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PubMed1983

Does almitrine bismesylate improve V/Q matching? An animal study.

Pulmonary vascular actions of almitrine bismesylate were studied in ferrets, rats, cats and dogs in conditions which simulated those of patients with hypoxic lung disease. All or part of a lung was made hypoxic or hypoventilated so that affected vessels were constricted. Rats were made chronically hypoxic (10%, O2, normobaric chamber). In vivo and isolated preparations were used. In all preparations and species almitrine bismesylate caused vasoconstriction in normoxia, constriction followed by dilation in hypoxia or hypoventilation. In hypoventilated lung there is ventilation/perfusion mismatching which was not improved by almitrine bismesylate . Ventilatory measurements in chronically hypoxic/hypercapnic rats showed that almitrine bismesylate increased tidal volume but not frequency. It is uncertain whether vascular (Q) or small ventilatory (V) changes are the cause of the improved gas tensions and V/Q matching in patients with chronic obstructive lung disease receiving almitrine bismesylate .

Almitrine↗
PubMed1983

Pharmacological properties of almitrine bismesylate.

There is direct evidence in dogs and circumstantial evidence in man that almitrine bismesylate stimulates peripheral chemoreceptors. In anaesthetized dogs, almitrine bimesylate causes an increased activity in afferent fibres from the sinus nerve, in inspiratory neurons of the nucleus tractus solitarius, in expiratory neurons of the nucleus retroambigualis, and in the phrenic nerve. The mechanism whereby almitrine bismesylate stimulates chemoreceptors is poorly understood to date. As a result of chemoreceptor stimulation by almitrine bismesylate , ventilation is higher or unchanged even though PaCO2 has fallen and PaO2 has risen. However, in many patients with chronic obstructive lung disease given almitrine bismesylate , the improvement in arterial blood gases cannot be fully explained by the increased ventilation. This suggests an improved matching of ventilation and perfusion that could be due to diversion of blood flow from poorly towards better ventilated zones. However, all animal experiments have failed to demonstrate such a diversion. Redistribution of ventilation could also explain the improved V/Q matching but has not been unequivocally proven.

Afferent Pathways↗
PubMed1994

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.

Almitrine↗
PubMedDate not supplied

Relative bioavailability of almitrine bismesylate in humans.

Bioavailability and bioequivalency studies of almitrine bismesylate from U.S. manufactured film coated, waxed, 50 mg tablets were compared in 34 normal healthy volunteers to 50 mg European film coated, waxed and unwaxed, tablets and a 0.5 per cent (w/v) oral reference solution of almitrine bismesylate in d,l malic acid. The U.S. manufactured formulations were 85.88 and 87.85 per cent of the calculated mean area under the individual concentration-time curve for almitrine bismesylate reference solution compared to 88.40 and 88.86 per cent for the waxed and unwaxed film coated European tablets, respectively. The mean peak plasma concentrations for the U.S. formulations were 176.3 ng ml-1 and 180.1 ng ml-1 compared to 196.3 and 200.1 ng ml-1 for the waxed and unwaxed European formulations, respectively. Mean time to peak plasma concentrations for the two U.S. formulations and the waxed and unwaxed European formulations were 3.22, 3.33, 3.06, and 3.26 h, respectively. In addition, the oral reference solution yielded a mean peak plasma concentration of 222.8 ng ml-1 and a mean time to peak plasma concentration of 2.68 h. Analysis of variance and multiple range comparisons (p less than 0.05) indicated that the tablet formulations were bioequivalent. The results of this study show that the U.S. formulated almitrine bismesylate tablets exceed 85 per cent relative bioavailability with respect to the oral reference solution and are bioequivalent compared to the marketed standard European tablet formulations.

Adult↗
PubMed1989

Ventilatory, circulatory, endocrine, and renal effects of almitrine infusion in man: a contribution to high altitude physiology.

Diuresis at altitude was thought to be the result of chemoreceptor stimulation leading to a reduction of cardiac volume overload. This hypothesis was tested in ten young, healthy subjects by infusion of almitrine (0.5 mg.kg-1 body mass within 30 min) assuming analogous sites of action, i.e. arterial chemoreceptors and pulmonary vessels, for almitrine as for hypoxic hypoxia. The results show that almitrine increases ventilation, heart rate, systolic blood pressure, central venous pressure and natriuresis, but fails to increase significantly atrial natriuretic peptide plasma concentration and diuresis. It is concluded: (1) that almitrine has similar sites of action as hypoxic hypoxia at about 5000 m, (2) that natriuresis during arterial chemoreceptor stimulation might reduce cardiac volume overload, (3) that the volume excretion hypothesis, in particular the pathways from the cardiac volume overload to the water diuresis, need, for an understanding of the hypoxia-induced diuresis, further direct investigations at altitude.

Adult↗
PubMed1993

Relationships between age-dependent changes in the effect of almitrine on H(+)-ATPase/ATPsynthase and the pattern of membrane fatty acid composition.

The effects of almitrine on ATPase/ATPsynthase previously described in beef heart mitochondria (Rigoulet et al. (1990) Biochim. Biophys. Acta 1018, 91-97) are also observed in liver mitochondria isolated from rats older than 7 weeks. In contrast, in rats younger than 5 weeks, almitrine at the same concentration has no effect on the ATPase/ATPsynthase complex. This age-dependent action of almitrine is well correlated with age-dependent modifications of two fatty acids: linoleic and docosahexaenoic acids. The possibility of a change in H+/ATP stoichiometry of the ATPase/ATPsynthase induced by almitrine seems related to more general modifications of membrane properties during growth of the rat.

Aging↗
PubMed1983

Nucleus tractus solitarii respiratory neurons in the chemoreceptor pathway activated by almitrine.

In anaesthetized, paralysed and artificially ventilated dogs, activities were recorded from the phrenic nerve and from respiratory units within the nucleus tractus solitarii (NTS). The inspiratory neurons were classified according to their discharge pattern and their response to lung inflation. Two categories of cells with an augmenting discharge pattern were detected: the R alpha inspiratory neurons (18 units) inhibited by lung inflation and the R beta cells (10 units) activated by inflation. Prolonged stimulation of peripheral chemoreceptors by almitrine (50 micrograms/kg i.v.) induced an increase in the firing rate of R alpha and R beta inspiratory neurons. In addition almitrine stimulated R beta cells classified as expiratory-inspiratory units. Two expiratory neurons were found in the NTS and the firing rate of these cells was enhanced by almitrine. It is concluded that the NTS respiratory neurons are strongly involved in the chemoreceptor pathway activated by almitrine.

Almitrine↗
PubMed1989

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 anaesthetized cats with the use of the dynamic 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.

Almitrine↗
PubMed1982

The effects of almitrine on the ventilatory response to hypoxia and hypercapnia in normal subjects.

1. Almitrine at a dose of 0.5 mg h-1 kg-1 given intravenously over 2 h had no effect on resting ventilation in normal males. 2. There was a small, but insignificant, rise in the hypercapnic drive to breathe as compared with placebo. 3. A large rise in the hypoxic drive to breathe was seen in response to almitrine. 4. These findings support the claim that almitrine has its action on ventilation via the peripheral chemoreceptors. 5. No correlation between blood levels of almitrine and the rise in hypoxic response was seen.

Adult↗
PubMed1997

The effects of inhaled nitric oxide and its combination with intravenous almitrine on Pao2 during one-lung ventilation in patients undergoing thoracoscopic procedures.

UNLABELLED: The aim of this study was to assess whether hypoxemia during one-lung ventilation (OLV) can be prevented by inhaled nitric oxide (NO) (Part I) or by its combination with intravenous (IV) almitrine (Part II) in 40 patients undergoing thoracoscopic procedures. In Part I, 20 patients were divided into two groups: one received O2 (Group 1) and one received O2/NO (Group 2). In Part II, 20 patients were divided into two groups: one received O2 (Group 3) and one received O2/NO/almitrine (Group 4). In Groups 2 and 4, NO (20 ppm) was administered during the entire period of OLV, and almitrine was continuously infused (16 microg x kg(-1) x min[-1]) in Group 4. Arterial blood gases were measured during two-lung ventilation with patients in the supine position, after positioning in the lateral decubitus position, and then every 5 min for a 30-min period during OLV. During OLV, Pao2 values decreased similarly in Groups 1 and 2. After 30 min of OLV, the mean Pao2 values in Groups 1 and 2 were 132 +/- 14 mm Hg (mean +/- sem) and 149 +/- 27 mm Hg (not significant [NS]), and the Pao2 value was less than 100 mm Hg in four patients in Group 1 and five patients in Group 2. Pao2 values were greater in Group 4 than in Group 3 after 15 and 30 min of OLV. After 30 min of OLV, the mean Pao2 values were 146 +/- 16 mm Hg in Group 3 and 408 +/- 33 mm Hg in Group 4 (P < 0.001). Pao2 was less than 100 mm Hg during OLV (NS) in four patients in Group 3 and in no patient in Group 4. We conclude that NO inhalation alone has no effect on Pao2 evolution during OLV, although its combination with IV almitrine limits the decrease of Pao2 during OLV. This beneficial effect of NO/almitrine could be attributed to an improvement in ventilation-perfusion relationships. IMPLICATIONS: Decrease in oxygenation during one-lung ventilation is quite common. Our study showed that inhaled nitric oxide alone did not influence Pao2 evolution. We then tried adding intravenous almitrine to nitric oxide with amazingly good results on Pao2. This nonventilatory technique should be of great use during special thoracic acts, such as thoracoscopic procedures.

Adult↗
PubMed1989

Extensive oxidative metabolism of dextromethorphan in patients with almitrine neuropathy.

Almitrine bismesylate can induce a stereotypical sensory peripheral neuropathy probably through a toxic mechanism. High plasma concentrations of almitrine have been reported in a patient with neuropathy. Since large inter-individual variations in plasma drug concentrations are found it is possible that the development of toxicity may be linked to genetically determined polymorphic oxidation of the drug. Oxidation phenotyping was performed in fifteen patients with almitrine neuropathy using dextromethorphan, a test compound subject to oxidative metabolism similar to that of debrisoquine. All patients were of the extensive metaboliser phenotype. This result shows that, in contrast to perhexiline neuropathy, almitrine neuropathy is not related to slow oxidation of the compound with regard to the particular P-450 iso-enzyme involved in dextromethorphan and debrisoquine metabolism.

Aged↗
PubMed1996

Effect of arterial chemoreceptor stimulation with almitrine bismesylate on plasma renin activity, aldosterone, ACTH and cortisol in anaesthetized, artificially ventilated cats.

1. Changes in plasma renin activity (PRA) and in the plasma concentration of aldosterone, adrenocorticotrophic hormone (ACTH) and cortisol in response to an intravenous infusion of the chemoreceptor stimulant almitrine bismesylate (0.2 mg/kg) were studied in two groups of anaesthetized, paralysed and constantly ventilated cats. In one group, the peripheral arterial chemoreceptors remained innervated, whereas in the other they were denervated by bilateral cervical vagotomy and section of the carotid sinus nerves. 2. Animals with innervated chemoreceptors (n = 16) reacted to almitrine bismesylate with a significant (P <0.05) increase in both ACTH and cortisol. These responses were not present in cats in which the peripheral arterial chemoreceptors had been surgically denervated (n = 16). 3. Plasma renin activity and plasma aldosterone increased with time during experiments on both the chemoreceptor-intact and chemoreceptor-denervated cats. Almitrine did not affect the time course of the rise in PRA and plasma aldosterone in either group of animals. 4. These data indicate that, under the conditions of our experiments, almitrine induced arterial chemoreceptor reflex mechanisms stimulate ACTH and cortisol release, but has no chemoreceptor-dependent influence on PRA or plasma aldosterone.

Adrenocorticotropic Hormone↗
PubMed1992

Characteristics of augmented breaths provoked by almitrine bismesylate in cats.

The contribution of almitrine bismesylate to the occurrence and pattern of augmented breaths was studied in fifteen spontaneously breathing, anaesthetized cats. Breathing was via a tracheostomy, while the laryngeal resistance to airflow was measured with the larynx isolated in situ. Almitrine bismesylate at a dose of 0.5 mg kg-1 of body weight was injected intravenously in the intact animals and following bilateral vagotomy which spared the right recurrent laryngeal nerve. Almitrine injected intravenously elicited augmented breaths within the first 45 s in thirteen cats and within 1 min in the remaining two cats. During augmented breaths inspiratory and expiratory airflows rose, the mean increases being 385.2 and 159.6% respectively above the controls (P less than 0.01). The inspiratory laryngeal resistance declined to 77.7% of the control (P less than 0.01) and expiratory laryngeal resistance increased by 95.4% above the control level (P less than 0.01). The inspiratory and expiratory times were prolonged by 56 and 58% compared with baseline breathing. Following the augmented breaths the respiratory airflows exceeded baseline values, the respiratory timing was slightly reduced, and the inspiratory laryngeal resistance was significantly lowered below the control level (P less than 0.01). The expiratory laryngeal resistance showed the same trend without statistical significance. Bilateral vagotomy abolished the occurrence of augmented breaths following almitrine injection.

Airway Resistance↗
PubMed1987

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.

Almitrine↗
PubMed1989

Dopamine and ventilatory effects of hypoxia and almitrine in chronically hypoxic rats.

We hypothesized that the temporary blunted ventilatory response to hypoxia seen in chronically hypoxic rats could be related to the increased amount of dopamine found in their carotid bodies. Rats, kept 2-3 wk in 10% O2, showed reduced nonisocapnic ventilatory responses to 21-12% inspiratory O2 fraction compared with control rats. Stimulus-response curves to almitrine, which simulates the action of hypoxia on the carotid body, were also depressed in chronically hypoxic rats. Responses to hypoxia and almitrine were significantly correlated in the two groups of rats. Dopamine depressed ventilation during normoxia, hypoxia, and almitrine stimulation in both groups, an action abolished by the dopamine-2 antagonist domperidone. Domperidone slightly increased responses to hypoxia and almitrine in control rats but had a greater enhancing effect in chronically hypoxic rats, such that there was no longer a difference between the responses of the two groups.

Almitrine↗
PubMed1988

Curative effect of an almitrine-raubasine combination in the postischemic syndrome following transient cerebral ischemia in dogs.

Cerebral hemodynamic and metabolic changes, occurring during delayed hypoperfusion following transient cerebral ischemia, and the influence of treatment with almitrine plus raubasine were studied in mongrel dogs. 10 min of transient cerebral ischemia was induced by bilateral clamping of both carotid and vertebral arteries. After declamping, the mean time necessary until cerebral venous PO2 (cvPO2) reached a value of 3.6 kPa, threshold for tissue hypoxia, was 80 min. At this time (T0), venous cerebral blood flow (vCBF) and cerebral perfusion pressure (Perf P) were below (60 and 20%, respectively) preischemic values, while cerebral vascular resistance (CVR) and oxygen and glucose extraction rates increased despite a normal cerebral oxygen consumption (CMRO2). At T0 ventilatory assistance without (control group) or with (treated group) intravenous infusion of almitrine plus raubasine was applied for 110 min. Between T0 and T110 min, 2 dogs died in the control group. During this period vCBF decreased by more than 60% in the control group while it slightly increased in the treated group. A strong decrease in Perf P (40%) and increase in CVR (140%) was observed in the control group while in the treated group Perf P and CVR slightly decreased (14 and 35%, respectively). CMRO2 decreased by 60% in the control group but remained within the normal range in the treated group. The fact that cvPO2 remained constantly below the initial value of 3.6 kPa in the control group and, on contrary, above this value in the group infused with raubasine plus almitrine indicates that the vCBF improvement leads to an increase in oxygen supply and is involved in the keeping of the adequacy between flow and metabolism. Our results support the hypothesis that the post-ischemic syndrome may play an important role in the acute prognosis of stroke. They clearly indicate that early cerebral resuscitation by infusion of almitrine plus raubasine, maintaining oxygen availability and CBF above initial thresholds, should improve the long-term neurological outcome.

Almitrine↗
PubMed1992

Almitrine and doxapram in experimental lung injury.

Almitrine and doxapram, two structurally unrelated peripheral chemoreceptor agonists, have been shown to enhance hypoxic pulmonary vasoconstriction in anesthetized dogs. We hypothesized that these drugs would increase pulmonary vascular tone and improve gas exchange in canine lung injury caused by oleic acid (OA). Pulmonary hemodynamics and gas exchange were investigated in pentobarbital-anesthetized dogs before and after intravenously administered OA 0.09 ml/kg and again after placebo (n = 6), almitrine 2 micrograms/kg/min (n = 6), or doxapram 20 micrograms/kg/min (n = 6) in a randomized order. Cardiac output (Q) was manipulated using a femoral arteriovenous bypass and an inferior vena cava balloon catheter to construct mean pulmonary artery pressure (Ppa)-Q plots in order to discriminate active from passive changes in Ppa. Gas exchange was assessed by measuring arterial PO2 and intrapulmonary shunt, determined using a sulfur hexafluoride infusion. OA increased Ppa over the range of Q studied, and it deteriorated gas exchange by an increase in intrapulmonary shunt. After OA, placebo had no effect on Ppa, arterial PO2, or intrapulmonary shunt. Both almitrine and doxapram further increased Ppa at all levels of Q studied, but they did not affect indices of gas exchange after OA. We conclude that in this experimental model of acute lung injury, almitrine and doxapram induce pulmonary vasoconstriction without, however, diverting blood flow toward better oxygenated lung regions.

Almitrine↗
PubMed1983

Enhancement of hypoxic pulmonary vasoconstriction by almitrine in the dog.

In order to test the hypothesis of enhancement of hypoxic pulmonary vasoconstriction by Almitrine, 12 anesthetized and paralyzed dogs with normal lungs were studied under controlled ventilation. They were ventilated in random sequence with air, 12% O2, and 100% O2, and almitrine (0.1 mg/kg body weight) was infused over 30 min during each O2 mixture. The multiple inert gas elimination technique was used to detect alterations in ventilation-perfusion (VA/Q) mismatching before and during the interventions and to measure cardiac output (QT). Arterial, mixed venous and expired gases, inert gas concentrations, and hemodynamic measurements were made while the dogs were breathing the different O2 mixtures before infusing the drug, near the end of 30 min of infusion and 30 min after infusion had ended. There were no significant changes in pH, PaO2, PaCO2, QT, oxygen uptake, oxygen delivery index, systemic vascular resistance, mean systemic arterial pressure, heart rate, stroke volume index, or VA/Q distribution during the experiment. Significant increases in: (a) pulmonary artery pressure (PA), (b) the pressure difference between PA and pulmonary capillary wedge pressure (PCw), and (c) pulmonary vascular resistance (PVR) occurred when the drug was infused during 12% O2 and air, but not during 100% O2. The PVR increased 59.7% with almitrine infusion during 12% O2 and 38.4% during air breathing (p less than or equal to 0.01), but there was no significant change during 100% O2. Vascular responses were not dependent on the order in which the different O2 mixtures were administered. These data strongly suggest that almitrine enhances hypoxic vasoconstriction in the lung, and this effect may explain reported improvement in PaO2 in hypoxic patients given the drug.

Almitrine↗