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PubMed1984

[Clinical pharmacokinetics of almitrine dimesylate].

In healthy subjects, almitrine bismesylate taken orally as tablets is rapidly absorbed from the digestive tract, with an overall bioavailability of about 70%. Drug kinetics are linear and independent of route of administration and therapeutic doses. Protein binding is approximately 99%, irrespective of plasma concentrations. Wide diffusion through body tissues is reflected in the apparent volume of distribution approaching 15 l/kg. In all animal species studied, almitrine is primarily metabolized in the liver. Its main metabolites are the tetrahydroxyl, mono-deallyl, di-deallyl and detriazinyl derivatives, all devoid of pharmacological activity and excreted mostly through the bile. Plasma elimination half-life varies from 45 to 50 hours. Plasma clearance (4 ml/min/kg) is about the same as hepatic clearance. As compared with healthy subjects, the pharmacokinetic values of almitrine bismesylate are identical in patients with chronic respiratory failure and not significantly different (notably with regard plasma clearance) in patients with renal impairment. However, absorption may be normal, reduced or delayed in patients with impaired liver functions, resulting in more variable values. Following repeated administration of the drug to healthy volunteers, steady state is reached in about 15 days. In chronic obstructive lung disease, long-term oral administration of almitrine bismesylate 100 mg/day divided into two 50 mg doses results in plasma concentrations that are 2 to 3 times higher than after one single 100 mg dose.

Adult↗

PubMedDate not supplied

Respiratory stimulation by almitrine during acute or chronic hypoxia/hypercapnia in rats.

In anaesthetized rats studied in a body plethysmograph, 1-(4'6-diallylamino-2'-triazinyl)-4(bis parafluorobenzydryl) piperazine (almitrine) caused large increases in ventilation (VE) which were abolished by cutting the IXth and Xth cranial nerves. Maximal effects followed infusions of 0.5-1 mg X kg-1; the solvent had no action. When the rats breathed 10% O2 or 10% O2 + 5% CO2, gas mixtures which increased VE, almitrine caused further increases in VE and improved blood gas tensions. Chronically hypoxic (4 weeks in 10% O2) and chronically hypoxic and hypercapnic rats (4 weeks in 10% O2 + 4% CO2), kept in an environmental chamber, were similarly studied. While they breathed, under anaesthesia, the gas mixture to which they had been chronically exposed, infusions of almitrine caused further large increases in VE and improved blood gas tensions. Thus almitrine stimulates VE, probably through peripheral chemoreceptors, when these are already strongly stimulated. This drug increased both tidal volume and frequency and thus increased alveolar ventilation. No convulsant action was observed. It caused a fall in blood pressure which lasted 5-10 min and was seen with urethane but not pentobarbitone anaesthesia; it was not due to the solvent.

Almitrine↗

PubMedDate not supplied

Acute effects of almitrine infusion on pulmonary haemodynamics in normal man.

The aim of the study was to assess haemodynamic and ventilatory effects of almitrine infusion in normal subjects. Five males aged 19-49 years were studied using a floating catheter technique. The investigation consisted of three consecutive periods, lasting 20 min each. During the first one, the subject was allowed to settle down and baseline measurements were made. During the second period, a total dose of 0.33 mg X kg-1 of almitrine was infused over 20 min. During the third period, postinfusion effects were observed. Almitrine produced the expected increase in minute ventilation that was entirely due to that in tidal volume. Haemodynamic changes consisted of an increase in pulmonary vascular resistance and pulmonary arterial pressure. As there was no concomitant change in cardiac output or wedge pressure, the increase in pulmonary vascular resistance was apparently due to constriction of pulmonary muscular arteries. Pulmonary vasoconstrictor effects of almitrine were of short duration and were already tapering off before completion of the infusion, so that pulmonary arterial pressure was back to the baseline value 10 min after the infusion was completed.

Adult↗

PubMed1984

[Pulmonary hemodynamic monitoring in chronic respiratory insufficiency treated with almitrine bismesilate for 4 months in a double-blind study].

Six subjects suffering from chronic airflow obstruction and respiratory failure were treated with oral almitrine bismesylate (3 mg/kg/day). Studies were made before and after 2 and 4 months treatment on: total ventilation, arterial blood gases, pulmonary artery pressure by a micro-catheter and cardiac out-put by rebreathing CO2. The results were compared with those of a placebo group of 3 subjects. While in the almitrine group a significant improvement in blood gases was observed, no change was seen in the two populations in either the haemodynamic or ventilatory variables. The medium term haemodynamic stability observed is contrasting with single dose effects of almitrine. This discrepancy could be due, at least in part, to a balance between the possible vasoconstrictor effect of almitrine bismesylate and vasodilator consequences of blood gases improvement.

Adult↗

PubMed1983

Effects and handling of almitrine bismesylate in healthy subjects.

Almitrine bismesylate was administered to young, healthy, non-smoking male subjects as single oral doses, multiple oral doses and multiple oral doses with food. A variety of physiological parameters and blood parameters were tested at specified times in relationship to drug ingestion, and multiple blood samples for plasma almitrine bismesylate levels were obtained. Evaluation of the data revealed almitrine bismesylate to be safe at all doses tested, up to 400 mg per day, with symptoms of mild nausea and headache occurring most frequently when the drug was administered in the fasting state. A striking complaint of shortness of breath on exertion was reported by subjects, with increased frequency and severity related to total amount of drug ingested and level of physical activity. Increased oxygen uptake and tidal volume were found after multiple oral dosing. Plasma almitrine bismesylate levels were highly variable, and marked individual differences in peak levels and terminal phase rate constants and half lives were found. Multiple oral dosing, either fasting or with food, significantly prolonged the terminal phase half life when compared to single oral dosing.

Adult↗

PubMed1995

Effects of almitrine on the ventilatory control, breathing pattern and maximal exercise tolerance in hypoxemic patients with chronic obstructive pulmonary disease.

Almitrine bismesylate improves arterial blood gases in patients with chronic obstructive pulmonary disease (COPD), but side effects such as increase of ventilatory drive and dyspnea have been reported in some studies. We studied 18 COPD patients (mean age = 59.1 years; mean FEV1 = 0.92 1; mean PaO2 = 58.6 mmHg) in a double-blind randomized study using placebo or almitrine 50 mg twice a day by mouth, for 60 days. In contrast to the placebo group, 40% of the patients in the almitrine group presented a significant increase in PaO2 and a decrease in P(A-a)O2 > or = 5 mmHg during submaximal exercise after 60 days of treatment. Ventilatory drive and the breathing pattern were measured at rest and during submaximal exercise. Both groups showed high levels of ventilatory drive and a tachypneic breathing pattern before drug treatment and no modification was found 30 and 60 days after treatment. Metabolic, cardiovascular and ventilatory variables were studied during an incremental to maximum exercise symptom-limited test (cycloergometry). Maximal VO2 ranged from 46 to 52% and heart rate from 76 to 78% in relation to the predicted values. The percent ratio of ventilation at maximal exercise to maximal voluntary ventilation at rest ranged from 86 to 94%. These results show that the reduction of ventilatory capacity was the main factor decreasing the aerobic performance of our COPD patients. Maximal exercise tolerance (VO2 max) did not change after almitrine treatment. Negative factors like an increase in neuromuscular drive did not occur, and positive factors like an increase in PaO2 and oxygen transport had no critical influence on exercise performance in our ventilatory-limited COPD patients.

Adult↗

PubMed1980

Long-lasting hyperventilation induced by almitrine: evidence for a specific effect on carotid and thoracic chemoreceptors.

In anesthetized dogs, almitrine (0.5-3 mg/kg i.v.) induced a dose-dependent increase in respiratory rate and ventilation. The aortic and carotid chemoreceptors were involved in the effects of almitrine. Section of both carotid sinus nerves and vagus nerves abolished the effects of the drug on respiration. The respiratory response did not occur in dogs with bilateral lesions of the nucleus of the solitary tract. The electrical activity of chemoreceptor fibres was increased. Perfusion of almitrine into the carotid artery stimulated respiration. Inhalation of pure oxygen shifted the dose-response curve of the respiratory effect towards the right. Almitrine slightly stimulated ventilation in dogs with bilateral section of carotid sinus nerves and aortic nerves and this disappeared when both vagus nerves were cut indicating that this effect was mediated through some chemoreceptor fibres present in the vagus nerves or through afferent vagal fibres.

Animals↗

PubMedDate not supplied

Single oral dose proportionality pharmacokinetics of almitrine bismesylate in humans.

A single-blind study was conducted in 10 healthy male subjects. Each subject was tested with four single oral doses of capsules containing 25, 50, 100, 200mg almitrine bismesylate and one dose of placebo. Blood samples were drawn as a function of time and the concentration of almitrine in plasma was determined by gas chromatography utilizing nitrogen-phosphorus detection. Linear regression analysis of the data suggested that a deviation from linearity existed between the area under the plasma concentration time curves and the dose (R = 0.96). Linear analysis of the individual data indicates that a slight negative deviation from linearity is apparent for the 200 mg dose. The same trend was observed for the mean maximum almitrine plasma concentration, Cmax, which ranged from 38.9 +/- 11.8 to 286.2 +/- 99.1 ng ml-1 for the 25 and 200 mg dose, respectively. The time to peak was relatively constant regardless of the administered dose and ranged from 2.4 +/- 0.5 h to 2.8 +/- 0.8 h. Good agreement was obtained between the observed bioavailability parameters and those predicted from the nonlinear fit of the data. Further kinetic analysis of the data revealed mean total body clearance over fraction of dose absorbed ranging from 268.2 +/- 132.8 to 436.4 +/- 191.4 ml min-1 for doses 50 and 200mg, respectively.

Administration, Oral↗

PubMed1993

Almitrine prevents some hypoxia-induced metabolic injury in rat astrocytes.

During reperfusion of ischemic brain tissue, the production of reactive oxygen species initiates several modifications of the astroglial functional and ultrastructural integrity. During 24 h after ischemic treatment, modification of cellular superoxide free radical scavenging systems have been observed in primary culture of rat astroglial cell. Mitochondrial Mn superoxide dismutase activity (Mn-SOD) gradually decreases, whereas that of the cytosolic Cu,Zn form of the enzyme remains unaffected. We observed in parallel a significant decrease of glutamine synthetase (GS), an astrocyte specifically located enzyme. Addition of almitrine (dialylamine-4',6'-triazinyl 2')-1-(bis-parafluoro-benzydryl)-4-piperazine or dibucaine (a phospholipase A2 inhibitor) antagonizes the decrease of Mn-SOD activity, but does not affect modification of GS activity. Combined effects are observed by simultaneous addition of both drugs. Our data demonstrate that almitrine may increase the synthesis of some mitochondrial proteins, like Mn-SOD, and provide support for further study on the therapeutic potential of almitrine in ischemic astroglial cell injury.

Almitrine↗

PubMed2000

Dose-dependent effects of almitrine on hemodynamics and gas exchange in an animal model of acute lung injury.

OBJECTIVE: To determine the dose-response relationship of almitrine (Alm) on pulmonary gas exchange and hemodynamics in an animal model of acute lung injury (ALI). DESIGN: Prospective, randomized, controlled study. METHODS: Twenty anesthetized, tracheotomized and mechanically ventilated (FIO2 1.0) pigs underwent induction of ALI by repeated saline washout of surfactant. Animals were randomly assigned to either receive cumulating doses of Alm intravenously (0.5, 1.0, 2.0, 4.0, 8.0 and 16.0 micrograms.kg-1.min-1) for 30 min each (treatment; n = 10) or to receive the solvent malic acid (controls; n = 10). MEASUREMENTS AND RESULTS: Measurements of pulmonary gas exchange and hemodynamics were performed at the end of each infusion period. Alm < 4.0 micrograms.kg-1.min-1 improved arterial oxygen pressure (PaO2) (105 +/- 9 mmHg for Alm 1.0 vs 59 +/- 5 mmHg) and decreased intrapulmonary shunt (Qs/Qt) (32 +/- 4% for Alm 1.0 vs 46 +/- 4%) (P < 0.05). Alm > or = 8.0 micrograms.kg-1.min-1 did not improve pulmonary gas exchange compared to controls. When compared to low doses of Alm < 4.0 micrograms.kg-1.min-1, high doses > or = 8.0 micrograms.kg1.min-1 decreased PaO2 (58 +/- 11 mmHg for Alm 16.0) and increased Qs/Qt (67 +/- 10% for Alm 16.0) (P < 0.05). CONCLUSIONS: In experimental ALI, effects of almitrine on oxygenation are dose-dependent. Almitrine is most effective when used at low doses known to mimic hypoxic pulmonary vasoconstriction.

Almitrine↗

PubMed1983

Increased respiratory chemosensitivity induced by oral almitrine in healthy man.

Cardiorespiratory effects of 50 mg and 100 mg doses of almitrine and placebo given orally on separate test days to twelve healthy volunteers were assessed in a double-blind crossover study. The drug caused no significant changes in ventilation, mixed venous CO2 tension, metabolic rate, heart rate or blood pressure while they were resting and breathing room air. With progressive hypercapnia, however, the ventilatory response increased by 5% after the 50 mg dose (NS) and by 27% after the 100 mg dose (P less than 0.05). There were greater increases in the response to progressive hypoxia by 78% after 50 mg of almitrine (P less than 0.01) and by 120% after 100 mg (P less than 0.01), which was also significantly greater than the increase after the 50 mg dose (P less than 0.01). In contrast there were only minor and inconsistent changes in chemosensitivity after administering placebo. The findings are consistent with an agonist action of almitrine in the peripheral chemoreceptors and suggest that it may have clinical value in managing respiratory failure due to hypoventilation.

Administration, Oral↗

PubMed1984

Ventrolateral medullary respiratory neurons and peripheral chemoreceptor stimulation by almitrine.

In anaesthetized, paralysed and artificially ventilated dogs, activities were recorded from the phrenic nerve and from respiratory units within the nucleus ambiguus (nA) and within the nucleus retroambigualis (nRA). The respiratory neurons were classified according to their discharge pattern. Almitrine (50 micrograms/kg i.v.) induced an increase in the firing rate of late peak inspiratory neurons (40 units) and in early burst inspiratory cells (10 units) of the nA. In the nRA, almitrine (50 micrograms/kg i.v.) also stimulated late peak expiratory neurons (17 units) and early burst expiratory cells (9 units). It is concluded that the chemoreceptor pathway is not restricted to the inspiratory neurons of the nTS and that both inspiratory and expiratory neurons of the nA and nRA are involved in the chemoreceptor pathway activated by almitrine.

Almitrine↗

PubMed1985

Ventilatory and cardiovascular responses of the unanaesthetized chicken, Gallus domesticus, to the respiratory stimulants etamiphylline and almitrine.

The ventilatory and cardiovascular effects of i.v. administration of the respiratory stimulants etamiphylline and almitrine were investigated in conscious or decerebrate adult female domestic fowl. Infusion of etamiphylline (100 mg . kg-1) or injection of almitrine (2 mg . kg-1) evoked a potent long-lasting stimulation of ventilation in both conscious and decerebrate fowl. The pattern of the respiratory response was characteristically different to that observed in mammals in that the increased minute volume of ventilation was attained by large increases in respiratory frequency accompanied by a reduction in tidal volume. The pattern of respiration following drug-induced stimulation was, in some birds, typical of thermal panting although neither etamiphylline nor almitrine caused significant increases in body temperature. Differences in the pattern of responses of the rate and depth of breathing may be attributed in part to the differences in pulmonary receptor systems involved in the control of breathing in birds and mammals.

Almitrine↗

PubMed1986

Changes in ventilation, breathing pattern and acid-base balance of conscious rabbits following intravenous almitrine.

Five conscious rabbits each received a single injection of almitrine bismesylate via a marginal ear vein. Measurements were made of ventilation and breathing pattern using a barometric method, and blood gases, pH and lactate concentration ([Lac]) were measured from arterial blood samples throughout the hour following the injection. Almitrine caused an immediate increase in ventilation through an increase in tidal volume (VT), frequency (f) showing a small decline. After 15 min f increased to above control level and VT declined. Slower, deeper breathing was reinstated by 40 min post-injection. Large changes in blood gases occurred in the first 15 min, with PO2 raised by 30 Torr and PCO2 lowered by 20 Torr. These recovered to be within 10 and 7.5 Torr of control at the end of 1 h. [Lac] increased steeply at first, then declined towards control levels. The acid-base situation was mixed, comprising a respiratory alkalosis, resulting from CO2 washout, and a metabolic acidosis from high [Lac]. These results are discussed in the context of assessing the primary and secondary effects of almitrine and recognition of the possibility that the drug may act at more than one site to alter respiration.

Acid-Base Equilibrium↗

PubMed1982

Effect of a new analeptic drug, almitrine, on fentanyl-induced respiratory depression and analgesia in man.

Five female patients received fentanyl 0.0066 mg kg-1 i.v. (group A); five other female patients received the same dose of fentanyl, followed immediately by almitrine 0.5 mg kg-1 i.v. (group B) and 20 minor gynaecological operations were performed under a combination of almitrine 0.5 mg kg-1 and fentanyl 0.0066 mg kg-1 (group C). In group A, fentanyl produced a marked and significant respiratory depression (P less than 0.001). In group B and C, almitrine antagonized the fentanyl-induced respiratory depression. Analgesia did not seem to be affected.

Adult↗

PubMed1990

Efficacy of almitrine-raubasine in cognitive disorders of aging: a double-blind, placebo-controlled, clinical and psychometric study.

Early treatment of age-related cognitive impairment can be decisive in enabling elderly patients to remain at home. A double-blind, placebo-controlled trial of almitrine-raubasine was conducted in 40 elderly outpatients (25 women, 15 men; mean age: 73.5 years) with moderate cognitive impairment randomized into two groups, one receiving almitrine and raubasine, the other placebo, two tablets daily for 90 days. They were assessed at T0, T45 and T90 days, using the Toulouse-Pieron test, 8 subtests from the Wechsler Adult Intelligence Scale (WAIS) and the Sandoz Clinical Assessment for Geriatrics (SCAG). End-of-study results were significantly better in the almitrine-raubasine group in all tests: Toulouse-Pieron test (p less than 0.001), WAIS (p less than 0.001), and SCAG (p less than 0.001).

Aged↗

PubMed1989

Low dose almitrine bismesylate improves pulmonary gas exchange during canine one-lung hypoxia.

The effects of low dose almitrine bismesylate on pulmonary gas exchange, venous admixture, and pulmonary perfusion were examined in a canine one-lung hypoxic model. The left lung was ventilated with 10.4% oxygen, 89.3% nitrogen, and 0.3% halothane, while the right lung was ventilated with 99.7% oxygen and 0.3% halothane. Group 1 (n = 8) was given no other drug for 60 min. In group 2 (n = 10), consecutive almitrine doses of 0.5, 1, and 2 micrograms/kg.min were administered iv for 20 min/dose. Blood gas and central hemodynamic values remained unchanged in group 1. In group 2, significant increases in PaO2 and significant decreases in venous admixture, dependent on the dose administered, were observed. Mean PaO2 increased from 222 +/- 78 (SD) to 292 +/- 75 torr, and mean venous admixture decreased from 22 +/- 7% to 18 +/- 6% at 2 micrograms/kg.min. Both the decrease in mean left pulmonary blood flow and the increase in mean right pulmonary blood flow were slight, although the cardiac output was unchanged. These results indicate that iv infusion of 2 micrograms/kg.min of almitrine weakly enhances pulmonary vasoconstriction in a hypoxic area and improves pulmonary gas exchange in a moderately hypoxic condition.

Almitrine↗

PubMed1991

Metabolism of almitrine in extensive and poor metabolisers of debrisoquine/sparteine.

1. Almitrine bismesylate displays wide inter-subject variation in peak plasma concentrations and can induce peripheral polyneuropathy. 2. The phenotyped volunteer panel approach was used to examine whether almitrine oxidation displayed a genetic polymorphism of the debrisoquine/sparteine type. 3. There was no difference between poor and extensive metabolisers of debrisoquine with respect to the pharmacokinetics and metabolism of almitrine.

Adult↗