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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 -
Anesthesiology Mar 2001Inhaled prostacyclin and intravenous almitrine have both been shown to improve pulmonary gas exchange in acute lung injury (ALI). This study was performed to investigate...
BACKGROUND
Inhaled prostacyclin and intravenous almitrine have both been shown to improve pulmonary gas exchange in acute lung injury (ALI). This study was performed to investigate a possible additive effect of prostacyclin and almitrine on pulmonary ventilation-perfusion (VA/Q) ratio in ALI compared with inhaled prostacyclin or intravenous almitrine alone.
METHODS
Experimental ALI was established in 24 pigs by repeated lung lavage. Animals were randomly assigned to receive either 25 ng.kg(-1).min(-1) inhaled prostacyclin alone, 1 microg.kg(-1).min(-1) almitrine alone, 25 ng.kg(-1).min(-1) inhaled prostacyclin in combination with 1 microg.kg(-1).min(-1) almitrine, or no specific treatment (controls) for 30 min. For each intervention, pulmonary gas exchange and hemodynamics were analyzed and VA/Q distributions were calculated using the multiple inert gas elimination technique. The data was analyzed within and between the groups by analysis of variance for repeated measurements, followed by the Student-Newman-Keuls test for multiple comparison when analysis of variance revealed significant differences.
RESULTS
All values are expressed as mean +/- SD. In controls, pulmonary gas exchange, hemodynamics, and VA/Q distribution remained unchanged. With prostacyclin alone and almitrine alone, arterial oxygen partial pressure (PaO2) increased, whereas intrapulmonary shunt (QS/QT) decreased (P < 0.05). Combined prostacyclin and almitrine also increased PaO2 and decreased QS/QT (P < 0.05). When compared with either prostacyclin or almitrine alone, the combined application of both drugs revealed no additional effect in gas exchange or VA/Q distribution.
CONCLUSIONS
The authors conclude that, in this experimental model of ALI, the combination of 25 ng.kg(-1).min(-1) prostacyclin and 1 microg.kg(-1).min(-1) almitrine does not result in an additive improvement of pulmonary gas exchange or VA/Q distribution when compared with prostacyclin or almitrine alone.
Topics: Almitrine; Analysis of Variance; Animals; Antihypertensive Agents; Drug Interactions; Epoprostenol; Female; Hemodynamics; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Respiratory System Agents; Swine; Ventilation-Perfusion Ratio
PubMed: 11374607
DOI: 10.1097/00000542-200103000-00017 -
The European Respiratory Journal Dec 1999The combination of inhaled nitric oxide with almitrine bismesylate has been proposed for the management of acute respiratory distress syndrome in order to divert... (Clinical Trial)
Clinical Trial Comparative Study
The combination of inhaled nitric oxide with almitrine bismesylate has been proposed for the management of acute respiratory distress syndrome in order to divert pulmonary blood flow away from poorly ventilated toward well-ventilated areas. The aims of this prospective and comparative study were to: 1) confirm the beneficial effects on oxygenation of this association; 2) evaluate the haemodynamic effects of this association; and 3) evaluate the influence of noradrenaline (a nonspecific vasoconstrictor) on the modification of gas exchange related to inhaled NO and/or almitrine bismesylate. Forty-one sedated paralysed and ventilated patients were investigated. Haemodynamic and blood gas measurements were performed in a fixed order: baseline; inhalation of NO for 30 min.; intravenous infusion of almitrine bismesylate; and concomitant administration of inhaled NO and almitrine bismesylate. Inhaled NO and almitrine bismesylate increased arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2) (p<0.001). The association of inhaled NO with almitrine bismesylate resulted in a dramatic improvement in Pa,O2/FI,O2 (p<0.0001 versus almitrine bismesylate, p<0.05 versus inhaled NO). In patients receiving noradrenalin (n = 19), almitrine bismesylate had no effect on oxygenation. The present study confirmed that the combination of inhaled NO with almitrine bismesylate improved oxygenation, and demonstrated that almitrine bismesylate has no effect on oxygenation in patients receiving noradrenalin.
Topics: Administration, Inhalation; Adult; Aged; Almitrine; Drug Interactions; Drug Therapy, Combination; Female; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Nitric Oxide; Norepinephrine; Prospective Studies; Pulmonary Gas Exchange; Reference Values; Reproducibility of Results; Respiratory Distress Syndrome; Respiratory Function Tests; Respiratory System Agents; Statistics, Nonparametric; Vasoconstrictor Agents
PubMed: 10624756
DOI: 10.1183/09031936.99.14612839 -
The European Respiratory Journal Dec 1999
Topics: Administration, Inhalation; Almitrine; Bronchodilator Agents; Drug Therapy, Combination; Humans; Injections, Intravenous; Nitric Oxide; Respiratory Distress Syndrome; Respiratory System Agents; Treatment Outcome
PubMed: 10624749
DOI: 10.1183/09031936.99.14612449 -
Anesthesiology Nov 1998The partition of pulmonary blood flow between normal and shunting zones is an important determinant of oxygen tension in arterial blood (PaO2). The authors hypothesized... (Clinical Trial)
Clinical Trial
BACKGROUND
The partition of pulmonary blood flow between normal and shunting zones is an important determinant of oxygen tension in arterial blood (PaO2). The authors hypothesized that the combination of inhaled nitric oxide (iNO) and almitrine infusion might have additional effects related to their pharmacologic properties to improve PaO2. Such a combination was tested in patients with hypoxia caused by focal lung lesions, distinct from the acute respiratory distress syndrome.
METHODS
Fifteen patients with hypoxic focal lung lesions despite optimal therapy were included and successively treated with (1) 5 ppm iNO, (2) low-dose almitrine infusion (5.5 +/- 1.7 microg x kg(-1) min(-1)) during iNO, and (3) almitrine infusion alone (with NO turned off). Then iNO was reintroduced and we studied the effect of the coadministration in reducing the fractional concentration of oxygen in inspired gas (FI(O2)) and positive end-expiratory pressure (PEEP) levels. Changes in blood gases and pulmonary and systemic hemodynamics were measured.
RESULTS
Systemic hemodynamic variables remained stable in all protocol conditions. Use of iNO improved arterial oxygenation and decreased intrapulmonary shunt. Almitrine similarly improved PaO2 but increased pulmonary artery pressure and right atrial pressure. Coadministration of iNO and almitrine improved PaO2 compared with each drug alone and with control. All patients responded (that is, they had at least a +30% increase in PaO2) to this coadministration. When the drug combination was continued, FI(O2) and PEEP could be reduced over 8 h. The hospital mortality rate was 33% and unrelated to hypoxia.
CONCLUSIONS
In hypoxemic focal lung lesions, iNO or low-dose almitrine markedly improved PaO2 to a similar extent. Furthermore, the coadministration amplified the PaO2 increase at a level that allowed reductions in FI(O2) and PEEP levels.
Topics: Administration, Inhalation; Adult; Aged; Almitrine; Blood Pressure; Cardiac Catheterization; Female; Humans; Hypoxia; Infusions, Intravenous; Lung Diseases; Male; Middle Aged; Nitric Oxide; Pulmonary Gas Exchange; Respiratory Function Tests; Respiratory System Agents
PubMed: 9822004
DOI: 10.1097/00000542-199811000-00016 -
Anesthesiology Oct 1998Intravenous almitrine, which augments hypoxic pulmonary vasoconstriction, is used for short-term improvement of arterial oxygenation. However, recent research has... (Clinical Trial)
Clinical Trial
BACKGROUND
Intravenous almitrine, which augments hypoxic pulmonary vasoconstriction, is used for short-term improvement of arterial oxygenation. However, recent research has suggested a potentially harmful effect on lactate metabolism and hepatic function.
METHODS
Arterial oxygenation, hemodynamic parameters, plasma lactate, and hepatic function were monitored prospectively in 25 patients with acute lung injury (defined as a ratio of arterial oxygen pressure to inspiratory oxygen fraction < or = 150 mmHg) who where treated with intravenous almitrine. In 21 of 25 patients, acute lung injury was related to primary lung lesions, including pneumonia, postcardiosurgical atelectasis, and lung contusions.
RESULTS
Intravenous almitrine increased the ratio of arterial oxygen pressure to inspiratory oxygen fraction from 93 +/- 33 mmHg to 207 +/- 107 mmHg (mean +/- SD). In eight patients (three men), the plasma lactate concentration increased by an average of +3.5 +/- 1.8 mM, and the pH and bicarbonate concentration both decreased during the first 24 h of treatment. In this group of patients, the total bilirubin concentration was elevated before almitrine administration, and the results of other hepatic function tests, such as aspartate aminotransferase, alanine aminotransferase, and prothrombin time, were altered by almitrine administration. Therefore, intravenous almitrine was discontinued. Lactic acidosis and hepatic dysfunction improved. In the other 17 patients (14 men), the plasma lactate concentration and the hepatic function tests remained unaltered during intravenous almitrine therapy for > 60 h. Univariate and multivariate analyses revealed that an abnormal plasma concentration of total bilirubin before almitrine administration and female gender were the two factors significantly linked with lactic acidosis during almitrine infusion.
CONCLUSIONS
This study confirms that intravenous almitrine greatly improves arterial oxygenation in patients with acute lung injury but may also induce lactic acidosis and hepatic dysfunction. The coexistence of lactic acidosis and hepatic dysfunction in the same patients strongly suggests that the liver is the primary source of intravenous almitrine-induced lactic acidosis.
Topics: Acidosis, Lactic; Acute Disease; Adolescent; Adult; Aged; Almitrine; Analysis of Variance; Bilirubin; Chemical and Drug Induced Liver Injury; Female; Humans; Injections, Intravenous; Lactic Acid; Lung Diseases; Male; Middle Aged; Oxygen; Partial Pressure; Respiratory System Agents
PubMed: 9777998
DOI: 10.1097/00000542-199810000-00005 -
Journal of Applied Physiology... Jul 1997The effects of almitrine bimesylate and doxapram HCl on isometric force produced by in vitro rat diaphragm were studied during direct muscle activation at 37 degrees C....
The effects of almitrine bimesylate and doxapram HCl on isometric force produced by in vitro rat diaphragm were studied during direct muscle activation at 37 degrees C. Doxapram and almitrine ameliorate respiratory failure clinically by indirectly increasing phrenic nerve activity. This study was carried out to investigate possible direct actions of these agents on the diaphragm before and after fatigue of the fibers. Two age groups of animals were chosen [6-14 wk (group 1) and 50-55 wk (group 2)] because it is known that increasing age decreases a muscle fiber's resistance to fatigue. Muscle strips were isolated from both group 1 and group 2 and directly stimulated (2-ms pulse duration, 5-15 V) to produce twitch tensions of 1.3 and 2.1 N/cm2, respectively. At low concentrations, doxapram (=20 microg/ml) and almitrine (=12 microg/ml) had no effect on twitch contraction or 100-Hz tetanic tension. However, 40 microg/ml doxapram and 30 microg/ml almitrine increased twitch tension by 9.0 +/- 1.4 and 11.6 +/- 1.9%, respectively, in animals of group 2 (n = 5). A fatigue protocol consisting of low-frequency stimulation (30-Hz trains, 250-ms duration every 2 s for 5 min) caused a reduction of twitch tension in animals of group 1 (48 +/- 4% of control) and group 2 (28 +/- 4% of control). At 90 min postfatigue, the twitch tension recovered to 72 +/- 3 and 42 +/- 2% of control values in group 1 and group 2, respectively. In the presence of doxapram (20 microg/ml), there was a significant increase in the recovery of twitch tension at 90 min in group 1 and group 2 (84.5 +/- 3.2 and 80.1 +/- 2.8%, respectively) compared with controls at 90 min postfatigue. In the presence of almitrine (12 microg/ml), there was a full recovery from fatigue in group 1 animals (100% of control) and a recovery to 95.6 +/- 2.1% of control in group 2 animals at 90 min. These results demonstrate a significant improvement in the rapidity and magnitude of recovery from fatigue in the rat diaphragm muscle in the presence of both doxapram and, especially, almitrine. These effects may be due to changes in intracellular calcium, ADP/ATP ratios, or oxygen free radical scavenging.
Topics: Almitrine; Animals; Diaphragm; Doxapram; Electric Stimulation; In Vitro Techniques; Isometric Contraction; Male; Muscle Contraction; Muscle Relaxation; Rats; Rats, Wistar; Respiratory System Agents
PubMed: 9216944
DOI: 10.1152/jappl.1997.83.1.52 -
Anesthesiology Jun 1997Enhancement of hypoxic pulmonary vasoconstriction (HPV) in nonventilated lung areas by almitrine increases the respiratory response to inhaled nitric oxide (NO) in... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Enhancement of hypoxic pulmonary vasoconstriction (HPV) in nonventilated lung areas by almitrine increases the respiratory response to inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). Therefore the authors hypothesized that inhibition of HPV in nonventilated lung areas decreases the respiratory effects of NO.
METHODS
Eleven patients with severe ARDS treated by venovenous extracorporeal lung assist were studied. Patients' lungs were ventilated at a fraction of inspired oxygen (F[I(O2)]) of 1.0. By varying extracorporeal blood flow, mixed venous oxygen tension (P[O2]; partial oxygen pressure in mixed venous blood [PV(O2)]) was adjusted randomly to four levels (means, 47, 54, 64 and 84 mmHg). Extracorporeal gas flow was adjusted to prevent changes in mixed venous carbon dioxide tension [PV(CO2)]). Hemodynamic and gas exchange variables were measured at each level before, during, and after 15 ppm NO.
RESULTS
Increasing PV(O2) from 47 to 84 mmHg resulted in a progressive decrease in lung perfusion pressure (PAP-PAWP; P < 0.05) and pulmnonary vascular resistance index (PVRI; P < 0.05) and in an increase in intrapulmonary shunt (Q[S]/Q[T]; P < 0.05). PV(CO2) and cardiac index did not change. Whereas the NO-induced reduction in PAP-PAWP was smaller at high PV(O2), NO-induced decrease in Q(S)/Q(T) was independent of baseline PV(O2). In response to NO, arterial P(O2) increased more and arterial oxygen saturation increased less at high compared with low PV(O2).
CONCLUSION
In patients with ARDS, HPV in nonventilated lung areas modifies the hemodynamic and respiratory response to NO. The stronger the HPV in nonventilated lung areas the more pronounced is the NO-induced decrease in PAP-PAWP. In contrast, the NO-induced decrease in Q(S)/Q(T) is independent of PV(O2) over a wide range of PV(O2) levels. The effect of NO on the arterial oxygen tension varies with the level of PV(O2) by virtue of its location on the oxygen dissociation curve.
Topics: Administration, Inhalation; Adult; Extracorporeal Membrane Oxygenation; Female; Hemodynamics; Humans; Hypoxia; Lung; Male; Middle Aged; Nitric Oxide; Oxygen; Perfusion; Pulmonary Circulation; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Vasoconstriction
PubMed: 9197293
DOI: 10.1097/00000542-199706000-00005 -
Anesthesiology Nov 1995Inhaled nitric oxide, a selective pulmonary vasodilator, in combination with intravenous almitrine, a selective pulmonary vasoconstrictor, markedly improves arterial... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Inhaled nitric oxide, a selective pulmonary vasodilator, in combination with intravenous almitrine, a selective pulmonary vasoconstrictor, markedly improves arterial oxygenation in 50-60% of patients with acute lung injury. The goal of this study was to assess dose response of inhaled nitric oxide with and without almitrine in patients with acute respiratory distress syndrome responding to nitric oxide.
METHODS
Six critically ill patients (aged 44 +/- 7 yr) were studied during early stage of their acute respiratory failure (Murray score: 2.6 +/- 0.1). All responded to 15 parts per million (ppm) of inhaled nitric oxide by an increase in Pao2 of at least 40 mmHg at FIo2 1. Hemodynamic and respiratory parameters were recorded continuously from pulmonary artery and systemic catheters. Inspiratory, expiratory, and mean intratracheal nitric oxide concentrations were monitored continuously using a fast response time chemiluminescence apparatus (NOX 4000, Sérès, Aix-en-provence, France). On day 1, 6 inspiratory concentrations of nitric oxide were randomly administered: 0.15, 0.45, 1.5, 4.5, 15, and 45 ppm to determine the dose response of inhaled nitric oxide on Pao2, pulmonary shunt, mean pulmonary artery pressure, and pulmonary vascular resistance index. On day 2, a continuous intravenous infusion of almitrine at a dose of 16 micrograms.kg-1.min-1 was administered and dose response to inhaled nitrix oxide was repeated according to the same protocol as during day 1. A constant FIo2 of 0.85 was used throughout the study.
RESULTS
Nitric oxide induced a dose-dependent increase in Pao2 for inspiratory nitric oxide concentrations ranging between 0.15 and 1.5 ppm. Almitrine increased Pao2/FIo2 from 161 +/- 30 to 251 +/- 45 mmHg (P < 0.001) and pulmonary vascular resistance index from 455 +/- 185 to 527 +/- 176 dyn.s.cm-5.m2 (P < 0.05), and decreased pulmonary shunt (Qs/QT) from 35 +/- 2 to 33 +/- 3% (P < 0.001). During almitrine combined with nitric oxide, a dose-dependent increase in Pao2 was observed for inspiratory nitric oxide concentrations ranging between 0.15 and 1.5 ppm. Almitrine plus nitric oxide 1.5 ppm increased Pao2/FIo2 from 161 +/- 30 to 355 +/- 36 mmHg (P < 0.001), decreased Qs/QT from 35 +/- 2 to 24 +/- 2% (P < 0.001), pulmonary vascular resistance index from 455 +/- 185 to 385 +/- 138 dyn.s.cm-5.m2 (P < 0.05), and mean pulmonary artery pressure from 31 +/- 4 to 28 +/- 4 mmHg (P < 0.001).
CONCLUSIONS
In 6 patients with early acute respiratory distress syndrome and highly responsive to inhaled nitrix oxide, the administration of intravenous almitrine at a concentration of 16 micrograms.kg-1.min-1 induced an additional increase in Pao2. Dose response of nitric oxide was not changed by the administration of almitrine and a plateau effect was observed at inspiratory nitric oxide concentrations of 1.5 ppm.
Topics: Administration, Inhalation; Adult; Almitrine; Critical Care; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Nitric Oxide; Positive-Pressure Respiration; Respiration; Respiratory Distress Syndrome; Respiratory System Agents
PubMed: 7486178
DOI: 10.1097/00000542-199511000-00005 -
Biochimica Et Biophysica Acta Mar 1995Autonomous cell growth may result from interactions of cellular growth factors with their receptors leading to the establishment of external or internal autocrine loops...
Autonomous cell growth may result from interactions of cellular growth factors with their receptors leading to the establishment of external or internal autocrine loops which can induce tumor formation. Tumor progression above a small volume also requires an increase in blood supply. This is achieved by the release from the tumor of angiogenic growth factors which diffuse toward preexisting capillaries. The search for compounds interfering with growth factors and their receptors represents a field of investigation of increasing importance. In this report we show that almitrine interferes with the binding of basic fibroblast growth factor and vasculotropin/vascular endothelial growth factor to their receptors present on vascular endothelial cells, smooth muscle cells or retinal pigment epithelium. This molecule inhibits reversibly serum and basic growth factors stimulated cell growth and motility without affecting epidermal growth factor-stimulated proliferation.
Topics: Almitrine; Animals; Aorta; Cattle; Cells, Cultured; Endothelium, Vascular; Fibroblast Growth Factor 2; Growth Substances; Muscle, Smooth, Vascular; Pigment Epithelium of Eye; Receptors, Cytokine; Receptors, Fibroblast Growth Factor; Receptors, Growth Factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 7696345
DOI: 10.1016/0167-4889(94)00215-z