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At least 19 recordsLinked to original sources
PubMed1992

Almitrine mimics hypoxic vasoconstriction in isolated rat lungs.

The effect of almitrine bimesylate or the solvent malic acid on pulmonary vascular perfusion pressure was assessed in isolated rat lungs and on the contractile behavior of rat aorta and main pulmonary artery rings. Addition of almitrine to the lung perfusate during normoxia caused a dose-dependent, transient increase in pulmonary artery pressure with no change of the lung microvascular pressure. In systemic or pulmonary conduit arteries, the contractile tension was unaffected by almitrine. This indicates a precapillary locus of drug action. We also examined almitrine's effect on hypoxic pulmonary vasoconstriction (HPVC) in isolated lungs perfused with blood or with physiological salt solution (PSS). Low-dose almitrine potentiated hypoxic vasoconstriction in blood- but not in PSS-perfused lungs. However, a high dose of almitrine reduced hypoxic vasoconstriction dose dependently. When almitrine was added to the lung perfusate during hypoxia- or cyanide-induced (NaCN, 5 x 10(-5) M) pulmonary vasoconstriction, almitrine caused no further vasoconstriction. However, when the pulmonary perfusion pressure was elevated by KCl (20 mM) to the same magnitude as by alveolar hypoxia or cyanide, almitrine elicited a pressor response comparable to that observed during normoxia. Almitrine-induced pulmonary vasoconstriction resembled hypoxic vasoconstriction in that agents known to enhance hypoxic vasoconstriction (phorbol myristate acetate, vanadate, and 4-aminopyridine) enhanced, and known inhibitors of HPVC (the Ca2+ entry blocker nifedipine and hypothermia) inhibited, the almitrine-induced vasoconstriction. These findings lead us to speculate that almitrine also affects the oxygen-sensing limb of the hypoxic pressor response, not simply the effector (contractile apparatus of the vascular muscle cell).

Almitrine↗
PubMed1992

Acute and chronic effects of low dose almitrine bismesylate in the treatment of chronic bronchitis and emphysema.

OBJECTIVES: Study of the acute and chronic effects of low-dose almitrine therapy in stable hypoxaemic patients with chronic bronchitis and emphysema. METHODS: A low daily dose of 75 mg almitrine bismesylate was administered for six months in 23 patients with chronic bronchitis and emphysema. Nine patients (group 1) were placed on oral almitrine bismesylate 25 mg t.i.d. after they had received a single intravenous dose of 60 mg almitrine three months earlier. Fourteen additional patients, seven receiving almitrine (group 2) and seven placebo (group 3) were randomized for a 6 month double-blind evaluation of both acute and chronic effects of 75 mg almitrine on pulmonary gas exchange and on pulmonary haemodynamics. All patients were followed-up with regular measurements of blood gases, body plethysmography and with evaluation of peripheral nerve function. RESULTS: Acute effects of almitrine were a significant increase in arterial oxygen tension by 14 mmHg after intravenous (p < 0.001) and by 15 mmHg after oral administration (p < 0.001), amelioration of hypercapnia, a slight transient increase in mean pulmonary artery pressure from 26 +/- 7 to 29 +/- 6 mmHg (NS) and a decrease of shunt due to improvement in ventilation/perfusion mismatching. In contrast, no acute changes in blood gases and pulmonary pressures were seen in the placebo group. A combination of almitrine with oxygen (8-10 L/min) was most effective in amelioration of hypoxaemia and shunt. With chronic almitrine therapy, the improvements in gas exchange persisted without elevation of pulmonary artery pressure (26 +/- 8 mmHg), whereas a negative trend in change of blood gases and pulmonary artery pressure occurred in the placebo treated group (NS). No significant changes in external ventilation, other spirometric parameters or adverse effects concerning peripheral nerve function were seen after almitrine or placebo treatment. The elimination of almitrine was fitted to a three compartment model and the terminal half-life in the patient population was found to be 32 +/- 29 days after intravenous dosing. CONCLUSION: Acute and six-month almitrine bismesylate therapy at a low daily dose of 75 mg is found to be safe, even in severely compromised patients, with regard to pulmonary haemodynamics and peripheral nerve function. The agent is beneficial to pulmonary gas exchange, with reduction of hypercapnia, of intrapulmonary shunt and also with regard to sustained elevation of arterial oxygen tension. A combination with inhaled oxygen seems especially efficacious.

Aged↗
PubMed1991

Almitrine in low dose potentiates vasoconstrictor responses of isolated rat lungs to moderate hypoxia.

To test whether the effect of almitrine on hypoxic pulmonary vasoconstriction was dose-dependent, two series of experiments were performed on isolated rat lungs perfused with constant flow of blood. In the first series, the effects of different doses of almitrine on perfusion pressure were measured. Baseline perfusion pressure was not changed by solvent or by 0.25 micrograms.ml-1 almitrine, but it was increased by 0.5 and 2.0 micrograms.ml-1 almitrine. The increase in perfusion pressure in response to 10 min ventilation with hypoxic gas mixture (5% O2) was significantly (p less than 0.05) higher after 0.25 micrograms.ml-1 almitrine (12.0 +/- 0.8 torr) than before addition of the drug (5.43 +/- 1.8 torr). Responses to hypoxia were insignificant after higher doses (0.5 and 2.0 micrograms.ml-1) of almitrine. In the second series of experiments the responses to varying degrees of hypoxia were measured after administration of one dose of almitrine (0.25 micrograms.ml-1). Almitrine, compared to solvent alone, significantly altered the shape of the dose-response curve to hypoxia. Increases in perfusion pressure in response to moderate degrees of hypoxia were potentiated (10% O2: 8.7 +/- 1.8 torr after almitrine, 2.1 +/- 0.6 torr after solvent, p less than 0.05), whereas responses to severe hypoxia (3% O2) were not changed by almitrine. Reactivity to angiotensin II was decreased by 0.25 micrograms.ml-1 almitrine. We conclude that almitrine in low but not in high dose augments pulmonary vasoconstriction induced by mild degrees of hypoxia.

Almitrine↗
PubMed1985

Effects of almitrine on hypoglossal and phrenic electroneurograms.

Almitrine increases breathing by stimulating peripheral chemoreceptors. Previous studies suggest clinical usefulness in the adult with chronic obstructive pulmonary disease, but little data are available to decide whether almitrine would be helpful in diseases involving pharyngeal airway obstruction, such as apnea of prematurity or obstructive sleep apnea. We investigated the effect of intravenous almitrine on hypoglossal (HG), an upper airway nerve, and phrenic (PHR) neural activity in eight alpha-chloralose-urethan anesthetized, paralyzed, vagotomized, and artificially ventilated cats. Recordings were made of raw and integrated HG and PHR electroneurograms (ENGs), alveolar PCO2, arterial PO2, arterial blood pressure, and rectal temperature. A dose-response study of cumulative almitrine doses ranging from 0.1 to 4.0 mg/kg was performed in three cats. The interactive effects of almitrine and hypoxic stimulation were investigated in four cats. The interactive effects of almitrine and hypercapnic stimulation were investigated in five cats. The interactive effects of almitrine and ventilatory timing were investigated in six cats. We found that 1) almitrine doses as low as 0.1 mg/kg iv increased both HG and PHR ENG activity, with a maximum effect at approximately 1.0 mg/kg; 2) almitrine markedly increased HG and PHR ENG activity at all arterial PO2 values from 35-175 Torr; 3) almitrine increased HG and PHR ENG activity at all arterial PCO2 values from 30-70 Torr; and 4) almitrine increased the ratio of tidal volume to inspiratory time and decreased the inspiratory muscle duty cycle at normoxia and eucapnia.

Airway Obstruction↗
PubMed1989

In vitro studies on the blood distribution of almitrine.

Blood binding of almitrine, a highly lipophilic drug, was investigated in vitro. [3H]-Almitrine was incubated in a serum pool and isolated protein and lipoprotein fractions. The investigations were performed by using ultracentrifugation and another method which measures the uptake by proteins from glass beads coated with almitrine. Our results with ultracentrifugation show that the distribution of almitrine in serum takes place predominantly in the lipoprotein fraction (78%) and to a minor extent (22%) in the fraction of d greater than 1.20 (albumin-rich fraction). Experiments using glass beads coated with almitrine were then conducted to measure the binding of almitrine to isolated plasma proteins. The maximal uptake values (mol almitrine/mol lipoprotein) of almitrine by isolated lipoproteins decrease from VLDL (260) to LDL (20) to HDL (3) and seem to be related to the lipid content of the particles. The uptake by albumin and alpha 1-acid glycoprotein was low. The molar ratios of [almitrine]/[lipoprotein] are roughly proportional to almitrine concentrations within the therapeutic range. When almitrine was incubated in erythrocytes suspended in several dilutions of serum, almitrine partitioned less in erythrocytes as the serum protein concentration increased in the suspension.

Almitrine↗
PubMed1990

Effect of almitrine administration on pulmonary arterial pressure in resting and exercising dogs.

In addition to its well-known ventilatory effect, a small rise in pulmonary arterial pressure or pulmonary vascular resistance is occasionally observed with chronic administration of almitrine. In order to test the hypothesis of enhancement of exercise pulmonary vasoconstriction by almitrine, mongrel dogs were studied at rest and during submaximal exercise before and after 4 weeks of chronic ingestion of almitrine (10 mg/kg). It was shown that resting pulmonary arterial pressure (PAP) remained unchanged by almitrine treatment. However, when exercise was superimposed on almitrine medication, PAP was significantly increased throughout the exercise bout. Thus, the rise in PAP during the 20th min of exercise averaged 8.7 +/- 3.4 mm Hg after almitrine treatment while PAP increased by only 1.3 +/- 1.7 mm Hg before medication. The exaggerated exercise-induced PAP response in conjunction with the enhanced secretion of norepinephrine that we observed during almitrine treatment suggests that catecholamine could be involved in the pulmonary haemodynamic adjustments. Furthermore, mixed-venous PO2 (PvO2) both during rest and exercise declined with the prolongation of almitrine ingestion, suggesting that PvO2 might possibly be implicated in the pulmonary haemodynamic response to almitrine, in the same way as it is involved in the hypoxia-induced pulmonary vasoconstriction. These findings demonstrate that almitrine medication, even at a high dose, does not have any deleterious effect on pulmonary vasculature in resting conditions, but prolonged submaximal exercise should be proscribed in patients on a long-term therapy.

Almitrine↗
PubMed1986

A comparison of the effects of almitrine or oxygen breathing on pulmonary arterial pressure and right ventricular ejection fraction in hypoxic chronic bronchitis and emphysema.

Almitrine bismesylate is a new, orally administered, respiratory stimulant that improves arterial blood gas tensions in patients with chronic bronchitis and emphysema, and it may have an effect on the pulmonary circulation and on right ventricular performance. We have, therefore, compared the effects of Almitrine with those of oxygen (given as 3 L/min by nasal prongs) on arterial blood gas tensions, mean pulmonary arterial pressure (Ppa), and right ventricular ejection fraction (RVEF) measured both at rest and during exercise in patients with chronic hypoxemia caused by chronic bronchitis and emphysema. Arterial oxygen tension improved significantly both at rest and during exercise after either 100 mg Almitrine by mouth or when breathing oxygen, both at rest and during exercise. Almitrine increased the mean Ppa at rest from 22 +/- 4 to 35 +/- 5 mmHg (p less than 0.001), and mean Ppa rose further during exercise from 38 +/- 5 mmHg before Almitrine to 49 +/- 7 mmHg (p less than 0.001) after Almitrine. In contrast, oxygen breathing did not change Ppa when at rest but reduced the amount of rise in Ppa during exercise. The change in Ppa after Almitrine correlated with the plasma Almitrine concentration (r = 0.69, p less than 0.05) and was associated with a fall in RVEF at rest from 0.38 +/- 0.03 to 0.32 +/- 0.02 (p less than 0.001). In 5 of the patients who received 50 mg of Almitrine by mouth twice daily for 3 months, the Ppa both at rest and during exercise remained significantly higher than in the control study before receiving Almitrine, but RVEF was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Dose-response and pharmacokinetic study with almitrine bismesylate after single oral administrations in COPD patients.

To better define the dose-effect relationship and the pharmacokinetics of almitrine, sixteen stable hypoxaemic COPD patients received random single oral administrations of almitrine bismesylate 50, 100 and 150 mg or placebo at two-week intervals in a double-blind manner. Resting ventilation, arterial blood gases and plasma almitrine levels were measured. No significant changes were seen after placebo administration. Almitrine 50 and 100 mg caused a significant dose-related improvement in arterial oxygen tension (PaO2) in thirteen of the sixteen patients. Almitrine 150 mg caused little if any additional PaO2 increment. PaO2 returned to near basal values after 24 h. Two patients responded to almitrine 100 and 150 mg only, whereas one patient did not respond at all. Mean PaO2 increases in the sixteen patients were 0.9 kPa (7 mmHg), 1.5 kPa (11 mmHg) and 1.6 kPa (12 mmHg) 3 h after 50, 100 and 150 mg, respectively. A significant mean 0.9 kPa (7 mmHg) decrease in arterial carbon dioxide tension (PaCO2) and a l.min-1 increase in ventilation were observed after almitrine 150 mg. Mean maximum almitrine plasma concentration and area under the curve correlated linearly with dose. The relationship between mean PaO2 improvement and mean almitrine plasma level was curvilinear with a flattening of the curve over plasma levels of 150 ng.ml-1. Almitrine plasma half-life was found to be 116-140 h.

Aged↗
PubMed1986

Influence of alveolar hypoxia on pulmonary vasomotor responses to almitrine in the dog.

Almitrine bismesylate (5-10 micrograms/kg) was given as an intravenous bolus to anaesthetized, paralysed dogs with closed-chest (n = 5) and with open-chest (n = 7) in whom the retrocardiac lobe was separately ventilated. Pulmonary, lobar and systemic haemodynamics were measured under hypoxic, normoxic and hyperoxic conditions. Total pulmonary blood flow was measured by thermodilution and lobar flow by electromagnetic flow meter. In the closed-chest preparations, almitrine caused an increase in pulmonary vascular resistance (PVR) at all levels of inspired oxygen, the increments being 82% (30% O2), 91% (air) and 9% (13% O2). The control PVR varied inversely with arterial PO2 but there was no significant interaction between the almitrine and hypoxia induced vasoconstriction with multiple linear regression analysis. In the open-chest preparations, PVR and lobar vascular resistance (LVR) increased after almitrine by 48% and 41% respectively when both lung and lobe inspired 30% O2. When the lobe was switched to 12.5% O2 or nitrogen (lung inspiring 30%) PVR again increased (+52%) after almitrine but LVR decreased in five of seven lobes (lobar flow increasing despite constant cardiac output), the overall change being -4%. Analysis of covariance showed that the lobar response to almitrine was significantly different under hypoxic conditions compared with hyperoxic (P less than 0.05). With ventilation maintained constant, there was no significant change in arterial PO2 after almitrine in any experimental condition. In conclusion, almitrine is generally a pulmonary vasoconstrictor but can dilate vessels when they are constricted by local hypoxia. Almitrine does not enhance local hypoxic vasoconstriction in the dog.

Almitrine↗
PubMed1992

Interactions between hypoxic and almitrine-induced vasoconstriction in the rat lung.

1. To test whether almitrine might improve the arterial partial pressure of O2 in patients with chronic obstructive airways disease by improvement of ventilation-perfusion matching, we looked at the interaction between hypoxic and almitrine-induced vasoconstriction in isolated rat lungs perfused with blood at constant flow. Increases in pressure represented increases in resistance. 2. Almitrine, given in increasing doses between challenges with 2% O2, enhanced hypoxic vasoconstriction at low doses but attenuated it at high doses. 3. Stimulus-response curves to hypoxia of increasing severity gave a sigmoid curve. 4. Almitrine solvent caused small changes in pulmonary artery pressure and shifted the stimulus-response curve slightly in a parallel fashion. 5. Small doses of almitrine enhanced the action of mild to moderate hypoxia, medium doses attenuated moderately severe hypoxia, whereas high doses depressed vasoconstriction due to all degrees of hypoxia. 6. These effects of almitrine on hypoxic vasoconstriction were compared with the effect of solvent by analysis of variance; the results substantiated significant enhancement of hypoxia by small doses and attenuation by large doses. 7. In patients, if similar effects apply, small doses of almitrine would assist ventilation-perfusion matching, but large doses might worsen it. 8. Almitrine-induced vasoconstriction was attenuated by a fall in perfusate temperature in a similar manner to hypoxic vasoconstriction. It was also attenuated by three drugs, chlorpheniramine, propanolol and diethylcarbamazine, all of which also decrease hypoxic vasoconstriction. The similarity between hypoxic and almitrine-induced pulmonary vasoconstriction is further confirmed.

Almitrine↗
PubMed1990

A review of the EEG effects of the combination of almitrine and raubasine in animals and humans.

During recent years many studies on the electroencephalogram (EEG) changes induced by almitrine-raubasine (Duxil) have been performed in elderly patients and in animals. This article gives an overview of three questions raised by their results. Is there a simple addition of the raubasine and almitrine effects when they are coadministered? Are the EEG effects of this treatment dependent on the patient's disease? To what extent could EEG studies provide some knowledge about the mechanism of action of almitrine-raubasine therapy? In adult (8 months) and aged (22 months) rats the EEG changes induced by the coadministration of almitrine and raubasine were significantly different from the addition of individual almitrine and raubasine EEG effects. In adult rats the coadministration induced slighter EEG changes than those predicted by the addition of almitrine and raubasine effects. In aged rats, the coadministration induced a decrease in delta-theta power not predictable from the effects of almitrine or raubasine. These results could be taken as an indication that some biological targets are common for the two drugs and that the coadministration results in pharmacological effects more complicated than a simple addition of raubasine and almitrine properties. After 3 weeks of treatment in aged healthy subjects, the coadministration induced an increase in the alpha and beta power with a slight decrease of delta and beta-1 powers. In patients with cognitive decline of probable degenerative origin, 3 months of therapy with almitrine-raubasine was mainly associated with a decreased delta and theta power and a slight increase in high frequency components of the alpha band.(ABSTRACT TRUNCATED AT 250 WORDS)

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↗
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↗
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↗