benzofuran ring, a tertiary aminoethoxy side chain in position 6, and a N-methylurea group in position 5 led to the most active compounds. These were then tested orally in the Harris test in the dog. The two long-acting derivatives N-[4,7-dimethoxy-6-(2-pyrrolidinoethoxy)-5-benzofuranyl]-N'-methylurea (8j) and N-[4,7-dimethoxy-6-(2-piperidinoethoxy)-5-benzofuranyl]-N'-methylurea (8m) showed advantages when compared to quinidine and disopyramide and have been selected for further studies.

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.

Pharmacokinetics and pharmacodynamics were studied in three dogs with interventricular coronary artery ligatures (ligature of Harris) and in three control animals. Weighted nonlinear analysis was used to fit equations describing two and three compartment open models to the experimental data, obtained after intravenous injection (5 mg/kg) of the drug. The three compartment model gave a reduction in the weighted sum of squared residuals and an improvement in the randomness of scatter of the experimental points about the theoretical curve. The postdistribution elimination half-life was longer, the area under the plasma elimination curve larger, and the total body plasma clearance and apparent volume of distribution was reduced in the animals with arrhythmias. The pharmacological response was assessed by recording the ECG and calculating the percentage of normal sinus rhythm/min. A combined pharmacokinetic-pharmacodynamic model was used to analyze data from individual animals. keO, a measure of the lag time of pharmacological response behind changes in plasma concentration, and Ce (50), a measure of the sensitivity of the cardiac site of action of the drug, were determined.

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.

Erythromycin base was tested by brushing a solution onto the skin in various models of non-immune and immune inflammation produced in mouse ear, namely inflammations induced by croton oil and cantharidin, primary irritation by picryl chloride, and contact hypersensitivity reactions to oxazolone and picryl chloride. On the non-immune inflammations, erythromycin displayed a greater effect than indomethacin, phenylbutazone or acetylsalicylic acid, though less than that of hydrocortisone acetate. It inhibited the hypersensitivity reactions less well. These results suggest some participation of an anti-inflammatory mechanism in the clinical effectiveness of cutaneously applied erythromycin base in some forms of acne.

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.

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.

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.

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.

Administered by intravenous or oral route, carocainide, MD770207, abolished experimental ventricular arrhythmias in anaesthetized and conscious dogs. Slow rate intravenous infusion (0.5 mg/kg/min) studies in conscious coronary ligated dogs demonstrated a good arrhythmia conversion as well as a wide margin of safety; mean conversion to 95% of normal sinus rhythm was achieved at 10.5 +/- 2.1 mg/kg while first signs of reversible neuro and cardio-toxicity occurred at 37.8 +/- 8 mg/kg. The reference agents disopyramide and lidocaine showed less favourable safety margin. Carocainide reduced epicardial ST-segment elevation produced by short coronary artery occlusion and prevented the occurrence of ventricular fibrillation resulting from reperfusion after acute coronary artery ligation. At antiarrhythmic dose levels there were no undesirable effects noted on cardiovascular function. Given intravenously the compound increased the ventricular fibrillation threshold in spontaneously hypertensive rats.

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 3 X 10(-6) M for imipramine and 1 X 10(-5) M for midalcipran in normal (4 mM K+) and hyperpolarizing (2.7 mM K+) conditions. At the concentration of 1 X 10(-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.

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 C4-immunoreactive material (LTC4 im) in the exudate and decreased quantities of thromboxane B2 (TxB2) and of 6-Keto-F1 alpha-prostaglandin (6-Keto PGF1 alpha). 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 LTC4 im. Acetylsalicylic acid, phenylbutazone and indomethacin significantly inhibited the exudate, greatly lowered the quantities of cyclooxygenase derivatives and tended to increase LTC4 im. Phenidone, which inhibits the cyclooxygenase and lipoxygenase pathways, decreased the exudate and the three mediators. The phospholipase A2 inhibitor, chloroquine, decreased both the amount of exudate and moderately the concentration of LTC4 im. The glucocorticoids studied had no effect on the exudate or on the mediators. These results suggest that the role of the increased LTC4 im in the induction of the pleurisy is not clear.