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Respiration; International Review of... 2003Advanced chronic obstructive pulmonary disease (COPD) generates high costs, especially when patients require domiciliary long-term oxygen therapy (LTOT). Almitrine... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Effects of almitrine bismesylate on arterial blood gases in patients with chronic obstructive pulmonary disease and moderate hypoxaemia: a multicentre, randomised, double-blind, placebo-controlled study.
BACKGROUND
Advanced chronic obstructive pulmonary disease (COPD) generates high costs, especially when patients require domiciliary long-term oxygen therapy (LTOT). Almitrine bismesylate has been shown to improve gas exchange in the lungs. Our hypothesis was that long-term treatment with almitrine might postpone the prescription of LTOT.
OBJECTIVE
To evaluate the effects of almitrine sequential treatment on arterial blood gases in COPD patients with moderate hypoxaemia.
METHODS
COPD patients with moderate hypoxaemia [partial oxygen tension in arterialised blood (PaO(2)) between 7.33 and 8.66 kPa (56-65 mm Hg)] were investigated. After a 1-month run-in period, patients were given either almitrine 100 mg per day or placebo for sequential treatment for a total of 12 months.
RESULTS
115 patients in a steady state (57 in the almitrine and 58 in the placebo group) were included. Mean age was 60 years, mean forced expiratory volume in 1 s was 34 +/- 13% of predicted and mean PaO(2) was 8.04 +/- 0.5 kPa (60.5 +/- 3.8 mm Hg). 38 patients were lost to follow-up, 23 in the almitrine and 15 in the placebo group. The majority of drop-outs were due to adverse events (AE; 16 in the almitrine and 9 in the placebo group). Almitrine treatment resulted in PaO(2) improvement of 0.43 +/- 0.88 kPa (3.2 +/- 6.6 mm Hg) (p = 0.003). The treatment effect between almitrine and placebo was 0.45 kPa (3.4 mm Hg) (p = 0.003). In the almitrine group, two distinct subgroups were observed: responders (n = 19) and non-responders (n = 38). Almitrine treatment in responders resulted in a clinically significant improvement in PaO(2) of 1.36 +/- 0.7 kPa (10.2 +/- 5.3 mm Hg) (p < 0.0001) and a reduction of partial carbon dioxide tension in arterialised blood. 31 patients experienced serious AE: 17 in the almitrine and 14 in the placebo group. Five patients died during the study (3 in the almitrine and 2 in the placebo group). Most AE occurring during the study were related to underlying disease. Clinical diagnosis of polyneuropathy resulted in the withdrawal of 5 patients in the almitrine group and 3 patients in the placebo group. Four patients in the almitrine group experienced weight loss.
CONCLUSIONS
Almitrine treatment of patients with severe COPD and moderate hypoxaemia resulted in a small but significant improvement in PaO(2) over 12 months. A clinically important improvement in gas exchange was observed in 33% of treated patients. These patients may be candidates for long-term treatment.
Topics: Aged; Almitrine; Carbon Dioxide; Double-Blind Method; Female; Humans; Hypoxia; Male; Middle Aged; Oxygen; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Respiratory System Agents
PubMed: 12915747
DOI: 10.1159/000072009 -
Respiratory Medicine Jun 2003Almitrine bismesylate (AB) is a peripheral chemoreceptor agonist which is believed to improve oxygenation of COPD patients with chronic hypoxaemia, probably by improving... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Almitrine bismesylate (AB) is a peripheral chemoreceptor agonist which is believed to improve oxygenation of COPD patients with chronic hypoxaemia, probably by improving the ventilation perfusion mismatch. We studied the long-term effects of AB in COPD patients with chronic hypoxaemia.
DESIGN
Prospective, randomised, double-blind, placebo-controlled trial.
SETTING
Eight hundred bed teaching hospital with a catchment population of 350,000 inhabitants. PATIENT RECRUITMENT: COPD outpatients consulting between September 95 and September 99.
INCLUSION CRITERIA
(1) COPD (FEV1 < 50%). (2) PaO2 < or = 65 mmHg. (3) Stable arterial blood gases (ABG), spirometry (S) and clinical state.
EXCLUSION CRITERIA
Asthma, restrictive disease, sleep apnoea syndrome, advanced renal or hepatic disease, peripheral neuropathy, use of respiratory stimulants or psychotrophic drugs.
TREATMENT
AB 1 mg/kg/day (weight < 75 kg = 50 mg/day; weight > or = 75 kg = 100 mg/day) in an intermittent schedule with resting periods of 1 month after the third, 6th and 9th months during 1 year.
INSTRUMENTATION
Stabilisation period: S, ABG. Run-in period: S, ABG, 6-min walking test (WT), nocturnal pulse oximetry (NP) and quality of life evaluation (CRQ). Third, 6th and 9th months: S, ABG. End of the study: S, ABG, WT, NP, CRQ.
STATISTICS
ANOVA for repeated measurements.
RESULTS
Two hundred and eighty-nine patients were evaluated and 81 were included in the study. Sixty-six were followed for 6 months, 53 for 9 months and 42 for 1 year. Almitrine and placebo groups did not present significant differences in ABG and S in the 6th, 9th and 12th months. Evolution in WT, NP and CRQ were similar in the two groups. No relevant side-effects were detected: only two patients stopped treatment (one placebo and one AB).
CONCLUSION
In an intermittent schedule, although well tolerated, at doses of 1 mg/kg/day, AB was not effective in long-term treatment of chronic hypoxemia in COPD patients.
Topics: Aged; Almitrine; Analysis of Variance; Carbon Dioxide; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Hypoxia; Male; Oxygen; Partial Pressure; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory System Agents; Vital Capacity
PubMed: 12814142
DOI: 10.1053/rmed.2003.1486 -
Medicina 2003The hypoxemia of acute respiratory distress syndrome (ARDS) depends chiefly upon shunt and ventilation-perfusion (VA/Q) inequality produced by fluid located in the... (Review)
Review
The hypoxemia of acute respiratory distress syndrome (ARDS) depends chiefly upon shunt and ventilation-perfusion (VA/Q) inequality produced by fluid located in the interstitial space, alveolar collapse and flooding. Variables other tham inspired oxygen fraction and the underlying physiological abnormality can influence arterial oxygen partial pressure (PaO2). Changes in cardiac output, hemoglobin concentration, oxygen consumption and alcalosis can cause changes in PaO2 through their influence on mixed venous PO2. Gas exchange (GE) in ARDS may be studied using the inert gas elimination technique (MIGET) which enables to define the distribution of ventilation and perfusion without necessarily altering the FIO2 differentiating shunt from lung units with low VA/Q ratios and dead space from lung units with high VA/Q ratios. Different ventilatory strategies that increase mean airway pressure (positive end-expiratory pressure, high tidal volumes, inverse inspiratory-expiratory ratio, etc) improve PaO2 through increasing lung volume by recruiting new open alveoli and spreading the intra-alveolar fluid over a large surface area. Also prone-position ventilation would result in a marked improvement in GE enhancing dorsal lung ventilation by the effects on the gravitional distribution of pleural pressure and the reduction in the positive pleural pressure that develops in dorsal regions in ARDS. Inhaled nitric oxide (NO) has been shown to increase PaO2 in ARDS patients by inducing vasodilation predominantly in ventilated areas redistributing pulmonary blood flow away from nonventilated toward ventilated areas of the lung thus resulting in a shunt reduction. On the same way inhaled prostaglandins (PGI2 or PGE1) causes selective pulmonary vasodilation improving pulmonary GE. Intravenous almitrine, a selective pulmonary vasoconstrictor, has been shown to increase PaO2 by increasing hypoxic pulmonary vasoconstriction. A synergistic effect was found between inhaled NO and almitrine. In spite of the improval of GE shown by these different techniques on ARDS, no effect was demonstrated on mortality or duration of mechanical ventilation.
Topics: Acute Disease; Humans; Oxygen; Partial Pressure; Pulmonary Gas Exchange; Respiration, Artificial; Respiratory Distress Syndrome
PubMed: 12793087
DOI: No ID Found -
Vascular Pharmacology Nov 2002Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) following sepsis, major trauma and surgery are leading causes of respiratory insufficiency,... (Review)
Review
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) following sepsis, major trauma and surgery are leading causes of respiratory insufficiency, warranting artificial ventilation in the intensive care unit. It is caused by an inflammatory reaction in the lung upon exogenous or endogenous etiologies eliciting proinflammatory factors, and results in increased alveolocapillary permeability and protein-rich alveolar edema. The interstitial and alveolar inflammation and edema alter ventilation perfusion matching, gas exchange and mechanical properties of the lung. The current therapy of the condition is supportive, paying careful attention to fluid balance, relieving the increased work of breathing and improving gas exchange by mechanical ventilation, but in vitro, animal and some clinical research is done to evaluate the value of anti-inflammatory therapies on morbidity and outcome, including inflammatory cell-stabilizing corticosteroids, xanthine derivates, prostanoids and inhibitors, O(2) radical scavenging factors such as N-acetylcysteine, surfactant replacement, vasodilators including inhaled nitric oxide, vasoconstrictors such as almitrine, and others. None of these compounds has been proven to benefit survival in patients, however, even though carrying a physiologic benefit, except perhaps for steroids that may improve outcome in the later stage of ARDS. This partly relates to the difficulty to assess the lung injury at the bedside, to the multifactorial pathogenesis and the severity of comorbidity, adversely affecting survival.
Topics: Animals; Capillary Permeability; Endothelium, Vascular; Humans; Lung; Lung Diseases; Pulmonary Edema; Respiratory Distress Syndrome
PubMed: 12747964
DOI: 10.1016/s1537-1891(03)00013-2 -
Critical Care Medicine Apr 2003Acute respiratory distress syndrome (ARDS) is characterized by a marked maldistribution of pulmonary perfusion in favor of nonventilated, atelectatic areas of the lungs,... (Review)
Review
Acute respiratory distress syndrome (ARDS) is characterized by a marked maldistribution of pulmonary perfusion in favor of nonventilated, atelectatic areas of the lungs, and it is the main cause of pulmonary right-to-left shunting and hypoxemia. Therapeutic interventions to selectively influence pulmonary perfusion in ARDS became feasible with the introduction of inhaled nitric oxide, which provided a means not only to reduce pulmonary hypertension, but also to improve matching of ventilation to perfusion and, thus, hypoxemia. Clinical studies in ARDS subsequently demonstrated that the combination of inhaled nitric oxide with other interventions, such as positive end-expiratory pressure and prone positioning, yielded beneficial and additive effects on arterial oxygenation. Although the available randomized, controlled trials of this novel concept have so far failed to show an improved outcome in ARDS, inhaled nitric oxide is a clinically valuable option for the treatment of severe refractory hypoxemia in ARDS, and largely promoted the concept of selective pulmonary vasodilation in intensive care practice. Currently, aerosolization of various vasodilators, in particular prostaglandins, is under evaluation in models of acute lung injury and human ARDS. Ongoing research aims to augment the effectiveness of vasodilators with specific inhibitors of phosphodiesterases or by combination with intravenous vasoconstrictors. Consequently, several alternative ways to selectively modulate pulmonary vascular tone in patients with ARDS may be available in the near future. Cost-benefit analysis of these therapeutic options will largely determine their future perspective.
Topics: Administration, Inhalation; Adult; Almitrine; Humans; Infant, Newborn; Nitric Oxide; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome; Vasodilator Agents
PubMed: 12682462
DOI: 10.1097/01.CCM.0000057913.45273.1A -
Internal Medicine Journal Dec 2002
Topics: Adult; Almitrine; Humans; Male; Pulmonary Gas Exchange; Respiratory System Agents; Sleep Apnea, Central
PubMed: 12512759
DOI: 10.1046/j.1445-5994.2002.00284.x -
Journal of Applied Physiology... Dec 2002In a porcine model of oleic acid-induced lung injury, the effects of inhaled nitric oxide (iNO) and intravenous almitrine bismesylate (ivALM), which enhances the hypoxic...
In a porcine model of oleic acid-induced lung injury, the effects of inhaled nitric oxide (iNO) and intravenous almitrine bismesylate (ivALM), which enhances the hypoxic pulmonary vasoconstriction on the distribution of regional pulmonary blood flow (PBF), were assessed. After injection of 0.12 ml/kg oleic acid, 20 anesthetized and mechanically ventilated piglets [weight of 25 +/- 2.6 (SD) kg] were randomly divided into four groups: supine position, prone position, and 10 ppm iNO for 40 min followed by 4 microg x kg(-1) x min(-1) ivALM for 40 min in supine position and in prone position. PBF was measured with positron emission tomography and H(2)15O. The redistribution of PBF was studied on a pixel-by-pixel basis. Positron emission tomography scans were performed before and then 120, 160, and 200 min after injury. With prone position alone, although PBF remained prevalent in the dorsal regions it was significantly redistributed toward the ventral regions (P < 0.001). A ventral redistribution of PBF was also obtained with iNO regardless of the position (P = 0.043). Adjunction of ivALM had no further effect on PBF redistribution. PP and iNO have an additive effect on ventral redistribution of PBF.
Topics: Acute Disease; Administration, Inhalation; Almitrine; Animals; Disease Models, Animal; Lung Diseases; Male; Nitric Oxide; Oleic Acid; Prone Position; Pulmonary Circulation; Respiratory Mechanics; Respiratory System Agents; Supine Position; Swine; Tomography, Emission-Computed
PubMed: 12391113
DOI: 10.1152/japplphysiol.00313.2002 -
An investigation into the mechanism of action of almitrine on isolated rat diaphragm muscle fatigue.Respiration; International Review of... 2002Previous studies have shown that almitrine bismesylate, a respiratory stimulant which acts on the mitochondrial electron transport chain, enhances recovery of rat...
BACKGROUND
Previous studies have shown that almitrine bismesylate, a respiratory stimulant which acts on the mitochondrial electron transport chain, enhances recovery of rat diaphragm muscle from fatigue.
OBJECTIVES
Our aim is to investigate if the enhanced recovery is due to an anti-oxidant property of almitrine, since the electron transport chain is a major site of intracellular free radical production.
METHODS
A low-frequency fatigue protocol was used (30 Hz; 250 ms; delivered once every 2 s for 5 min), and the effects of almitrine before and after fatigue onset were compared to those of the anti-oxidant compound N-acetylcysteine (NAC).
RESULTS
Almitrine (6 and 10 microg/ml) given before fatigue gave better recovery rates than postfatigue application. In contrast, NAC (100 microM) application before fatigue onset was not as effective as NAC given immediately after the cessation of the fatigue protocol. However, almitrine (6 microg/ml) completely reversed the reduction in baseline twitch tension brought about by a free-radical-producing mixture of FeCl(3) + ADP (1 mM + 2.5 mM, respectively).
CONCLUSION
The results of this study confirm that almitrine enhances recovery from fatigue and, in contrast to NAC prefatigue application, is more effective. Also, almitrine was shown to have an anti-oxidant effect, but it does not act like a typical anti-oxidant.
Topics: Almitrine; Animals; Diaphragm; In Vitro Techniques; Male; Muscle Fatigue; Rats; Rats, Sprague-Dawley; Respiratory Muscles; Respiratory System Agents
PubMed: 12169748
DOI: 10.1159/000063267 -
American Journal of Respiratory and... May 2002We determined the effects of changing ventilatory stimuli on the hypocapnia-induced apneic and hypopneic thresholds in sleeping dogs. End-tidal carbon dioxide pressure...
We determined the effects of changing ventilatory stimuli on the hypocapnia-induced apneic and hypopneic thresholds in sleeping dogs. End-tidal carbon dioxide pressure (PET(CO2)) was gradually reduced during non-rapid eye movement sleep by increasing tidal volume with pressure support mechanical ventilation, causing a reduction in diaphragm electromyogram amplitude until apnea/periodic breathing occurred. We used the reduction in PET(CO2) below spontaneous breathing required to produce apnea (DeltaPET(CO2)) as an index of the susceptibility to apnea. DeltaPET(CO2) was -5 mm Hg in control animals and changed in proportion to background ventilatory drive, increasing with metabolic acidosis (-6.7 mm Hg) and nonhypoxic peripheral chemoreceptor stimulation (almitrine; -5.9 mm Hg) and decreasing with metabolic alkalosis (-3.7 mm Hg). Hypoxia was the exception; DeltaPET(CO2) narrowed (-4.1 mm Hg) despite the accompanying hyperventilation. Thus, hyperventilation and hypocapnia, per se, widened the DeltaPET(CO2) thereby protecting against apnea and hypopnea, whereas reduced ventilatory drive and hypoventilation narrowed the DeltaPET(CO2) and increased the susceptibility to apnea. Hypoxia sensitized the ventilatory responsiveness to CO2 below eupnea and narrowed the DeltaPET(CO2); this effect of hypoxia was not attributable to an imbalance between peripheral and central chemoreceptor stimulation, per se. We conclude that the DeltaPET(CO2) and the ventilatory sensitivity to CO2 between eupnea and the apneic threshold are changeable in the face of variations in the magnitude, direction, and/or type of ventilatory stimulus, thereby altering the susceptibility for apnea, hypopnea, and periodic breathing in sleep.
Topics: Acidosis, Respiratory; Alkalosis, Respiratory; Analysis of Variance; Animals; Carbon Dioxide; Chemoreceptor Cells; Disease Susceptibility; Dogs; Female; Hyperventilation; Hypocapnia; Hypoventilation; Hypoxia; Partial Pressure; Polysomnography; Positive-Pressure Respiration; Sleep Apnea, Central; Tidal Volume
PubMed: 11991874
DOI: 10.1164/rccm.2110041 -
Presse Medicale (Paris, France : 1983) Mar 2002Recent neurobiological data has led to renewed interest in oxygen (O2). The discovery of neuroglobin, protein varyingly present in the brain, has been enhanced by the...
Recent neurobiological data has led to renewed interest in oxygen (O2). The discovery of neuroglobin, protein varyingly present in the brain, has been enhanced by the elucidation of the mechanisms through which oxygen intervenes in neuronal metabolism. Almitrine/raubasine activates the metabolism of hypoxic/ischemic neurones by increasing O2 bioavailability. This mechanism supports the effects on behaviour obtained in various animal models and the benefits observed during clinical trials in elderly patients presenting with cognitive defects.
Topics: Aged; Almitrine; Alzheimer Disease; Animals; Brain; Brain Ischemia; Energy Metabolism; Humans; Neurons; Nootropic Agents; Oxygen Consumption; Secologanin Tryptamine Alkaloids; Yohimbine
PubMed: 11984975
DOI: No ID Found