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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 -
Anaesthesia, Critical Care & Pain... Aug 2020
Topics: Aged; Almitrine; Betacoronavirus; COVID-19; Case-Control Studies; Coronavirus Infections; Female; Humans; Hypoxia; Injections, Intravenous; Male; Middle Aged; Oxygen; Pandemics; Partial Pressure; Patient Positioning; Pneumonia, Viral; Prone Position; Respiratory Distress Syndrome; Respiratory System Agents; SARS-CoV-2
PubMed: 32505756
DOI: 10.1016/j.accpm.2020.05.013 -
Anaesthesia, Critical Care & Pain... Jun 2020
Topics: Almitrine; Betacoronavirus; COVID-19; Capillary Leak Syndrome; Coronavirus Infections; Humans; Hypoxia; Lung; Lung Compliance; Pandemics; Patient Positioning; Pneumonia, Viral; Positive-Pressure Respiration; Pulmonary Circulation; Pulmonary Edema; Respiratory Mechanics; SARS-CoV-2; Switzerland; Tomography, X-Ray Computed; Vasoconstriction; Vasoconstrictor Agents
PubMed: 32305591
DOI: 10.1016/j.accpm.2020.04.003 -
Respiratory Medicine Jul 2001Almitrine (A) and medroxyprogesterone acetate (MA) given separately improve arterial blood gases in some patients with chronic obstructive pulmonary disease (COPD); the... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Almitrine (A) and medroxyprogesterone acetate (MA) given separately improve arterial blood gases in some patients with chronic obstructive pulmonary disease (COPD); the aim of this study was to assess the effect of the two drugs given together. Forty-eight patients with irreversible COPD and hypoxaemia were prospectively enrolled into a 14-day run-in period and received single-blind oral treatment with double placebo. Patients whose PaO2 remained stable (less than 10% change; n = 29, 25 males, mean age 65.6 years) were included in a 14-day active treatment period and randomly assigned to three groups. They received double-blind oral treatment with: A (50 mg bid, group A, n = 10); MA (20 mg tid, group MA, n = 9); A (50 mg bid) and MA (20 mg tid, group A+MA, n = 10). Anthropometric and spirometric measurements were similar in the three groups and so were the arterial blood gas values at the beginning and the end of the run-in period. At the end of the active treatment period, blood gas changes (mean+/-SE) were significantly different between groups (P<0.05, Kruskal-Wallis test), with improvement in both hypoxaemia and hypercapnia in group A+MA only: delta PaO2 = 7.4+/-1.9 mmHg, delta PaCO2 = -5.1+/-1.7 m mHg (P<0.05, Wilcoxon test). In short-term treatment, the association of A and MA is more efficient than either drug alone at improving arterial blood gases in COPD patients.
Topics: Aged; Almitrine; Blood Gas Analysis; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Humans; Lung Diseases, Obstructive; Male; Medroxyprogesterone Acetate; Middle Aged; Prospective Studies; Respiratory System Agents; Statistics, Nonparametric; Treatment Outcome
PubMed: 11453318
DOI: 10.1053/rmed.2001.1110 -
Thorax Jan 1990The effect of oral treatment with the thiazine derivative almitrine bismesylate was studied in 28 patients with chronic obstructive pulmonary disease and arterial... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The effect of oral treatment with the thiazine derivative almitrine bismesylate was studied in 28 patients with chronic obstructive pulmonary disease and arterial hypoxaemia receiving long term domiciliary oxygen therapy in a placebo controlled, double blind crossover trial. The initial treatment was given for three months and the second for two months. Because almitrine had an unexpectedly prolonged washout effect crossover analysis could not be performed; data from the placebo treatment administered in the second arm of the trial were used to calculate the half life of almitrine. Nine patients were withdrawn from the study (5 almitrine, 4 placebo). Patients' tolerance of the drug was good. The estimated plasma half life of almitrine was 20.5 days, considerably longer than previously reported. Almitrine caused a significant improvement in arterial oxygen tension (PaO2) with a mean maximum increase of 0.7 kPa at a plasma concentration of 500 ng/ml. Higher plasma concentrations were not associated with any further increase in PaO2. There was no significant effect on arterial carbon dioxide tension (PaCO2). In a second, acute study at the end of each arm of the chronic trial nine patients were subjected to increasing oxygen delivery rates (2, 4, and 6 l/min) for 90 minutes or until blood gas concentrations plateaued. Almitrine increased PaO2 in a dose dependent fashion at all delivery rates, but the effect diminished as PaO2 approached normoxic levels. There was no significant effect on PaCO2. Almitrine treatment results in a significant improvement in PaO2 over that achieved by oxygen alone, an effect that diminishes at high flow rates. Whether this is of clinical benefit is not known. In view of the prolonged half life revised dosage schedules are required.
Topics: Almitrine; Carbon Dioxide; Double-Blind Method; Female; Half-Life; Humans; Male; Middle Aged; Oxygen; Oxygen Inhalation Therapy; Pulmonary Heart Disease; Randomized Controlled Trials as Topic
PubMed: 2108510
DOI: 10.1136/thx.45.1.16 -
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 -
Anesthesiology Oct 1987The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in seven closed-chest dogs anesthetized with pentobarbital and...
The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in seven closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2, while the left lung was ventilated with either 100% O2 ("hyperoxia") or with an hypoxic gas mixture ("hypoxia": end-tidal PO2 = 50.1 +/- 0.1 mmHg). Cardiac output (CO) was altered from a "normal" value of 3.10 +/- 0.18 l . min-1 to a "high" value of 3.92 +/- 0.16 l . min-1 by opening arteriovenous fistulae which allowed measurements of two points along a pressure-flow line. These four phases of left lung hypoxia or hyperoxia with normal and high cardiac output were repeated in the presence and absence of almitrine. Almitrine bismesylate was administered as a constant infusion of 14.3 micrograms . kg-1 . min-1 for a mean plasma concentration of 219.5 +/- 26.4 ng . ml-1. Relative blood flow to each lung was measured with a differential CO2 excretion (VCO2) method corrected for the Haldane effect. With both lungs hyperoxic, the percent left lung blood flow (%QL-VCO2) was 44 +/- 1%. When the left lung was exposed to hypoxia, the %QL-VCO2 decreased significantly to 22 +/- 1%. However, with the administration of almitrine, the %QL-VCO2 during left lung hypoxia increased significantly to 36 +/- 2%. The arterial oxygen tension decreased significantly between hyperoxia (PaO2 = 633 +/- 6 mmHg) and hypoxia (271 +/- 31 mmHg). With the addition of almitrine, there was no change during hyperoxia; however, during hypoxia, the PaO2 decreased significantly to 124 +/- 15 mmHg. Cardiac output did not influence these findings. The pulmonary vascular conductance (G) is the slope of the pressure-flow line.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Almitrine; Animals; Central Nervous System Stimulants; Dogs; Female; Hypoxia; Lung; Piperazines; Vasoconstriction
PubMed: 2889404
DOI: 10.1097/00000542-198710000-00015 -
Saudi Journal of Anaesthesia 2021
PubMed: 33824652
DOI: 10.4103/sja.SJA_782_20 -
Anesthesiology Aug 2011
Topics: Almitrine; Humans; Hypoxia; Intraoperative Complications; Nitric Oxide; Respiration, Artificial
PubMed: 21792000
DOI: 10.1097/ALN.0b013e318223bbc0 -
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