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PubMed1998

Effects of almitrine bismesylate on the ionic currents of chemoreceptor cells from the carotid body.

Almitrine is a drug used in the treatment of hypoxemic chronic lung diseases such as bronchitis and emphysema because it is a potent stimulant of the carotid bodies in human and different animal species that produces a long-lasting enhancement of alveolar ventilation, ameliorating arterial blood gases. However, the mechanism of action of almitrine remains unknown. We investigated the effect of almitrine on ionic currents of chemoreceptor cells isolated from the carotid body of rat and rabbits by using the whole-cell and inside-out configurations of the patch-clamp technique. Almitrine at concentrations up to 10 microM did not affect whole-cell voltage-dependent K+, Ca2+, or Na+ currents in rat or rabbit cells. However, this concentration of almitrine significantly inhibited the Ca2+-dependent component of K+ currents in rat chemoreceptor cells. This effect of almitrine on the Ca2+-dependent component of K+ currents was investigated further at the single-channel level in excised patches in the inside-out configuration. In this preparation, almitrine inhibited the activity of a high-conductance (152 +/- 13 pS), Ca2+-dependent K+ channel by decreasing its open probability. The IC50 value of the effect was 0. 22 microM. The inhibitory effect of almitrine on Ca2+-dependent K+ channels also was observed in GH3 cells. We conclude that almitrine inhibits selectively the Ca2+-dependent K+ channel and that in rat chemoreceptor cells, this inhibition could represent an important mechanism of action underlying the therapeutic actions of the drug.

Almitrine↗
PubMed2004

Assessment of the therapeutic activity of a combination of almitrine and raubasine on functional rehabilitation following ischaemic stroke.

BACKGROUND AND OBJECTIVES: Stroke is a major cause of disability. Certain experimental studies have suggested that a combination of almitrine + raubasine (Duxil) increases the supply of oxygen to cerebral tissues and may be beneficial in post-stroke rehabilitation. This multicentre clinical study was carried out in order to assess the efficacy of this combination on poststroke rehabilitation. METHODS: The trial was a randomised, double-blind, placebo-controlled study. Patients that had experienced an ischaemic cerebrovascular accident (confirmed by CT scan) were included 4-6 weeks after the acute onset and received randomised treatment of either almitrine + raubasine or placebo 2 tablets daily for 3 months. Before treatment, there was a 2-week washout period for stopping all other drugs, except for antihypertensive and antidiabetic drugs. We assessed the patients by Barthel Index (BI), Neurological Functional Deficit Scores (NFDS), and Hasagawa Dementia Scales (HDS) each month after treatment. RESULTS: A total of 83 patients were entered into the study and data were available for 74. Of these, 38 patients received almitrine + raubasine and 36 received placebo. The baseline characteristics were comparable between both groups. Almitrine + raubasine was significantly more effective than placebo at increasing BI at 1, 2 or 3 months (14.6 +/- 13.8 versus 3.3 +/- 13.2, p = 0.01; 19.3 +/- 13.6 versus 8.8 +/- 14.0, p = 0.02; 22.6 +/- 14.7 versus 10.7 +/- 17.0, p = 0.02 respectively) and reducing NFDS at 1 month (3.6 +/- 3.2 versus 1.9 +/- 3.5, p = 0.034) after treatment. More almitrine + raubasine-treated patients' NFDS had improved compared with placebo-treated patients at 2 and 3 months (97 versus 78%, p = 0.013; 100 versus 86%, p = 0.023 respectively). Compared with pretreatment, there was a strong tendency towards an improvement of HDS with almitrine + raubasine. The number of adverse events reported was low for the almitrine + raubasine-treated group and the placebo group and all events were mild, of short duration and resolved without treatment. Almitrine + raubasine had no clinically significant effect on blood pressure, heart rate or other laboratory tests. CONCLUSION: The results indicate that almitrine + raubasine can accelerate neurological function recovery after stroke to some degree and is well tolerated.

Aged↗
PubMed1990

Low-dose almitrine bismesylate enhances hypoxic pulmonary vasoconstriction in closed-chest dogs.

The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor response was studied in six closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2; the left lung was ventilated either with 100% O2 ("hyperoxia") or with an hypoxic gas mixture ("hypoxia": end-tidal oxygen tension = 60.3 +/- 0.6 mm Hg). On two consecutive days, each dog received either almitrine (Vectarion, Servier Lab) or malic acid. Consecutive almitrine doses of 0.003, 0.03, 0.3, and 3.0 micrograms.kg-1.min-1, or the equivalent volumes of malic acid without almitrine, were administered intravenously as a constant peripheral infusion for 15 min. Percent blood flow to each lung was calculated based on a variation of the traditional shunt equation. The change in percent left lung blood flow (delta %QL-VA) increased significantly between the hypoxia-no drug and the hypoxia-almitrine (3.0 micrograms.kg-1.min-1) phase. No significant changes occurred during the other almitrine doses or the respective malic acid control phases. The change in arterial oxygen tension (delta PaO2) also increased significantly between the hypoxia-no drug and the hypoxia-almitrine (3.0 micrograms.kg-1.min-1) phase. No significant changes occurred during the other almitrine doses or the respective malic acid control phases. It is concluded that in dogs low-dose almitrine enhances hypoxic pulmonary vasoconstriction and that this enhancement is dose-related.

Almitrine↗
PubMed1987

[Neuropathies and almitrine. 14 cases].

Previously reported cases of peripheral neuropathies occurring during almitrine therapy had only a few weeks follow-up after having stopped the drug. We have studied clinical and electrophysiological data 6 to 12 months after almitrine had been given up in 9 patients from a group of 14 whose epidemiologic, clinical, electrophysiological and pathological data had been registered. In 7 of them, without any chronic respiratory deficiency, almitrine was administered as almitrine bismésilate and raubasine, and in 7 others (6 with chronic respiratory deficiency) as almitrine bismesilate alone. In patients who had another possible cause of neuropathy, clinical disorders appeared after a lesser total quantity of almitrine (p less than 0.05). Clinical data were suggestive of sensory peripheral neuropathies of feet and lower third of legs. Electrophysiological data suggested distal axonopathy in spite of the absence of denervation: amplitudes of sensory potentials were reduced and nerve conduction velocities were moderately decreased. Biopsies revealed mild neurogenic atrophy of muscles and distal axonopathy. Clinical improvement was very slow and 6 to 12 months later, most of the patients still presented decreased vibration sense and ankle reflexes loss, but all of them were still improving. Amplitudes of sensory potentials and sensory nerve conduction velocities were significantly improved (p less than 0.05) but motor nerve conduction velocities were not (p greater than 0.05). Our study shows: 1) clinical, electrophysiological and pathological data similar to those previously reported; 2) subclinical disturbances of motor functions in lower limbs and sensory functions in upper limbs; 3) some patients presented with unusual signs: posture tremor (3 cases), painful legs and moving toes (1 case); 4) peripheral neuropathies may occur during almitrine therapy even in patients without any chronic respiratory insufficiency; 5) peripheral neuropathies occurred with lower doses in patients with other factors predisposing to neuropathies; 6) patients' improvement was very slow; 7) in 9 cases the imputability of these peripheral neuropathies to almitrine is plausible. We suggest not to prescribe almitrine without caution, especially in patients with other factors of neuropathy. Treatment should be regularly interrupted.

Aged↗
PubMedDate not supplied

One year administration of almitrine bismesylate (Vectarion) to chronic obstructive pulmonary disease patients: pharmacokinetic analysis.

A double blind study utilizing orally administered almitrine bismesylate was conducted involving 36 stable chronic obstructive pulmonary disease (COPD) patients with hypoxia and with and without hypercapnia. The patients received 50 mg tablets twice daily for 360 days. Blood samples were taken both at predose and 3 hours postdose at different periods throughout 1 year dosage regimen and plasma levels were analyzed by a GLC method using a nitrogen-phosphorous detector. Plasma almitrine concentrations indicate large variability at each time sample. Results suggest an increasing trend in the almitrine plasma levels as a function of time. Plasma almitrine levels increased significantly (p less than 0.01) between test day 14 and test day 360 (243 +/- 213 per cent and 199 +/- 170 per cent for predose and 3h postdose samples, respectively) indicating that steady state is not achieved by day 14. Almitrine plasma levels appear to stabilize between test day 90 and test day 180. The effective multiple dose half-life for almitrine bismesylate in plasma is estimated to be 32 days. About half of the patients exhibited steady state peak plasma almitrine levels above 500 ng ml-1. In addition, 19 per cent of the patients achieved maximum apparent steady state almitrine levels greater than 700 ng ml-1. Mean accumulation was estimated to be 4.21 +/- 1.98 at one year.

Almitrine↗
PubMed1990

Double-blind placebo controlled clinical trial of almitrine bismesylate in patients with chronic respiratory insufficiency.

The efficacy and safety of almitrine bismesylate, a new respiratory stimulant, in patients with the hypoxaemic form of chronic respiratory insufficiency caused by chronic bronchitis and emphysema has been assessed. The multicentre trial of 12 weeks duration was double-blind and placebo controlled, with individual and group comparisons. Twenty three patients received almitrine 50 mg b.d. p.o. and 17 took placebo. In the almitrine group a significant increase in PaO2 was achieved (control value 54.4 mm Hg, rising to 59.1 mm Hg after 6 weeks, and to 59.4 mm Hg after 12 weeks). There was also a significant decrease in PaCO2 in the almitrine group after 12 weeks. No correlation was found between the plasma almitrine concentration, PaO2 and PaCO2. Lung function (FVC, FEV1, FEV1/FVC, Raw, TLC, RV, FRC) did not change in either group, but the degree of dyspnoea and performance in the 6 min walking test were significantly improved in the almitrine group. Adverse reactions appeared in 6 out of 23 patients on almitrine bismesylate (headache, urticaria, breathlessness, diarrhoea, chest pain, nausea and vomiting), causing drop out of 4 patients. Thus, almitrine bismesylate can be considered useful in the treatment of patients with chronic respiratory insufficiency.

Adult↗
PubMed1998

Combined nitric oxide inhalation, prone positioning and almitrine infusion improve oxygenation in severe ARDS.

PURPOSE: To determine the efficacy and side effects of prone positioning (PP) and nitric oxide (NO) inhalation, alone, associated, or combined with i.v. almitrine for the treatment of hypoxaemia in severe acute respiratory distress syndrome (ARDS). METHODS: Over a period of 20 months, 27 consecutive critically ill patients with severe ARDS (Murray score > 2.5, PaO2/FiO2 < 170 after alveolar recruitment) were prospectively and randomly included. They inhaled NO for two hours at concentrations of 5 and 10 ppm for one hour each (H0-H2). One hour later, they were returned to the prone position for four hours (H3-H7). During the last two hours in this position (H5-H7), they were assigned to further inhalation of 10 ppm NO (Group B, n = 9) or to no further inhalation (Group A, n = 9). In group C (n = 9), the procedure for group B was combined with perfusion of 16 mg.kg-1.min-1 almitrine throughout the study. RESULTS: Compared with control values, two hours NO inhalation improves PaO2/FiO2 and shunt effect by +28% and -9%, PP by +88% and -27%, PP + almitrine by +132% and -28%, NO + almitrine by +153 and -28%, PP + NO by +94% and -29%, NO + PP + almitrine by +327 and -48%. NO inhalation reduces pulmonary vascular resistance. Other haemodynamic parameters remain unchanged, whatever the treatment. NO inhalation improves PaO2/FiO2 by over 20% in 50% of the patients and PP is effective in 78% of the cases. CONCLUSION: Prone Position improves PaO2/FiO2 significantly more than NO alone but less than PP + almitrine or NO + almitrine. The best results are obtained with the association of NO + Prone position + Almitrine.

Administration, Inhalation↗
PubMed1990

[Respiratory effects of almitrine on various levels of the fraction of inspired oxygen. A study in the anesthetized dog].

The effects of intravenous almitrine under normoxic, hyperoxic, and hypoxic conditions were studied in 5 male beagle dogs (mean weight 15.2 +/- 5 kg) anaesthetized with thiopentone. Plasma concentrations of thiopentone were maintained constant at 27-29 mg.1(-1). Each animal underwent twice the three different experiments, with a lapse of a fortnight between each experiment: a) breathing room air, with intravenous administration of 1 mg.kg-1 almitrine over 30 s, b) breathing room air, then pure oxygen for 15 min, followed by an intravenous administration of 1 mg.kg-1 almitrine over 30 s with the dog still breathing pure oxygen, and c) breathing room air, then progressively less oxygen (FIO2 0.18, 0.16, 0.14, 0.12 for 5 min each), followed by an intravenous administration of 1 mg.kg-1 almitrine over 30 s with the dog still breathing a mixture with 12% oxygen. Tidal volume, respiratory rate, minute ventilation, inspiratory and expiratory duration, arterial pH, PaO2 and PaCO2 were measured respectively in room air, after 100% oxygen, in hypoxia (FIO2 = 0.12), before, 5 and 10 min after the injection of almitrine. Hyperoxia depressed ventilation (-21%), whilst hypoxia stimulated it (+126%), although significantly less than in the awake animal. Almitrine restored the respiratory response to hypoxia, but hyperoxia did not suppress respiratory stimulation due to the drug. It would therefore seem likely that almitrine acts on peripheral arterial chemoreceptors, but also on other structures. The results of this study suggest that almitrine may be useful in restoring the respiratory response to hypoxia during recovery from anaesthesia.

Almitrine↗
PubMed1996

Effect of almitrine on ventilation and on diaphragm and geniohyoid muscle activity in the rat.

1. Ventilation was measured during normoxia, hypoxia and hypercapnia before and after administration of almitrine in conscious, unrestrained, tracheostomized rats with the superior laryngeal nerves intact or cut. In superior laryngeal nerve-intact animals breathing air, almitrine increased minute ventilation due to an increase in respiratory frequency with no change in tidal volume. In superior laryngeal nerve-sectioned animals, the minute ventilatory response to almitrine was reduced due to a reduced tidal volume component of the response. Almitrine increased the ventilatory response to hypercapnia in superior laryngeal nerve-intact but not in sectioned animals. 2. In anaesthetized, vagotomized rats breathing spontaneously through a low-cervical tracheostomy, diaphragm and geniohyoid electromyographic activities were recorded. Arterial blood pressure and rectal temperature were continuously monitored. A single dose of almitrine was administered intravenously. In all animals, the geniohyoid muscle had phasic inspiratory activity which slightly preceded diaphragm activity. Almitrine had no effect on respiratory frequency or inspiratory and expiratory duration but increased mean peak integrated diaphragm (+29.3 +/- 13.6%) and geniohyoid (+132.0 +/- 21.3%) muscle activity. 3. These results show that almitrine exerts part of its ventilatory effects through superior laryngeal nerve afferents. Almitrine preferentially excites upper airway compared with diaphragm muscle activity, suggesting a potential role in the alleviation of obstructive apnoea.

Almitrine↗
PubMed2005

Low- vs high-dose almitrine combined with nitric oxide to prevent hypoxia during open-chest one-lung ventilation.

BACKGROUND: Almitrine combined with inhaled nitric oxide (NO) can prevent hypoxia during one-lung ventilation (OLV). The optimal dose of almitrine that would provide therapeutic advantage with few side-effects during open-chest OLV has not been established. METHODS: Forty-two patients undergoing thoracotomy were randomly allocated to three groups: placebo, almitrine 4 microg kg(-1) min(-1) and inhaled NO 10 p.p.m. (ALM4+NO), and almitrine 16 microg kg(-1) min(-1) and inhaled NO 10 p.p.m. (ALM16+NO). Gas exchange, haemodynamic and respiratory variables and plasma concentrations of almitrine and lactate were monitored. Measurements were obtained with the patient awake (baseline), after induction of anaesthesia with two-lung ventilation (control 2LV), 20 min after treatment (2LV+T), and then at 10, 20 and 30 min of OLV (OLV10', OLV20' and OLV30') with FI(O2)1. RESULTS: In the placebo group, OLV impaired Pa(O2) and increased pulmonary shunt [16 (SD 7) kPa and 42 (10)% respectively]. These improved with ALM4+NO [26 (10) kPa and 31 (7)%; P<0.001]. ALM16+NO further improved PaO2) to 36 (13) kPa (P<0.0001) but gave no improvement in the shunt. Mean pulmonary artery pressure was similar in the placebo and ALM4+NO groups [20 (4) vs 23 (5) mm Hg], whereas it was increased in the ALM16+NO group to 28 (8) mm Hg (P<0.01). Plasma concentrations of almitrine and lactate were unaltered by the treatments. CONCLUSIONS: Low-dose almitrine (4 microg kg(-1) min(-1)) together with inhaled NO significantly improves oxygenation during open-chest OLV, without modifying pulmonary haemodynamics. An increased dose of almitrine (16 microg kg(-1) min(-1)) with inhaled NO further improves arterial oxygenation, but also increases mean pulmonary artery pressure.

Adolescent↗
PubMed1995

Dose-response curves of inhaled nitric oxide with and without intravenous almitrine in nitric oxide-responding patients with acute respiratory distress syndrome.

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.

Administration, Inhalation↗
PubMed1990

Almitrine bismesylate and oxygen therapy in hypoxic cor pulmonale.

The effect of oral treatment with the thiazine derivative almitrine bismesylate was studied in 28 patients with chronic obstructive pulmonary disease and arterial hypoxaemia receiving long term domiciliary oxygen therapy in a placebo controlled, double blind crossover trial. The initial treatment was given for three months and the second for two months. Because almitrine had an unexpectedly prolonged washout effect crossover analysis could not be performed; data from the placebo treatment administered in the second arm of the trial were used to calculate the half life of almitrine. Nine patients were withdrawn from the study (5 almitrine, 4 placebo). Patients' tolerance of the drug was good. The estimated plasma half life of almitrine was 20.5 days, considerably longer than previously reported. Almitrine caused a significant improvement in arterial oxygen tension (PaO2) with a mean maximum increase of 0.7 kPa at a plasma concentration of 500 ng/ml. Higher plasma concentrations were not associated with any further increase in PaO2. There was no significant effect on arterial carbon dioxide tension (PaCO2). In a second, acute study at the end of each arm of the chronic trial nine patients were subjected to increasing oxygen delivery rates (2, 4, and 6 l/min) for 90 minutes or until blood gas concentrations plateaued. Almitrine increased PaO2 in a dose dependent fashion at all delivery rates, but the effect diminished as PaO2 approached normoxic levels. There was no significant effect on PaCO2. Almitrine treatment results in a significant improvement in PaO2 over that achieved by oxygen alone, an effect that diminishes at high flow rates. Whether this is of clinical benefit is not known. In view of the prolonged half life revised dosage schedules are required.

Almitrine↗
PubMed1986

Effects of almitrine on genioglossal and diaphragmatic electromyograms.

We previously demonstrated dose-dependent increases in both hypoglossal and phrenic electroneurograms after almitrine in anesthetized, paralyzed, and vagotomized cats. We have now investigated the effect of this peripheral chemoreceptor stimulant on diaphragmatic and genioglossal (GG, an upper airway-maintaining muscle) electromyograms in five unanesthetized, chronically instrumented, spontaneously breathing adult cats during slow-wave sleep. In 12 studies almitrine doses of 1.0-6.0 mg/kg increased inspired minute ventilation (VI), frequency (f), and tidal volume (VT) and decreased expiratory time (TE). However, almitrine doses as high as 6.0 mg/kg failed to augment phasic inspiratory GG activity. To determine why almitrine induced phasic inspiratory upper airway activity in anesthetized, vagotomized cats but not in sleeping cats, additional studies were performed. In four dose-response studies in three pentobarbital-anesthetized cats, almitrine, 1.0-6.0 mg/kg, did not produce phasic inspiratory GG activity. Almitrine did induce phasic inspiratory GG activity in two of three studies in three vagotomized, tracheostomized, alpha-chloralose-urethan-anesthetized cats. These results suggest that almitrine would not be useful in obstructive sleep apnea, yet because almitrine markedly increased VI, f, and VT and decreased TE in unanesthetized sleeping cats the drug may be effective in patients who lack normal central neural respiratory drive, such as the preterm infant.

Almitrine↗
PubMed1989

Comparative effects of almitrine and raubasine, singly and in combination, on electroencephalographic activity in young and old rats.

A new method for quantification of electroencephalographic (EEG) signals was used to study the effects of almitrine and raubasine, alone and in combination, in two groups of six unanesthetized rats, aged 8 months (young) and 22 months (old). Coadministration of almitrine (7.5 mg/kg-1 i.p.) and raubasine (2.5 mg/kg-1 i.p.) induced an increased EEG power from 7 to 30 Hz; the frequencies concerned were identical in young and old rats, but the degree of their power variations was more marked in old rats. Almitrine induced a 20 to 50% increase in EEG power in young rats on nearly all spectral components. The effects of almitrine were only seen in the low-frequency range in old rats. Raubasine increased the EEG power in the 10 to 20 Hz frequency range; these effects were significantly greater in old rats. In both age groups, the effects on EEG power observed with coadministration of almitrine and raubasine were significantly different from those expected if raubasine and almitrine add their individual effects. These results show that a) almitrine and raubasine modify cortical electrical activity in a different manner as a function of age; b) the modification of the EEG activity induced by the coadministration is suggestive of an interaction between the cortical effects of each drug; and c) the modification of EEG power induced by the coadministration is qualitatively identical in young and old rats but quantitatively more marked in old rats.

Aging↗
PubMed1989

Almitrine, a new kind of energy-transduction inhibitor acting on mitochondrial ATP synthase.

At low concentrations, almitrine inhibits yeast cell multiplication by acting on oxidative metabolism. Studies on isolated mitochondria display the following features: (i) almitrine inhibits ATPase activity and decreases ATP/O ratio during oxidative phosphorylation; (ii) no direct effect on respiration can be evidenced; (iii) ATP/O value decreases without any change in the magnitude of delta p; (iv) the higher the ATP synthesis and respiratory fluxes, the larger is the decrease in ATP/O ratio induced by almitrine. These results indicate that almitrine does not act as a classical protonophoric uncoupler nor as previously studied non protonophoric uncouplers (e.g., general anesthetics). Our data show a direct inhibitory effect of almitrine on ATPase-ATP synthase complex. But, in contrast to the classical inhibitors of this complex, almitrine decreases the ATP/O ratio in a flux-dependent manner. Thus, almitrine could induce either an intrinsic uncoupling of H+/-ATPase (i.e., slip in this proton pump) or a change in the mechanistic H+/ATP stoichiometry at the ATPase level.

Adenosine Triphosphate↗
PubMed1990

Ventilatory effects of almitrine bismesilate in dogs breathing normoxic, hyperoxic and hypoxic mixtures.

The ventilatory effects of 1 mg.kg-1 i.v. almitrine were studied in five dogs anaesthetized with halothane 2% under conditions of normoxia, hyperoxia and hypoxia. Ventilation (minute ventilation, respiratory frequency, tidal volume, duration of inspiration and expiration, ratio TI/Ttot and VT/TI), Pao2, Paco2, pHa, systemic arterial pressure and heart rate were measured in air before and following almitrine; in air, after inhalation of pure oxygen and after almitrine in hyperoxia; in air, during hypoxia with Fio2 progressively decreased from 0.21 to 0.12 and after almitrine in hypoxia (FIO2 = 0.12). Halothane decreased ventilatory response to hypoxia. Almitrine stimulated ventilation irrespective of the level of oxygenation and restored the ventilatory response to hypoxia. Hyperoxia did not suppress ventilatory action of almitrine whose action is probably partly central. Hypoxia and almitrine did not induce major systemic haemodynamic modification.

Almitrine↗
PubMed1986

Action of almitrine bismesylate on ventilation-perfusion matching in cats and dogs with part of the lung hypoventilated.

Ventilation to one lobe of lung was reduced in anaesthetized open-chest cats and dogs to simulate the ventilation/perfusion (V/Q) mismatching of chronic lung disease. Blood flow to this lobe fell less than ventilation; thus lobar V/Q diminished. In seven cats almitrine (0.5 mg/kg + 10 micrograms/kg per min, i.v.) caused a rise in pulmonary artery pressure (PPA), increased flow through the hypoventilated lobe in six out of seven cats and both increased or decreased lobar vascular resistance (PVR); the lobar V/Q ratio therefore fell. Arterial and lobar venous oxygen tension (PO2) fell. In five dogs almitrine caused a rise in PPA and PVR but lobar flow changes were variable. Arterial and lobar venous PO2 fell. With fixed ventilation, almitrine failed to improve V/Q matching; there was no improvement in gas exchange in the hypoventilated lobe. In eight dogs the hypoventilated lobe was perfused at constant flow with right atrial blood (i.e. while V/Q was held constant). Almitrine caused a rise in perfusion pressure, vasoconstriction, followed, in five out of eight dogs, by vasodilatation. In six similar cat preparations, vasoconstriction but not vasodilatation was clearly shown. In two cats dilatation after almitrine was demonstrated during ventilation with Nitrogen. In all experiments there was no significant effect of the solvent. Thus the dual action of almitrine seen in other species was seen in a proportion of cats and dogs. Results do not support the view that improved arterial gas tensions in patients after almitrine are attributable to diversion of blood flow away from hypoxic lung. Alternative mechanisms are discussed.

Almitrine↗
PubMedDate not supplied

Effect of almitrine bismesylate on breathing pattern during hypoxia/hypercapnia in rats and ferrets.

1. Ventilatory measurements and functional residual capacity (FRC) were recorded from anaesthetized rats and ferrets using a whole body plethysmograph. Simulation of aspects of human chronic obstructive airways disease (COAD) was attempted by making animals acutely hypoxic or hypoxic and hypercapnic by causing them to breath appropriate gas mixtures or by increasing the tracheal resistance or dead-space. Some chronically hypoxic rats, which have muscularized pulmonary arterioles similar to COAD patients, were also studied. 2. In 18 chronically hypoxic (CH) rats and 17 littermate control rats (C), breathing air, doses of almitrine bismesylate caused greater increases in ventilation (VE) in C than in CH rats. FRC, which was initially greater in CH rats, increased significantly in both groups after almitrine. 3. In C rats, breathing hypoxic or hypoxic/hypercapnic gas mixtures caused large increases in VE. Slow infusions of almitrine caused a further increase in VE usually via an increase in tidal volume (VT) but not frequency (f). 4. In two series of rats (n = 9; n = 6) severe and moderate degrees of tracheal obstruction caused a fall in PaO2 and a rise in PaCO2, a fall in VE due to both VT and f and large changes in oesophageal pressure (Poes), which often became positive on expiration. Almitrine infusions usually caused a rise in PaO2, a rise in VT and no change in f; with moderate obstruction, Poes also rose. The results were thought to depend on the balance between improved ventilation and increased O2 demand of the respiratory muscles. 5. Eleven ferrets were made hypoxic and hypercapnic by adding a large dead-space to the trachea. A slow infusion of almitrine caused a significant rise in PaO2 before any significant change in VE was detected; PaCO2 fell at some time during the infusion, but not significantly. The initial significant rise in PaO2, at 2.5 min, was not associated with significant changes in T1 (time of inspiration) and VT/TI. At 5 min VT/TI and PaO2 were all significantly altered. 6. Infusions of almitrine into hypoxic and hypercapnic animals caused improvements in the arterial oxygen tension which were associated with subtle changes in the breathing pattern; inspiratory time and inspiratory flow rate changed in the absence of an increase in total VE. Possible conclusions with respect to the action of almitrine in patients with COAD are discussed.

Airway Obstruction↗