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European Neurology 1995
Cerebral ischemia: from pharmacology to modern techniques and clinical implications. Value of almitrine-raubasin (Duxil Duxaril). International symposium, Hangzhou, People's Republic of China, May 14, 1994.
Topics: Almitrine; Brain Ischemia; Drug Combinations; Humans; Neuroprotective Agents; Piperazines; Secologanin Tryptamine Alkaloids; Yohimbine
PubMed: 8529722
DOI: 10.1159/000119489 -
European Journal of Biochemistry Sep 1994Previously, we have shown in experiments with isolated mitochondria that almitrine, a drug used for patients with chronic lung disease, affects the H+/ATP stoichiometry...
Previously, we have shown in experiments with isolated mitochondria that almitrine, a drug used for patients with chronic lung disease, affects the H+/ATP stoichiometry of the F0F1-ATPase [Rigoulet, M., Fraisse, L., Ouhabi, R., Guérin, B., Fontaine, E. & Leverve, X. M. (1990) Biochim. Biophys. Acta 1018, 91-97]. In the present study, we have investigated the effect of almitrine on gluconeogenesis and oxygen consumption in isolated hepatocytes. Almitrine decreased both the cytosolic and mitochondrial ATP/ADP ratios but had no effect on oxygen consumption in cells incubated with and without octanoate. This must have been due to a double effect. On the one hand, a decrease in the ATP/ADP ratio decreases ATP utilization; on the other hand, in the presence of almitrine more oxygen is required to synthesize ATP. Almitrine did affect gluconeogenesis from various substrates (lactate + pyruvate, glycerone or fructose), but had no effect on glycerol or glutamine metabolism. The effect on gluconeogenesis from glycerone was due to an increase in glycolytic flux. The rate of lactate + pyruvate production increased whereas there was no effect on glycerone utilization. This effect was caused by an activation of pyruvate kinase. Our data indicate that this enzyme is an extremely sensitive sensor of the cytosolic ATP/ADP ratio. Hence, under our experimental conditions, the cytosolic ATP/ADP ratio decrease affects only the balance between glucose and lactate + pyruvate productions, and not the phosphorylation of glycerone, the first and controlling step of this pathway.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Almitrine; Animals; Cells, Cultured; Cytosol; Enzyme Activation; Fasting; Gluconeogenesis; Glycolysis; Liver; Male; Oxygen; Pyruvate Kinase; Rats; Rats, Wistar
PubMed: 7925421
DOI: 10.1111/j.1432-1033.1994.00967.x -
The European Respiratory Journal May 1994The aim of this double-blind, placebo-controlled study was to determine whether acute administration of almitrine enhances hypoxic pulmonary vasoconstriction in patients... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The aim of this double-blind, placebo-controlled study was to determine whether acute administration of almitrine enhances hypoxic pulmonary vasoconstriction in patients with chronic obstructive pulmonary disease (COPD). Haemodynamics and blood gases were studied at various inspiratory fractional concentrations of oxygen (FIO2): 0.15, 0.21, 0.30 and 1.0, randomly administered for 20 min periods under constant infusion of either placebo or almitrine (8 micrograms.kg-1.min-1) in 20 patients with COPD. The almitrine group exhibited a significant increase in mean pulmonary artery pressure, pulmonary vascular resistance and arterial oxygen tension (PaO2) at FIO2 0.15, 0.21 and 0.30. During hypoxia, the increase in mean pulmonary pressure and pulmonary vascular resistance was three times greater in the almitrine group than the placebo group. No significant difference in cardiac output and systemic haemodynamics was found. These results suggest that almitrine at the dose used, enhances pulmonary vasoconstriction in COPD patients.
Topics: Almitrine; Carbon Dioxide; Double-Blind Method; Female; Hemodynamics; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Oxygen; Oxygen Consumption; Pulmonary Circulation; Vasomotor System
PubMed: 8050541
DOI: No ID Found -
Thorax Aug 1993
Topics: Almitrine; Antidepressive Agents, Tricyclic; Carbonic Anhydrase Inhibitors; Chronic Disease; Humans; Lung Diseases, Obstructive; Medroxyprogesterone Acetate; Respiratory Insufficiency; Theophylline
PubMed: 8211866
DOI: 10.1136/thx.48.8.781 -
The Journal of Physiology Apr 19931. The effect of blockade of nitric oxide synthesis in pulmonary endothelium by two L-arginine analogues was tested in isolated blood-perfused lungs of normal rats and...
1. The effect of blockade of nitric oxide synthesis in pulmonary endothelium by two L-arginine analogues was tested in isolated blood-perfused lungs of normal rats and rats exposed chronically to 10% O2. 2. In both groups of rats the analogues (N-monomethyl-L-arginine (L-NMMA) and N-nitro-L-arginine methyl ester (L-NAME)) enhanced hypoxic vasoconstriction. In normal rats, with rare exceptions, these analogues had little or no effect on pulmonary artery pressure (Ppa) at constant blood flow during normoxia. However, chronically hypoxic rats have pulmonary hypertension and in these rats the analogues always raised Ppa; the rise in Ppa after L-NMMA but not L-NAME could be partially reversed by L-arginine. L-NAME was more potent than L-NMMA. 3. To see whether the difference between rat groups was due to the high Ppa in chronically hypoxic rats, in control rats we raised Ppa passively by lung inflation to values higher than found in chronically hypoxic rats. L-NAME did not alter the effects of lung inflation on Ppa. 4. Ppa was also raised passively by plotting pressure-flow lines up to high flow rates; the lines were changed minimally by both analogues in control rats but in chronically hypoxic rats the lines were raised to higher pressures and steepened substantially. 5. In control rats, during vasoconstriction caused by hypoxia, endothelin 1 and almitrine, L-NAME caused further rises in pressure. We conclude that a stimulus for nitric oxide release in control rats is the narrowing of vessels caused by vasoconstriction rather than passive increases in intravascular pressure. 6. In chronically hypoxic rats arterioles are narrowed by growth of new muscle and there is some muscle tone even in normoxia. Thus narrowing of the vascular lumen is the stimulus common to both groups of rats which leads to nitric oxide synthesis and attenuation of Ppa by a negative feedback process. Narrowing is associated with a large increase in shear stress due to two factors; the pressure drop along a vessel segment is increased and the surface area of the lining of the affected segment is decreased. 7. Atrial natriuretic peptide caused dose-dependent pulmonary vasodilation in both rat groups but had a greater effect in chronically hypoxic rats. The action persisted and was enhanced after blockade of NO synthesis.
Topics: Almitrine; Animals; Arginine; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Endothelins; Endothelium, Vascular; Hypoxia; In Vitro Techniques; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pulmonary Circulation; Rats; Rats, Wistar; Respiration; Vasoconstriction; omega-N-Methylarginine
PubMed: 8246176
DOI: 10.1113/jphysiol.1993.sp019581 -
Experimental Physiology Nov 1992Chronically hypoxic (CH) and normoxic control rats were used to assess the action of S9581, a water-soluble analogue of almitrine bismesylate. S9581 increased...
Chronically hypoxic (CH) and normoxic control rats were used to assess the action of S9581, a water-soluble analogue of almitrine bismesylate. S9581 increased ventilation (Ve) by 34% in control and 20% in CH rats. During acute hypoxia Ve was raised and S9581 caused a further increase of 20% in both groups. Low doses of S9581 and almitrine enhanced the hypoxic ventilatory response in CH rats while high doses depressed it in both groups. Effects of S9581 on the pulmonary circulation were assessed in the isolated perfused lung of rats. As with almitrine a complex relationship of dose-dependent vasoconstriction and dilatation was revealed. In low doses, S9581 enhanced the hypoxic pulmonary vasoconstrictor response to 2% O2 whilst this was attenuated by high doses in both control and CH rats. S9581 seemed to act like almitrine bismesylate on both the ventilation (peripheral chemoreceptor) and the pulmonary circulation. For studying almitrine-like activity the water solubility of S9581 provides considerable advantages for the researcher.
Topics: Almitrine; Animals; Dose-Response Relationship, Drug; Germ-Free Life; Hypoxia; Lung Diseases; Male; Pulmonary Circulation; Rats; Rats, Wistar; Respiration
PubMed: 1489540
DOI: 10.1113/expphysiol.1992.sp003648 -
British Journal of Pharmacology Jul 19921. Almitrine increases ventilation by stimulating the carotid body (CB) arterial chemoreceptors but neither its intraglomic target nor its mechanism of action have been...
1. Almitrine increases ventilation by stimulating the carotid body (CB) arterial chemoreceptors but neither its intraglomic target nor its mechanism of action have been elucidated. 2. We have tested the hypothesis that chemoreceptor cells are targets for almitrine by studying its effects on the release of 3H-catecholamines in an in vitro rabbit CB preparation. 3. It was found that almitrine (0.3 and 1.5 x 10(-6) M; i.e. 0.2 and 1 mg ml-1) increases the resting release of 3H-catecholamines from CBs (previously loaded with [3H]-tyrosine) incubated in a balanced 95% O2/5% CO2-equilibrated solution. 4. Almitrine at a concentration of 3 x 10(-6) M (2 mg l-1) also augmented the release of 3H-catecholamines elicited by incubating the CBs in a hypoxic solution (equilibrated with 7% O2/5% CO2 in N2), by high external K+ (35 mM) and by veratridine (2 x 10(-5) M), but did not modify release induced by dinitrophenol (7.5 x 10(-5) M). 5. At the same concentration (3 x 10(-6) M), almitrine increased the rate of dopamine synthesis and was ineffective in modifying the cyclic AMP levels in either normoxic or hypoxic CBs. 6. It is concluded that chemoreceptor cells are the intraglomic targets for almitrine. The mechanisms of action of almitrine on chemoreceptor cells are discussed.
Topics: Almitrine; Animals; Carotid Body; Catecholamines; In Vitro Techniques; Malates; Rabbits; Tritium
PubMed: 1504753
DOI: 10.1111/j.1476-5381.1992.tb14397.x -
The Journal of Physiology Mar 19921. In four awake dogs we measured EMG activity of three inspiratory and four expiratory muscles during sustained central chemoreceptor stimulation (CO2 inhalation), and... (Comparative Study)
Comparative Study
1. In four awake dogs we measured EMG activity of three inspiratory and four expiratory muscles during sustained central chemoreceptor stimulation (CO2 inhalation), and peripheral chemoreceptor stimulation (intravenous infusion of almitrine bismesylate (almitrine)). By using this selective pharmacological stimulation of the peripheral chemoreceptors and reversibly cold-blocking pulmonary stretch receptors, we were able to determine the effects of each type of stimulation on respiratory muscle recruitment in the absence of such complicating influences as pulmonary stretch receptor feedback, cerebral hypoxia or hypocapnia, and differences in breathing pattern. 2. During 10 min of steady-state hyperpnoea (minute ventilation VI, approximately twice eupnoea) caused by either hypercapnia or isocapnic stimulation of the carotid bodies with almitrine, all three inspiratory and all four expiratory muscles demonstrated significant and sustained elevations in EMG activity. 3. With both types of chemoreceptor stimulation, as tidal volume, VT, increased, so did the mean electrical activities of the crural diaphragm (r = 0.88), costal diaphragm (r = 0.93), parasternals (r = 0.82), triangularis sterni (r = 0.74), transversus abdominis (r = 0.77), external obliques (r = 0.68) and internal intercostals (r = 0.75). 4. In each dog, the response of ventilation and of the diaphragmatic EMG to a given level of central or peripheral chemoreceptor stimulation is highly reproducible from one test day to the next. On the other hand, accessory inspiratory and expiratory abdominal and rib cage muscles in two of the four dogs showed highly significant changes from day to day in the amount of their EMG activity at any given VT. 5. During steady-state ventilatory stimulation, 2 min intervals were chosen during which the two types of chemoreceptor stimulation had caused hyperpnoeas with similar values for VT, total time per breath (TTOT) and inspiratory time divided by the total time (TI/TTOT). Comparison of EMG activities during these matched hyperpnoeas revealed that there were no differences in the activities of any of the muscles between the two forms of stimulation. We conclude that peripheral chemoreceptor stimulation causes significant and sustained recruitment of expiratory muscles even in the absence of pulmonary feedback and that both expiratory and inspiratory muscles are recruited to the same extent during peripheral chemoreceptor stimulation as they are during an identical hyperpnoea caused by central chemoreceptor stimulation.
Topics: Almitrine; Animals; Carbon Dioxide; Chemoreceptor Cells; Dogs; Electromyography; Female; Respiratory Muscles; Tidal Volume; Time Factors
PubMed: 1593481
DOI: 10.1113/jphysiol.1992.sp019061 -
Experimental Physiology Jan 1992The contribution of almitrine bismesylate to the occurrence and pattern of augmented breaths was studied in fifteen spontaneously breathing, anaesthetized cats....
The contribution of almitrine bismesylate to the occurrence and pattern of augmented breaths was studied in fifteen spontaneously breathing, anaesthetized cats. Breathing was via a tracheostomy, while the laryngeal resistance to airflow was measured with the larynx isolated in situ. Almitrine bismesylate at a dose of 0.5 mg kg-1 of body weight was injected intravenously in the intact animals and following bilateral vagotomy which spared the right recurrent laryngeal nerve. Almitrine injected intravenously elicited augmented breaths within the first 45 s in thirteen cats and within 1 min in the remaining two cats. During augmented breaths inspiratory and expiratory airflows rose, the mean increases being 385.2 and 159.6% respectively above the controls (P less than 0.01). The inspiratory laryngeal resistance declined to 77.7% of the control (P less than 0.01) and expiratory laryngeal resistance increased by 95.4% above the control level (P less than 0.01). The inspiratory and expiratory times were prolonged by 56 and 58% compared with baseline breathing. Following the augmented breaths the respiratory airflows exceeded baseline values, the respiratory timing was slightly reduced, and the inspiratory laryngeal resistance was significantly lowered below the control level (P less than 0.01). The expiratory laryngeal resistance showed the same trend without statistical significance. Bilateral vagotomy abolished the occurrence of augmented breaths following almitrine injection.
Topics: Airway Resistance; Almitrine; Animals; Cats; Chemoreceptor Cells; Female; Larynx; Male; Respiration; Respiratory Mechanics; Vagotomy; Vagus Nerve
PubMed: 1543580
DOI: 10.1113/expphysiol.1992.sp003565 -
Thorax Jul 1991The effects of oral almitrine bismesylate, a respiratory stimulant that acts on peripheral arterial chemoreceptors, was studied in patients with chronic obstructive... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The effects of oral almitrine bismesylate, a respiratory stimulant that acts on peripheral arterial chemoreceptors, was studied in patients with chronic obstructive airways disease and hypoxaemic cor pulmonale. Twenty three patients admitted to hospital with an acute exacerbation of ventilatory failure were randomised to receive either almitrine 100 mg twice a day reducing to 50 mg twice a day over 48 hours or placebo in addition to conventional treatment. On admission the mean (SE) values for blood gas tensions were PaO2 4.8 (0.3) and PaCO2 7.7 (0.3) kPa in the 12 patients who received almitrine and PaO2 4.9 (0.1) and PaCO2 7.6 (0.3) kPa in the 11 who received placebo. After three hours of oxygen therapy at 1 1/min there was a similar rise in PaO2 in both groups, 6.4 (0.2) kPa in those receiving almitrine and 6.6 (0.4) kPa in those receiving placebo. After 24 hours of oxygen therapy values of PaO2 were again similar at 6.3 (0.8) kPa and 6.7 (2.2) kPa respectively. Arterial blood gas tensions improved during the study in those who survived but no significant differences were apparent between the two groups. There were six deaths, five in the almitrine group and one in the placebo group. There were no differences between the groups in respiratory rate, results of spirometry, oxygen requirement, or degree of dyspnoea (on visual analogue scale). The results did not show any benefit from oral almitrine in patients with acute respiratory failure secondary to chronic obstructive airways disease. Plasma almitrine concentrations, however, were often below the optimum therapeutic range, suggesting impaired drug absorption.
Topics: Administration, Oral; Aged; Aged, 80 and over; Almitrine; Carbon Dioxide; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Oxygen; Pulmonary Heart Disease; Respiratory Insufficiency; Vital Capacity
PubMed: 1908604
DOI: 10.1136/thx.46.7.493