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PubMed1992

Effects of almitrine on the release of catecholamines from the rabbit carotid body in vitro.

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.

Almitrine↗
PubMed1991

Oral almitrine in treatment of acute respiratory failure and cor pulmonale in patients with an exacerbation of chronic obstructive airways disease.

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.

Administration, Oral↗
PubMed1987

Inhibitory effect of almitrine on dopaminergic activity of rat carotid body.

Almitrine increases ventilation by stimulating the peripheral arterial chemoreceptors. This study assessed the effects of acute and chronic almitrine treatments on the dopamine (DA) and norepinephrine (NE) contents and utilization rates in the rat carotid body. Almitrine (5 mg/kg ip) caused a 34% reduction in DA content after 30 min. Extending the almitrine treatment for 15 days (one daily ip injection) produced a further progressive diminution in DA stores (-55%; P less than 0.01). The utilization rate of DA measured after inhibiting catecholamine biosynthesis by alpha-methyl-p-tyrosine was strongly reduced by almitrine (-98% after 15 days; P less than 0.01). The effects of almitrine were dose dependent. The noradrenergic activity was much less altered by the drug. The data showed that almitrine can modify the dynamics of DA in rat carotid body producing a decrease in both content and utilization rate.

Almitrine↗
PubMed2002

An investigation into the mechanism of action of almitrine on isolated rat diaphragm muscle fatigue.

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.

Almitrine↗
PubMed1985

Almitrine increases the steady-state hypoxic ventilatory response in hypoxic chronic air-flow obstruction.

Almitrine, a peripheral chemoreceptor agonist, exerts beneficial effects on blood gases in patients with hypoxic chronic air-flow obstruction, but as these patients exhibit poor ventilatory responses to hypoxia, the mechanism for this improvement is not clear. The effect of a 100-mg dose of almitrine given orally on ventilation and the steady-state hypoxic ventilatory response (HVR) were measured in a randomized, double-blind, placebo-controlled manner in 7 patients with severe hypoxic chronic air-flow obstruction. The isocapnic HVR (delta VE/delta SaO2) was calculated from the changes in ventilation and SaO2 from breathing 60% O2 to breathing air with the addition of CO2 to maintain isocapnia (as estimated from a transcutaneous CO2 electrode). Resting ventilation while breathing air and isocapnic HVR were measured before and 3 h after almitrine or placebo. Almitrine caused no significant change in resting ventilation. There was, however, a large increase in HVR after almitrine (almitrine: -1.5 L/min/%SaO2; range, -0.5 to -3.1; control: -0.4; range, -0.3 to -1.3), but no change after placebo. Almitrine is a powerful stimulant of chemosensitivity and of the hypoxic ventilatory response in chronic hypoxemia, with potential benefit to patients with chronic air-flow obstruction in respiratory failure.

Aged↗
PubMed2004

Treatment of hypoxemia during one-lung ventilation using intravenous almitrine.

UNLABELLED: We performed this prospective randomized double-blinded study to assess the ability of almitrine to treat hypoxemia during one-lung ventilation (OLV). Twenty-eight patients were anesthetized with propofol, sufentanil, and atracurium; lung separation was achieved with a double-lumen tube. A transesophageal Doppler probe was inserted to evaluate cardiac index. If SpO(2) was equal to or decreased to <95% during OLV (inspired fraction of oxygen of 0.6), patients were included in the study and received a placebo or almitrine (12 microg x kg(-1) x min(-1) for 10 min followed by 4 microg x kg(-1) x min(-1)) infusion until SpO(2) reached 90% or decreased to <90% (exclusion from the study). Eighteen of the 28 patients were included and received either almitrine (n = 9) or a placebo (n = 9). Treatment was discontinued in 1 patient in the almitrine group and 6 in the placebo group (P < 0.05). Treatment was successful (SpO(2) remaining >or=95% during OLV) in 8 patients in the almitrine group and 1 in the placebo group (P < 0.01). Heart rate, arterial blood pressure, and cardiac index did not change throughout the study, but we could obtain an adequate aortic blood flow signal in only half of the patients. Almitrine could be used to treat hypoxemia during OLV. IMPLICATIONS: IV almitrine improves oxygenation during one-lung ventilation without hemodynamic modification. Such treatment could be used when conventional ventilatory strategy fails to treat hypoxemia or cannot be used.

Adolescent↗
PubMed1991

Comparison of the effects of intravenous almitrine and positive end-expiratory pressure on pulmonary gas exchange in adult respiratory distress syndrome.

The effects of almitrine on pulmonary gas exchange and haemodynamics were compared to those of positive end-expiratory pressure (PEEP) in 10 patients with a severe adult respiratory distress syndrome (ARDS) who required continuous mechanical ventilation. Haemodynamic and gas exchange measurements were made before and after 30 min of PEEP at a level of 10 cmH2O, then 30 min later, before and at the end of the intravenous infusion of almitrine at a dose of 0.25 mg.kg-1 in 30 min. There was no significant difference between baseline gas exchange and haemodynamic parameters. PEEP and almitrine increased Pao (p = 0.001) from 10.9 to 12.6 kPa and from 10.6 to 12.6 kPa (1 kPa = 7.5 mmHg), respectively, and ratio of venous admixture to total blood flow (Qs/Qt) decreased (p less than 0.001) from 34 to 29% and from 33 to 29%, respectively, the effects of PEEP and almitrine being not significantly different. Neither PEEP nor almitrine caused a significant change in arterial carbon dioxide tension (PaCO2). The haemodynamic parameters did not change significantly with almitrine, whereas mean systemic arterial pressure decreased from 85.4 to 81.1 mmHg (p less than 0.05) with PEEP. These results are consistent with the hypothesis that both treatments improve ventilation/perfusion (VA/Q) distributions, by an increase in functional residual capacity in the case of PEEP and a redistribution of pulmonary perfusion in the case of almitrine.

Adult↗
PubMed1990

The effect of almitrine on the steady-state ventilatory response to carbon dioxide at rest and during exercise in man.

Almitrine has potential as a tool for testing the physiological role of the peripheral chemoreceptor. The effects of almitrine on CO2 chemosensitivity were studied at rest and during light exercise using a constant inflow technique that avoids the hyperoxia of rebreathing methods. The steady-state ventilatory response to CO2 was measured in two groups of six normal men before and 150 min after 100 mg oral almitrine bismesylate or placebo. One group was studied at rest, the other while pedalling at 50 W. The resting group showed a significant increase in CO2 response slope after almitrine when compared with placebo but there was no significant change in the response intercept. During exercise the individual results were very variable and after almitrine no significant change was seen in either the response slope or intercept. Control ventilation was not affected by almitrine in either group. Even in the absence of marked hyperoxia the effect of almitrine on CO2 sensitivity at rest in small. The lack of effect at 50 W is against any important role for the peripheral chemoreceptor during light exercise but other interpretations are possible.

Adult↗
PubMed1985

[Almitrine bismesylate and ventilation-perfusion ratios].

Almitrine bismesilate (Vectarion) is characterised by its specific activity on carotid and aortic chemoreceptors. A simultaneous study of the ventilatory and blood gas changes in the anaesthetised dog has shown a dissociation between these two effects. At a dose of 10 to 30 micrograms/kg IV Almitrine bismesilate induces a significant rise in the PaO2 whereas no change in the ventilatory output is observed. A significant transitory rise in the pulmonary arterial pressure also appears at these doses. The juxta position of these results suggests that a feeble doses Almitrine bismesilate improves the blood gases of the arterial blood by a re-distribution of the pulmonary blood flow. Clinical pharmacological studies carried out in bronchitic patients have shown an improvement in the distribution of ventilation perfusion ratios VA/Q by Almitrine bismesilate. These experiments were carried out in animals in order to determine whether the drug had a preferential action on one or other side of the VA/Q ratio. Whereas in an animal with intact lungs, Almitrine bismesilate potentiates hypoxia induced vaso-constriction, in animals whose lungs are ventilated in a heterozygous fashion in such a way as to reproduce zones with a shunt effect, the potentiation of hypoxic vasoconstriction was not again found. At low doses in the hypoxic rat Almitrine bismesilate increases alveolar ventilation (VH) by a significant rise in tidal volume and inspiratory output (VT/TI) without increasing external ventilation. Overall the rise of PaO2 induced by Almitrine bismesilate at low doses may be accompanied by a similar effect on the pulmonary circulation noted in the anaesthetised dog. In the hypoxic rat, it is changes in the alveolar ventilation that are observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Almitrine↗
PubMed1986

Long term studies on almitrine bismesylate in COPD patients.

Almitrine bismesylate is a chemoreceptor agonist which has been shown to improve arterial blood gas values in chronic obstructive pulmonary disease (COPD) patients, possibly through better ventilation/perfusion matching. On these basis, long term studies were undertaken to evaluate the therapeutic activity of almitrine bismesylate in COPD. We report here the overall results of 4 studies: a 6 months double blind placebo controlled study on clinical and biochemical data in 200 patients. a 12 months double blind placebo controlled study on clinical and hemodynamic data in 15 patients. a 12 months open study on clinical and biochemical data in 108 patients. a 52 months follow-up including therapeutic gap in 8 patients. Almitrine bismesylate group showed significant improvement of PaO2 and PaCO2 levels as compared with placebo group; this was found after 6 months of treatment and persisted after 12 months of treatment. 75% of almitrine treated patients were considered as responders, i.e. improved PaO2 and PaCO2 levels by at least 5 mmHg (0.665 KPa). Almitrine bismesylate groups showed significantly decreased dyspnea scores, received significantly less hospital care for acute decompensation or pulmonary infection and showed no significant change in hemodynamic parameters. After 20 months treatment interruption, patients showed progressively impairmed blood gas levels. Almitrine bismesylate ws well tolerated; nausea was occasionally observed and usually disappeared. Paresthesia was observed in some patients with identified predisposition. Altogether, these studies showed long term efficacy and acceptability of almitrine bismesylate in COPD patients with chronic respiratory failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Almitrine↗
PubMed1998

[Almitrine in therapy of chronic obstructive respiratory tract diseases with hypoxemia--a clinical multicenter study comparing 2 dosages].

In an 8-month prospective, placebo-controlled multi-centre trial involving 64 hypoxaemic COPD patients (mean +/- SD age, 64 +/- 8 years, paO2, 57 +/- 7 mmHg, paCO2, 41 +/- 6 mmHg), we compared the efficacy and acceptability of two different dosages of almitrine, 75 and 100 mg. 21 patients received continuous treatment with almitrine (75 mg), 23 sequential treatment (100 mg, one month of placebo after three months treatment), and 20 were in the placebo group. As defined by the inclusion criteria, none of the patients had clinical or subclinical signs of peripheral neuropathy. Clinical examinations, blood gas analyses and determinations of plasma almitrine levels were performed monthly. Patients underwent spirometry and detailed neurological examination upon entry and at the end of the trial. The percentage of drop-outs was considerably higher among patients under medication (59%) as compared to placebo (10%, p < 0.001) which was particularly due to impaired compliance in the almitrine groups. Comparing arterial paO2 or paCO2 over time by analysis of variance, there was no significant effect of medication on blood gases. However, in patients receiving 100 mg almitrine daily, paO2 was significantly increased vs. placebo after four and six months of treatment, and in patients receiving 75 mg almitrine, mean paCO2 was significantly lowered vs. placebo after four months of medication (t-test, p < 0.05). Neurological findings did not differ between treatments and over time. In conclusion, only certain individual patients may benefit from a treatment with 100 mg almitrine whereas the effect of the 75 mg dosage on paO2 did not differ from placebo.

Aged↗
PubMed1989

Almitrine bismesylate disposition in the human digestive tract.

The absorption of almitrine from the upper gastrointestinal tract has been evaluated in 6 healthy volunteers by an intubation technique. Almitrine bismesylate dissolved in malic acid was introduced into the stomach after homogenization with a meal containing the marker 14C-polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was infused into the second part of duodenum throughout the experiment. Samples of the luminal content were collected every 15 min for four hours from the stomach and at the ligament of Treitz. Blood was also collected. Almitrine was neither absorbed from nor metabolized in the stomach. About 37% of the quantity of drug emptied from the stomach was absorbed from the duodenum. Almitrine was detected in plasma 50 min after ingestion of the meal and its plasma concentration-time profile reflected the cumulative gastric emptying rate. The metabolite tetrahydroxy almitrine was found in intestinal samples as soon as unchanged drug was detected in plasma. The intraluminal rate of formation of the metabolite increased with time. The results suggest hepatic metabolism of almitrine followed by rapid excretion of the metabolite in the bile.

Adult↗
PubMed1988

Long-term effects of almitrine bismesylate on oxygenation during wakefulness and sleep in chronic obstructive pulmonary disease.

Hypoxemia in patients with chronic obstructive pulmonary disease (COPD) becomes more pronounced during sleep and can result in a number of serious consequences. Almitrine bismesylate is a peripheral chemoreceptor agonist that improves arterial oxygen tension (PaO2) in patients with COPD during wakefulness. Studies conducted for up to six months suggested the agonist may be useful in the management of nocturnal hypoxemia. In this double-blind, parallel, placebo-controlled study, patients with COPD received 50 mg of almitrine bismesylate (n = 9) or placebo (n = 11) twice a day for one year. Almitrine bismesylate increased PaO2 by 8.1 +/- 2.1 mm Hg (mean +/- SEM), decreased arterial carbon dioxide tension by 3.0 +/- 0.7 mm Hg (mean +/- SEM), and increased minute ventilation by 3.1 +/- 0.5 liters/minute (mean +/- SEM) during wakefulness. All of these changes were statistically significant. Five patients in the almitrine bismesylate group and eight patients in the placebo group completed sleep studies prior to and after 56, 180, and 360 days of almitrine bismesylate or placebo administration. Relative to placebo, almitrine bismesylate significantly increased oxygen saturation during sleep without any significant changes in the quantity or quality of sleep.

Adult↗
PubMed1990

Flux-dependent increase in the stoichiometry of charge translocation by mitochondrial ATPase/ATP synthase induced by almitrine.

After studying the effects of almitrine, a new kind of ATPase/ATP synthase inhibitor, on two kinds of isolated mammalian mitochondrion, we have observed that: (1) Almitrine inhibits oligomycin-sensitive ATPase; it decreases the ATP/O value of oxidative phosphorylations without any change in the magnitude of delta mu H+. (2) Almitrine increases the mechanistic H+/ATP stoichiometry of ATPase as shown by measuring either (i) the extent of potassium acetate and of potassium phosphate accumulation sustained by ATP utilisation, or (ii) the electrical charge/ATP (K+/ATP) ratio at steady-state of ATPase activity. (3) Rat liver mitochondria are at least 10-times more sensitive to almitrine than beef heart mitochondria. (4) The change in H+/ATP stoichiometry induced by almitrine depends on the magnitude of the flux through ATPase. The inhibitory effect of almitrine on ATPase/ATP synthase complex, as a consequence of such an H+/ATP stoichiometry change, is discussed.

Acetates↗
PubMed1989

Ganglioglomerular nerves influence responsiveness of cat carotid body chemoreceptors to almitrine.

A bolus injection of almitrine bismesylate (0.5 mg.kg-1 i.v.) in anaesthetised artificially ventilated cats caused a significantly greater increase in carotid chemosensory discharge in animals with sectioned ipsilateral ganglioglomerular sympathetic nerves in comparison with a group in which these nerves were intact. Plasma levels of almitrine were similar in both groups. Responses to hypoxia and hypercapnia post-almitrine were also bigger if the ganglioglomerular nerves were cut. Domperidone (10-50 micrograms.kg-1 i.a), a dopamine D2 receptor antagonist, greatly increaed the responsiveness of chemoreceptors to almitrine in ganglioglomerular nerve-intact preparations. Almitrine-induced chemosensory activity was unaffected by illuminating the carotid bifurcation with light from a fibre optic lamp, regardless of whether or not the ganglioglomerular nerves were cut. It is concluded that almitrine may directly or indirectly activate an efferent pathway in the ganglioglomerular nerves to cause depression of chemoreceptor activity, possibly by releasing dopamine to act at D2 dopamine receptors in the carotid body.

Action Potentials↗
PubMed1993

Haemodynamics and gas exchange in liver cirrhosis: the effect of orally administered almitrine bismesylate.

The present study was conducted to analyse the effect on haemodynamics and to evaluate the role of hypoxic pulmonary vasoconstriction (HPV) in cirrhotic patients with hypoxaemia using almitrine bismesylate, an agent which increases the response of HPV. Six male patients, mean age of 51 years, with hepatic cirrhosis and associated hypoxaemia were studied. All patients had normal lung and cardiac function tests. When the patients were clinically stable, right heart and radial artery catheterization were performed. Data from the pulmonary artery catheter and blood gases were obtained before and after 4 days of oral almitrine bismesylate. The results indicated that these cirrhotics were in a mild hyperdynamic circulatory state. The cardiac output (CO), cardiac index (CI), oxygen delivery (DO2), and oxygen consumption (VO2) were elevated while the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) were low. Almitrine significantly increased PVR (P < 0.05) and mean pulmonary artery pressure (mPAP) (P < 0.01). In addition, almitrine improved alveolar arterial oxygen content difference [D(A-a)O2] (P < 0.01) and shunt fraction (Qva/QT) (P < 0.01). The PaCO2 and PaO2 increased slightly but this was not statistically significant. In conclusion, in our group of patients with hepatic cirrhosis, four days of treatment with almitrine improved their gas exchange. The data suggest a weak HPV response in this group of cirrhotics; that response may be enhanced by almitrine.

Administration, Oral↗
PubMed2001

Effect of almitrine on upper airway muscle contraction in young and old rats.

The effects of almitrine on the contractile properties of isolated geniohyoid and sternohyoid muscles were determined in physiological salt solution at 30 degrees C in young and old rats. In young rats, almitrine had no effect on twitch or tetanic tension, twitch:tetanic tension ratio, contractile kinetics, active or passive tension-length relationships or frequency-tension relationship in both muscles. Almitrine significantly increased resistance to fatigue in both muscles. In old rats, almitrine had no effect on twitch or tetanic tension, twitch:tetanic tension ratio, contractile kinetics, active or passive tension-length relationships, frequency-tension relationship or fatigue in both muscles. These results show that almitrine, in both young and old rats, has no effect on most of the contractile properties of isolated geniohyoid and sternohyoid muscles. However, almitrine increases resistance to fatigue in both muscles in young but not in old rats.

Age Factors↗
PubMed1984

Oxygen drive to breathing during halothane anesthesia: effects of almitrine bismesilate.

The changes in ventilation and breathing pattern induced by the substitution of pure oxygen for room air were tested in patients during stable halothane anesthesia before and after the administration of almitrine bismesilate, a specific stimulant of the peripheral chemoreceptors. Ventilation was monitored in 25 patients for 15 min while breathing an air-halothane (1.5%) mixture and while breathing then for 10 min an O2-halothane (1.5%) mixture. The maneuver was repeated in 11 of these patients after the infusion of 0.5 mg/kg of almitrine bismesilate. Before almitrine administration, O2 inhalation caused a progressive decrease of minute-ventilation (VE) reaching 94.5 +/- 1.4% (mean +/- SEM) of the initial value at the tenth minute (P less than 0.01). This decrease was secondary to a progressive increase of inspiratory and expiratory times. Almitrine bismesilate caused a significant increase in VE (+11.6%), tidal volume (+14.0%), and mean inspiratory flow (+10.0%) when breathing the air-halothane mixture. Ten minutes after O2 administration, these variables were not different from those observed before almitrine infusion. This study shows that during halothane anesthesia, hypoxic ventilatory drive is not abolished but is depressed severely. Almitrine bismesilate can restore the hypoxic ventilatory drive.

Adult↗