Effects Of Almitrine Bismesylate Research Articles

Long-term effects of almitrine bismesylate in COPD patients with chronic hypoxaemia

Background: Almitrine bismesylate (AB) is a peripheral chemoreceptor agonist which is believed to improve oxygenation of COPD patients with chronic hypoxaemia, probably by improving the ventilation perfusion mismatch. We studied the long-term effects of AB in COPD patients with chronic hypoxaemia. Methods: Design Prospective, randomised, double-blind, placebo-controlled trial. Setting: Eight hundred bed teaching hospital with a catchment population of 350000 inhabitants. Patient recruitment: COPD outpatients consulting between September 95 and September 99. Inclusion criteria : (1)- COPD ( FEV 1 <50%). (2) P aO 2\\le65mmHg. (3) Stable arterial blood gases (ABG), spirometry (S) and clinical state. Exclusion criteria: Asthma, restrictive disease, sleep apnoea syndrome, advanced renal or hepatic disease, peripheral neuropathy, use of respiratory stimulants or psychotrophic drugs. Treatment: AB 1mg/kg/day (weight <75kg = 50mg/day; weight \\ge 75kg = 100mg/day) in an intermittent schedule with resting periods of 1 month after the third, 6th and 9th months during 1 year. Instrumentation: Stabilisation period: S, ABG. Run-in period: S, ABG, 6-min walking test (WT), nocturnal pulse oximetry (NP) and quality of life evaluation (CRQ). Third, 6th and 9th months: S, ABG. End of the study: S, ABG, WT, NP, CRQ. Statistics: ANOVA for repeated measurements. Results: Two hundred and eighty-nine patients were evaluated and 81 were included in the study. Sixty-six were followed for 6 months, 53 for 9 months and 42 for 1 year. Almitrine and placebo groups did not present significant differences in ABG and S in the 6th, 9th and 12th months. Evolution in WT, NP and CRQ were similar in the two groups. No relevant side-effects were detected: only two patients stopped treatment (one placebo and one AB). Conclusion: In an intermittent schedule, although well tolerated, at doses of 1mg/kg/day, AB was not effective in long-term treatment of chronic hypoxemia in COPD patients.

High or low doses of almitrine bismesylate in ARDS patients responding to inhaled NO and receiving norepinephrine?

To evaluate the effects on oxygenation and pulmonary haemodynamics of almitrine bismesylate (AB) 5 microg/kg per minute and 16 microg/kg per minute in ARDS patients responding to and receiving inhaled NO (iNO) and presenting septic shock requiring norepinephrine, while no difference was observed in a previous trial including iNO responders and nonresponders. Prospective, cohort study. Adult medico-surgical intensive care unit of a university hospital. Fifteen patients with ARDS receiving and responding to iNO (10 ppm) and presenting septic shock requiring norepinephrine (mean 0.5+/-0.45 microg/kg per minute, range 0.08- 2.08). The protocol consisted of two consecutive phases in a fixed order: continuous intravenous infusion of AB 5 microg/kg per minute for 30 min, and continuous intravenous infusion of AB 16 microg/kg per minute for 30 min. AB 5 microg/kg per minute significantly increased PaO2/FiO2 ( P<0.05) compared with iNO alone [160 (range 77-450) mmHg vs 122 (range 70-225) mmHg]. AB 16 microg/kg per minute produced a greater increase of PaO2/FiO2 ( P<0.05) when compared with 5 microg/kg per minute [227 (range 84-501) mmHg]. AB did not improve shunt at any dose regimen. AB produced an increase in mean pulmonary arterial pressure (MPAP) from 22+/-5 to 25+/-4 mmHg ( P<0.03). MPAP did not significantly increase between the two doses. Pulmonary vascular resistances and other haemodynamic and respiratory parameters were not affected by almitrine bismesylate. These results suggest that it is possible to obtain a further improvement in oxygenation by increasing AB infusion rate in ARDS patients iNO responders receiving norepinephrine. Due to the potential deleterious effects of AB, this strategy should be used in the most severely hypoxaemic patients.

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.

Effect of almitrine bismesylate on pulmonary vasoreactivity to hypoxia in chronic obstructive pulmonary disease

The aim of this double-blind, placebo-controlled study was to determine whether acute administration of almitrine enhances hypoxic pulmonary vasoconstriction in patients with chronic obstructive pulmonary disease (COPD). Haemodynamics and blood gases were studied at various inspiratory fractional concentrations of oxygen (FIO2): 0.15, 0.21, 0.30 and 1.0, randomly administered for 20 min periods under constant infusion of either placebo or almitrine (8 micrograms.kg-1.min-1) in 20 patients with COPD. The almitrine group exhibited a significant increase in mean pulmonary artery pressure, pulmonary vascular resistance and arterial oxygen tension (PaO2) at FIO2 0.15, 0.21 and 0.30. During hypoxia, the increase in mean pulmonary pressure and pulmonary vascular resistance was three times greater in the almitrine group than the placebo group. No significant difference in cardiac output and systemic haemodynamics was found. These results suggest that almitrine at the dose used, enhances pulmonary vasoconstriction in COPD patients.

Pattern of breathing and laryngeal patency following almitrine bismesylate in anesthetized cats

The effects of almitrine bismesylate on the pattern of breathing and laryngeal caliber were investigated in anesthetized, spontaneously breathing cats. Breathing occurred via a tracheostomy, while the laryngeal resistance to airflow was measured with the larynx isolated in situ. Almitrine bismesylate in a dose of 0.5 mg/kg of body weight was injected intravenously three times: in the intact animals, following bilateral vagotomy (sparing the right recurrent laryngeal nerve), and after a sensory denervation of the larynx. In each condition, almitrine stimulated ventilation by significantly increasing inspiratory airflow, by increasing the respiratory rate in the 10th and the 20th minutes following injection, and by reducing laryngeal resistance to airflow in both the inspiratory and expiratory phases. The stimulatory effects of almitrine were most apparent in the intact animals. Following vagotomy, these significant changes in the pattern of breathing as well as the enlarged laryngeal caliber persisted. However, these latter effects were short-lived and were followed by narrowing of the laryngeal lumen. Laryngeal afferents were not essential for the response to almitrine.

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.

Comparison of almitrine bismesylate and medroxyprogesterone acetate on oxygenation during wakefulness and sleep in patients with chronic obstructive lung disease.

The effects of almitrine bismesylate and medroxyprogesterone acetate on oxygenation during wakefulness and sleep were compared in six patients with chronic obstructive lung disease and carbon dioxide retention. Patients received 1.5 mg/kg almitrine (a peripheral chemoreceptor stimulant), 100 mg of medroxyprogesterone (a central respiratory stimulant), or matched placebo daily for 15 days in random order in a crossover trial. When subjects were awake almitrine increased the ventilatory response to hypoxia and increased arterial oxygen tension (PaO2) to a greater extent than medroxyprogesterone, whereas medroxyprogesterone augmented the ventilatory response to hypercapnia and decreased arterial carbon dioxide tension (PaCO2) to a greater extent than almitrine. Neither drug influenced sleep architecture significantly, except that medroxyprogesterone increased the number of arousals. Almitrine had a more favourable effect than placebo on oxygenation as estimated from arterial oxygen saturation (SaO2) during the different stages of sleep, the number of episodes of hypoxaemia, and the amount of time that SaO2 was below 80%. The only change with medroxyprogesterone by comparison with placebo was a decrease in the number of hypoxaemic episodes. It is concluded that both active drugs improved blood gases during wakefulness, but that 1.5 mg/kg of almitrine is superior to 100 mg of medroxyprogesterone in improving SaO2 during sleep.

Almitrine and the peripheral ventilatory response to CO2 in hyperoxia and hypoxia

The effects of almitrine bismesylate (initial intravenous dose 0.6 mg·kg−1 followed by continuous infusion of 0.4 mg·kg−1·h−1) on the ventilatory response to CO2 during hyperoxia and hypoxia were determined in 6 anaesthestized cats with the use of the dynamics end-tidal CO2 forcing technique. It was found that almitrine almost doubled the peripheral ventilatory sensitivity to CO2 during hyperoxia (mean PetO2 45.6 kPa) and also during mild hypoxia (mean PetO2 8.7 kPa). The apnoeic threshold (B) was in both cases shifted to substantially lower values than those of the control measurements. No significant effects of almitrine were found on the central ventilatory sensitivity to CO2 either during hyperoxia or during hypoxia. It is argued that the decrease of the apnoeic threshold may be due to an inhibitory effect of almitrine on the carotid body dopaminergic activity, and that the increase of the sensitivity to CO2 stems from a “hypoxia mimetic” mechanism.

Effect of Almitrine Bismesylate on Indices of Gas Mixing Efficiency in Patients with Chronic Bronchitis and Emphysema

Effect of Almitrine Bismesylate on Indices of Gas Mixing Efficiency in Patients with Chronic Bronchitis and Emphysema

The effect of almitrine bismesylate on the steady-state responses of arterial chemoreceptors to CO 2 and O 2 in the cat

The interaction between almitrine bismesylate, a pharmacological stimulant of peripheral chemo-receptors, and varying levels of oxygen (P O 2 50–600 Torr) and carbon dioxide (P CO 2 10–65 Torr)_on steady state carotid chemoreceptor discharge was investigated in pentobarbitone-anaesthetized cats. Almitrine was given as constant intravenous (50 μg/kg per min for 4 min) and intracarotid infusions (4–16 μg/kg per min) at different levels of alveolar P O 2 ad P CO 2 . Almitrine always excited discharge. The intracarotid infusions at the lower infusion rate (4–8 μg/kg per min) and the i.v. infusions increased the slope of the isoxic response to CO 2. This effect could be reversed by raising P O 2 to high levels. Higher infusion rates of almitrine (16 μg/kg per min) displaced the CO 2 response curve upwards but did not increase its slope above that obtained in control conditions at end-tidal P O 2 of 50 Torr. However, as these higher infusion rates caused levels of discharge greater than those achieved during control conditions, their effects on control CO 2 sensitivity could not be ascertained. Our results suggest that almitrine excites carotid body chemoreceptors by a mechanism similar to that of hypoxia and not like that of carbon dioxide.

High-dose almitrine bismesylate inhibits hypoxic pulmonary vasoconstriction in closed-chest dogs.

The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in seven closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2, while the left lung was ventilated with either 100% O2 ("hyperoxia") or with an hypoxic gas mixture ("hypoxia": end-tidal PO2 = 50.1 +/- 0.1 mmHg). Cardiac output (CO) was altered from a "normal" value of 3.10 +/- 0.18 l . min-1 to a "high" value of 3.92 +/- 0.16 l . min-1 by opening arteriovenous fistulae which allowed measurements of two points along a pressure-flow line. These four phases of left lung hypoxia or hyperoxia with normal and high cardiac output were repeated in the presence and absence of almitrine. Almitrine bismesylate was administered as a constant infusion of 14.3 micrograms . kg-1 . min-1 for a mean plasma concentration of 219.5 +/- 26.4 ng . ml-1. Relative blood flow to each lung was measured with a differential CO2 excretion (VCO2) method corrected for the Haldane effect. With both lungs hyperoxic, the percent left lung blood flow (%QL-VCO2) was 44 +/- 1%. When the left lung was exposed to hypoxia, the %QL-VCO2 decreased significantly to 22 +/- 1%. However, with the administration of almitrine, the %QL-VCO2 during left lung hypoxia increased significantly to 36 +/- 2%. The arterial oxygen tension decreased significantly between hyperoxia (PaO2 = 633 +/- 6 mmHg) and hypoxia (271 +/- 31 mmHg). With the addition of almitrine, there was no change during hyperoxia; however, during hypoxia, the PaO2 decreased significantly to 124 +/- 15 mmHg. Cardiac output did not influence these findings. The pulmonary vascular conductance (G) is the slope of the pressure-flow line.(ABSTRACT TRUNCATED AT 250 WORDS)

Almitrine bismesylate and the central and peripheral ventilatory response to CO2.

Effects of almitrine bismesylate on the peripheral and central chemoreflex to a CO2 challenge during normoxia were studied in nine alpha-chloralose-urethan anesthetized cats. With the dynamic end-tidal CO2 forcing technique the ventilatory response after a square-wave change in end-tidal PCO2 (PETCO2) was partitioned into a central and a peripheral part using a two-compartment model. With almitrine administered intravenously (0.6 mg/kg followed by a maintenance dose of 0.4 mg.kg-1 X h-1) the CO2 sensitivity of the peripheral chemoreflex increased on the average from 0.315 to 0.564 l.min-1 X kPa-1 (P less than 0.001, 6 cats, 73 runs), whereas the CO2 sensitivity of the central chemoreflex remained the same (P = 0.87). The extrapolated PETCO2 at zero ventilation (apneic threshold) of the (total) steady-state response curve decreased on the average from 3.50 to 2.36 kPa (P less than 0.001). With the artificial brain stem perfusion technique it was confirmed that almitrine did not affect ventilation by administering it to the blood perfusing the brain stem. We conclude that almitrine bismesylate during normoxia enhances the CO2 sensitivity of the peripheral chemoreflex loop and decreases the apneic threshold due to an action located outside the brain stem.

Respiration of conscious kittens in acute hypoxia and effect of almitrine bismesylate.

Respiration was measured noninvasively in conscious kittens at an ambient temperature of 28-32 degrees C. Inspired O2 fraction (FIO2) was reduced abruptly from 0.21 to 0.12, 0.10, or 0.08 for 5 min on the day of birth and then on days 4, 7, 14, and 28. The ventilatory response to hypoxia was biphasic, as reported previously in anesthetized kittens, with minute ventilation (VE) increasing in the first minute and then falling towards control over the next 4 min. The fall in VE was due to a consistent fall in tidal volume, the changes in frequency during the second phase being more variable. The size of the first phase of the response increased up to 14 days, but the time at which the peak increase in VE occurred was not correlated with age. The degree of the secondary fall in VE was similar at each age and at each FIO2 studied. The degree of the biphasic response was significantly reduced after administration of almitrine (2 mg/kg ip) on days 1 and 4, but almitrine did not affect the response in older kittens.