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A single orally administered dose of almitrine improves pulmonary gas exchange during exercise in patients with chronic air-flow obstruction.

To verify if the improvement in gas exchange observed at rest with almitrine in patients with chronic air-flow obstruction is maintained at exercise, we studied 10 patients on a randomized, crossover, double-blind exercise protocol. After assessment of steady state of their disease, patients with FEV 1 less than 1.5 L.s-1 and PaCO2 less than 70 mmHg cycled 8 to 11 min at 80% of their previously determined maximal O2 uptake. Blood gases, arterial lactate (La), expired ventilation, (VE), O2 uptake (Vo2), Co2 production (VCO2), heart rate (HR), and arterial blood pressure (BP) were measured at rest, at mid-exercise, at end-exercise, and at 2, 14, 15, and 35 min of recovery. We found that at all stages of the study PaO2 was significantly higher in those who had received almitrine than in those who had received placebo; the mean increment was 11.9 torr at rest, 8.9 at end-exercise, and 13.7 at 15 min of recovery. Changes in PaCO2 and arterial (H+) were the opposite of those in PaO2; at end-exercise PaCO2 was 5.9 torr lower in those who had received almitrine, and pH was 7.36 versus 7.32 in those who had received placebo. No significant difference was found at all stages of the study between drug and placebo with respect to VE, VO2, VCO2, HR, and BP. But the ventilatory equivalent for oxygen, VE/VO2, was slightly higher in those who had received almitrine than in those who had received placebo during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Almitrine bismesylate.

Almitrine bismesylate is a pharmacologically unique respiratory stimulant. It enhances respiration after both acute and chronic administration by acting as an agonist of peripheral chemoreceptors located on the carotid bodies. In comparison with traditional central-acting respiratory stimulants, almitrine has advantages of oral activity, prolonged duration of effect, and an improved adverse effect profile. Almitrine is generally well tolerated, with headache and minor gastrointestinal disturbances being the most frequently observed side effects. This investigational agent has been shown to increase arterial oxygen tension while decreasing arterial carbon dioxide tension in patients with chronic obstructive pulmonary disease both at rest and during exercise through increased ventilation and improved ventilation/perfusion matching. It may also prove useful in the treatment of nocturnal oxygen desaturation because of its ability to reduce the frequency and severity of nocturnal hypoxemia without impairing the quality of sleep. Additional research is needed to further define the role of almitrine in the relief of hypoxemia.

Adult↗

Almitrine decreases the distensibility of the large pulmonary arteries in man.

Almitrine improves blood gas values in patients with COPD, primarily through better ventilation-perfusion matching. The improvement comes largely from a vasomotor effect of the drug. The vasomotor mechanism is unknown. We suspected that decreased distensibility of the large pulmonary arteries was one probable effect of the drug. If present, reduced distensibility would explain many of the hemodynamic alterations produced by almitrine. To test this idea, we measured the diameter of the right pulmonary artery during systole and diastole both before and after almitrine administration in nine patients who were undergoing pulmonary cineangiography. Our calculations of the distensibility of the right pulmonary artery showed that almitrine caused a 60 percent decrease. This significant alteration in the stiffness of the large pulmonary arteries can account for the rise in systolic pressure, a change that would be expected to redistribute pulmonary blood flow upwards and thereby improve ventilation-perfusion balance.

Adult↗

[Effect of almitrine in acute canine lung injury induced by paraquat].

The effects of intravenously administered almitrine (0.3 or 1.0 micrograms/kg/min, for 30 min) on hemodynamics and pulmonary gas exchange were assessed in eight dogs with acute lung injury induced by paraquat under controlled ventilation. Arterial blood gases, pulmonary and systemic hemodynamics, and ventilation-perfusion distribution (VA/Q) using the multiple inert gas elimination technique were examined before (control) and during infusion of almitrine. Almitrine produced significant increases in mean pulmonary arterial pressure from 17.4 +/- 3.3 (control, mean +/- SD) to 20.4 +/- 1.5 mmHg (1.0 micrograms/kg/min), and in total pulmonary vascular resistance. There was no change in other hemodynamic parameters, arterial gas tensions, or VA/Q distribution. These results indicate that almitrine causes pulmonary vasoconstriction without changing ventilation-perfusion distribution in dogs with paraquat-induced lung injury.

Acute Disease↗

Natriuresis secondary to carotid chemoreceptor stimulation with almitrine bismesylate in the rat: the effect on kidney function and the response to renal denervation and deficiency of antidiuretic hormone.

Almitrine bismesylate simulates the effects of arterial hypoxia in producing a specific and long-lasting excitation of the peripheral arterial chemoreceptors. Previous work has shown that almitrine produces a diuresis and natriuresis when given intravenously to anaesthetised rats in a stable mannitol induced diuresis. This response is abolished by glossopharyngeal nerve section implying that it is afferently mediated via the carotid body chemoreceptors. We have studied further the efferent limb of this response. The diuresis and natriuresis occurs without significant detectable changes in effective renal plasma flow and glomerular filtration rate suggesting that it is produced mainly by inhibition of renal tubular sodium and water reabsorption. Almitrine produces a diuresis and natriuresis in rats after bilateral nephrectomy and transplantation of a kidney from a donor rat. This effect is not therefore efferently mediated by the renal nerves and probably involves a humoral agent. Almitrine produces a diuresis and natriuresis in rats after bilateral adrenalectomy and in rats with congenital hypothalamic diabetes insipidus indicating that neither adrenal hormones nor changes in antidiuretic hormone levels are implicated.

Almitrine↗

Two years treatment with almitrine bismesylate in patients with hypoxic chronic obstructive airways disease.

Eighty nine patients with hypoxic chronic obstructive airways disease (COAD) were enrolled into the 1 year Vectarion International Multicentre Study-VIMS in 4 centres, Sheffield (UK), and Antwerp, Liege and Namur (Belgium). At the end of the year the remainder were invited to continue taking placebo or almitrine bismesylate (100-200 mg daily) in the same double blind manner for a further 12 months. In the almitrine treated patients mean arterial oxygen tension (Pao2) at the end of the treatment period improved from 7.5 (0.5) kPa to 8.2 (1.3) kPa (p less than 0.01) and arterial carbon dioxide tension (Paco2) fell from 6.1 (0.8) kPa to 5.8 (0.9) kPa (p less than 0.01). Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and measurements of breathlessness were unchanged. In the placebo treated group changes in the above variables were not significant. Twenty nine patients withdrew from the almitrine group with seven deaths and six cases of peripheral neuropathy, and 22 patients withdrew from the placebo group with six deaths and two cases of peripheral neuropathy. Death rates between the groups were not significantly different. In conclusion, 2 yrs of almitrine treatment (100-200 mg daily) leads to a persistent slight improvement in PaO2 and PaCO2 but no benefit in survival was demonstrated. Patients in this study had a high incidence of drug related side-effects. Lower dose schedules should be investigated.

Almitrine↗

[Long-term therapy with almitrine dimesilate has no effect on pulmonary hemodynamics at rest and during stress].

A 6-month double-blind study was conducted in 26 patients suffering from a severe obstructive disturbance of ventilation and respiratory insufficiency to find out the behaviour of blood gases and pulmonary haemodynamics under Almitrin treatment compared with placebo. The acute administration of 75 mg Almitrin resulted in a significant increase of PaO2 by 11.7 mmHg, as well as of PAPR by 4.4 mmHg. Statistical significance was seen only for the systolic pressure of the a. pulmonalis. After subsequent 6-month treatment with 3 x 25 mg Almitrin, a significantly higher PaO2 is seen at T6 than in the control group. Another additional administration of 75 mg Almitrin results in a further increase of PaO2 by 7.7 mmHg. At T6 the behaviour of pulmonary haemodynamics is identical in both groups A and P.

Almitrine↗

Effect of hypobaric hypoxia and almitrine on voluntary salt and water intake in carotid body denervated spontaneously hypertensive rats.

The effect of moderate hypobaric hypoxia and almitrine bismesylate (almitrine) on salt and water intake was investigated in carotid body denervated (CBD) and sham-operated (SO) spontaneously hypertensive rats (SHR). The animals were kept singly in metabolic cages and given free access to food, water and a 2.5% NaCl-solution. Oral administration of almitrine and exposure to hypobaric hypoxia for five days evoked a suppression of voluntary salt intake in SO-SHR, but not in CBD-SHR. Exposure of SO and CBD-SHR to hypobaric hypoxia resulted in a significant decrease in water intake in animals of both groups on the first day of hypoxia. Stimulation of the arterial chemoreceptors by almitrine induced no change in water intake similar to that evoked by hypobaric hypoxia. These results prove that stimulation of the arterial chemoreceptors has a direct effect on salt appetite but not on water intake in SHR.

Almitrine↗

[Double-blind study on the action of almitrine in patients with polycythemia of high altitude].

Chronic polycythaemia in people living at high altitude is associated with hypoxaemia due to a marked reduction in hypoxic and hypercapnic drives. The effect of almitrine, a chemoreceptor stimulant, was evaluated in 40 patients, with haematocrit values over 57%, living in La Pa2 (3,600-4,000 m). Two studies were carried out. The aim of the first was to assess the ventilatory response, and the increase in PaO2 due to almitrine in a double blind, placebo controlled protocol including 40 patients (mean haematocrit 66.8%). Almitrine was given orally at a dose of 3 mg X kg-1. Variance analysis showed that three hours later there was a significant increase in PaO2 (+0.46 kPa), pH and respiratory frequency, with a significant reduction in PaCO2 (-0.4 kPa). The increase in ventilation (+17%) was not significant. The aim of the second study was to assess the effect of almitrine on the polycythaemia. It was given orally at a dose of 1.5 mg X kg-1 X day-1 to twelve patients over a four week period. Blood gases, ventilation (VE), oxygen consumption (VO2), carbon dioxide, production (VCO2) and haematocrit were measured every week. There was a slight but significant reduction in haematocrit (-3.5%). PaO2 and all the other measured parameters (VE, PaCO2, pH, VO2 VCO2) remained constant. The reduction in haematocrit was not therefore due to an increase in diurnal PaO2 but is perhaps due to the improvement in pulmonary ventilation during sleep.

Adult↗

[Autohistoradiographic study of the pulmonary retention of almitrine bismesylate].

The histo-autoradiographic distribution of labelled Almitrine was quantitatively assessed on semi-fine cuts of rat lung. The experimental set-up consisted of an isolated heart-lung preparation, perfused for two hours with homologous blood containing 10 microCi per ml of H3 almitrine (990 mCi/mM) et 0.1 microCi per ml of C14 almitrine (9.9 mCi/MM). Sequential histological biopsies were made. There was an apparent heterogeneous radioactivity of the tissues overall with no observed increase in fixation with perfusion time (v.i.). Nevertheless the auto-radiograph enabled this conclusion to be rectified by revealing the cause of the heterogeneity, the embolisation of micro-aggregates of the labelled product. After correction was made for this factor the scattering of the fixed radioactivity in the samples was weak. The localisation of the labelled product showed a good stability for the fixed marker in the tissues, and identified the distribution of the tracers H3 and C14, a preferential fixation by alveolar macrophages, type-2 pneumocytes, Clara cells and adipocytes. A remarkable fixation was noted in the cardiac fibres of the pulmonary veins. Amongst the cells of the bronchi, the mucus cells were notably active for the fixation of Almitrine. There was no detectable fixation associated with the nervous tissues and the neuro-epithelial body was not labelled. A sequential analysis showed that only fixation in smooth muscle fibres rose significantly with perfusion time.

Almitrine↗

[Microfluorimetric study of the effect of almitrine bismesylate (Vectarion) on intrapulmonary neuroepithelial bodies].

As Almitrine bismesylate is a potent peripheral chemo-receptor stimulant we have studied its action, after intra-peritoneal injection, on the intra-neuro-epithelial bodies (NEB) of 24 young rabbits (4 to 17 days old) measuring the intensity of the cytoplasmic fluorescence. The administration of Almitrine bismesylate in pharmacological doses provoked a marked rise (around 25%) in the intensity of fluorescence of NEB compared to a placebo group, indicating a raised cytoplasmic concentration of serotonin. These observations show that Almitrine bismesylate, in stimulating all the peripheral chemo-receptors equally, influences the NEB at the same time corroborating the intra-pulmonary chemoreceptor mature of the latter. The mechanism of action of Almitrine bismesylate on the NEB remains unexplained at a cellular level. Some supplementary studies are planned to elucidate these aspects.

Almitrine↗

Effect of almitrine on renal sodium excretion in chemoreceptor denervated spontaneously hypertensive rats.

The effect of almitrine on urinary sodium excretion was investigated in conscious carotid body-, sino-aortic- and sham-denervated SHR. The animals were kept singly in metabolic cages and had free access to food and tap water. Oral application of almitrine (0.5 mg/kg bwt) during five days induced a twofold natriuresis in sham-operated rats. The first natriuretic response on the fourth day of almitrine treatment was observed in animals of all groups indicating that this effect is not chemoreceptor mediated. The second natriuresis seen on the sixth day of the post-treatment period in both sino-aortic and sham-operated SHR but not in the carotid-body denervated rats does not permit clear conclusions to be drawn. We tend to assume that the natriuretic action of almitrine is not chemoreceptor mediated in conscious SHR.

Almitrine↗

Renal hemodynamics and excretory function of healthy young men during stimulation of their peripheral arterial chemoreceptors by almitrine bismesylate.

Renal hemodynamics and excretory function were studied using clearance-techniques in 13 healthy, normotensive, normoxic young men undergoing moderate osmotic diuresis. Each subject was measured in two experiments both lasting from 7:30 a.m. to 6:00 p.m. In one of them 50 mg almitrine bismesylate (Vectarion) was ingested at 12:00 o'clock, whereas the other test served as control. There were only negligible changes of the parameters measured in the control experiments. Immediately after ingestion of the drug a renal vasodilation occurred, but 2-3 h later renal hemodynamic resistance tended to increase. Urinary sodium excretion rose after administration of almitrine. Initially this increase seemed to be caused by the kidney vasodilation but between the 3rd and 6th hour after giving the agent a natriuresis occurred that resulted from inhibition of renal tubular sodium reabsorption. The maximum of this renal tubular response was apparently not reached at the end of the experiments, i.e. 6 h after oral administration of the drug. Almitrine did not increase the renal potassium excretion. The data indicate that pharmacological stimulation of the peripheral arterial chemoreceptors by almitrine bismesylate in normoxic healthy humans causes reflectorically a slight renal vasoconstriction and a long-lasting inhibition of renal tubular sodium reabsorption. These findings are in good agreement with previously published data obtained in animal experiments.

Adult↗

Plasma vasopressin levels in healthy young men in response to stimulation of the peripheral arterial chemoreceptors by almitrine bismesylate.

The plasma arginine vasopressin (AVP) concentration, the plasma osmolality as well as the systemic arterial blood pressure, the heart rate, and the minute ventilation were determined in four healthy, normotensive, normoxic young men undergoing moderate osmotic diuresis. Each subject was measured in two experiments, both lasting from 7:30 a.m. to 6:00 p.m.. In one of them they obtained 50 mg almitrine bismesylate (Vectarion) at 12:00 o'clock, whereas the other test served as control experiment. There were only negligible changes of the parameters measured in the control experiments and also only weak responses of the cardiorespiratory values in the almitrine treated group. Compared with the data obtained 30 min before administration of the drug, measurements carried out 90 min after the ingestion showed a decrease of plasma AVP in all four subjects through plasma osmolality was increased in three of the four cases. A comparison of the mean values of all data obtained in the morning, i.e. before the oral administration of the drug, with those determined in the afternoon revealed that three out of four subjects had responded to almitrine with a fall of plasma AVP regardless of an increase of plasma osmolality in all these three cases. One person did not react to almitrine ingestion, neither with plasma AVP nor with plasma osmolality. In the control experiments the corresponding reaction pattern was uncharacteristic. The data do not support the assumption that arterial chemoreceptor stimulation increases plasma AVP. They rather indicate that excitation of these pO2-sensors in normoxic humans suppresses plasma AVP by mechanisms so far unknown.

Adult↗

Comparison of the response of renal sodium excretion to almitrine and hypoxia in conscious normotensive and spontaneously hypertensive rats.

The effect of hypobaric hypoxia and almitrine on renal sodium excretion and systolic blood pressure was investigated in conscious adult normotensive control rats (NCR) and spontaneously hypertensive rats (SHR). Moderate hypoxia caused a significant natriuresis within the first two days in both NCR and SHR. The systolic blood pressure was significantly diminished in SHR only. Oral application of almitrine (1.0 mg/kg b.w.) induced natriuresis in SHR and NCR. However, there are considerable differences in the pattern of natriuresis between the animals of both strains and when compared to the effect of hypoxia. The urinary sodium excretion by almitrine was not associated with a decrease in systolic blood pressure neither in SHR nor in NCR. The results indicate that both hypoxia and almitrine induce a strong natriuresis in conscious rats apparently by different mechanisms. However, there is no real evidence at present as to whether the peripheral arterial chemoreceptors are indeed involved in these mechanisms, or not, and if so, to what degree.

Almitrine↗

The acute effect of a single oral dose of 200 mg almitrine on gas exchange in patients with chronic obstructive bronchitis and emphysema, bronchial asthma and lung fibrosis.

We studied the acute effect of a single, oral dose of 200 mg almitrine and of placebo on arterial blood gas tensions, ventilation, gas exchange and pulmonary mechanics in 28 patients with chronic obstructive bronchitis and emphysema (COPD), 20 patients with bronchial asthma and 10 patients with interstitial lung disease. Almitrine significantly increased PaO2 in COPD, had a borderline effect in bronchial asthma and no effect in lung fibrosis. In all groups of patients almitrine significantly increased minute ventilation and decreased arterial carbon dioxide tension (PaCO2). Placebo had no effect on arterial oxygen tension (PaO2) and PaCO2 in any of the groups. Therefore, despite similar effects on ventilation, the improvement of arterial PO2 by almitrine depends on the underlying disease.

Administration, Oral↗

[Competitive study of the effects of naloxone and of almitrine on fentanyl analgesia in the anesthetized dog: effects on the muzzle opening reflex and blood gases].

UNLABELLED: The search for a technique making it possible to dissociate the analgesia and ventilatory depression of central analgesics led to a comparison of the effects of naloxone, a specific morphinomimetic antagonist, with almitrine, a ventilatory stimulant with a peripheral action, on muzzle opening reflex and blood gases. Five male dogs (Beagles, aged one year), anaesthetised with Alfetesine were treated separately with the two drugs used alone and after fentanyl analgesia (injection of fractionnated doses up to the threshold of apnoea). The association of the two drugs was also tested in tyhe dog after analgesia. The parameters studied were muzzle opening reflex, as an indication of analgesia, and blood gases, and were observed for 45 minutes, including 15 minutes control. RESULTS: 1 - The intravenous injection of 1,2 mg of naloxone had the effect of increasing the surface area of muscle potentials with a maximum of 7 per cent (p 0.001) at the 15 th minute. By contrast, no significant change in blood gases was seen. In the same dogs given fentanyl analgesia, naloxone not only reversed respiratory depression but had a stimulatory effect on MOR reaching 7 per cent (p 0.001) at the 30 th minute. 2 - The effects of 1 mg.kg-1 of almitrine were characterised by a fall in MOR for a period equal to that of the study and a minimum of 7.8 per cent (p 0.001) at the 20 th minute. At the same time, marked ventilatory stimulation was seen. PO2 rose by 22.7 per cent (p 0.02) at the 5 th minute. PCO2 fell during the 30 minutes studied with a minimum of 39.6 per cent (p 0.01) at the 20 th minute. Almitrine did not antagonise the depression of MOR caused by fentanyl but reversed the respiratory depression of the analgesic, increasing PO2 by 26 per cent (p 0.01) and decreasing PCO2 by 25.7 per cent (p 0.01). 3 - The combination of both drugs cancelled out the abolition of the reflex by fentanyl then facilitated it up to 24.7 per cent (p 0.001) in comparison with the animal not receiving any analgesic. By contrast, the ventilatory action of almitrine was not potentialised by naloxone. In view of these data, and in the absence of any emergency, the choice of naloxone as an antagonist of ventilatory depression of central analgesics should not be preferential in order to avoid the rebound effect.

Almitrine↗

Effects of almitrine and oxygen on ventilation and gas exchange in patients with chronic respiratory insufficiency.

Effects of a new respiratory stimulant almitrine on lung ventilation and gas exchange were studied in 15 patients suffering from chronic respiratory insufficiency. The variables examined were measured during 4 consecutive periods lasting 30 min each. During the first period initial data were collected. From the second period to the end of the investigation, oxygen, 1.5 1/min, was administered. During the third phase, almitrine was infused at a dose of 0.33 mg/kg. Administration of oxygen increased arterial oxygen tension without change in lung ventilation. Infusion of almitrine increased minute ventilation by 27%. The increase in VE was entirely due to increase in tidal volume. There was a significant rise in arterial oxygen tension and decrease in carbon dioxide tension. Hyperventilation and improvement in blood gases were still observed 30 min after the infusion was completed. It is suggested that almitrine increases minute ventilation in patients with respiratory failure receiving oxygen.

Adult↗