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PubMed1981

The response of few-fiber carotid chemoreceptor preparations to almitrine in the dog.

Almitrine, a long-lasting peripheral chemoreceptor stimulant, was given to nine dogs via intracarotid injection. Carotid chemoreceptor activity was recorded from single or few-fiber afferent nerve preparations. Doses of 10-20 microgram/kg were generally sufficient to produce a brisk stimulatory response of less than 30 min duration. In four dogs decreasing arterial PO2 was found to allow a greater than additive response to almitrine. Infusions of NaHCO3 appeared to depress the response to almitrine whereas changing arterial PCO2 had little effect on the carotid chemoreceptor response to almitrine. Neither dopamine infusion nor dopamine receptor blockade altered the responsiveness of the carotid chemoreceptors to almitrine.

Almitrine↗
PubMed1988

Effects of almitrine on respiration in unanesthetized newborn rabbits.

We previously demonstrated that almitrine, a peripheral chemoreceptor stimulant, increased tidal volume (VT), expired minute ventilation (VE), and respiratory frequency (f) and decreased inspiratory (TI) and expiratory time (TE) in sleeping adult cats. We now hypothesized that almitrine would induce an increase in ventilation in a young animal model. Respiration was studied by the barometric method in 11 unanesthetized New Zealand White rabbit pups between 3 and 6 days of age. Recordings were made in 0.21 FIO2 at base line and after cumulative intraperitoneal infusions of almitrine (2.5, 5.0, and 7.5 mg/kg). The chamber pressure deflection (proportional to VT after appropriate calculation) was computer sampled at 200 Hz. At least 100 breaths for each dose in each animal were analyzed. We found that a 7.5-mg/kg intraperitoneal dose of almitrine increased f to 135 +/- 9% (SE) of base line and decreased TE and TI to 72 +/- 8% and 79 +/- 8% of base line, respectively. Changes in VE, VT/TI, and VT were not significant. Recognizing that apnea is associated with inadequate ventilation and a prolonged TE (failure of the "inspiratory on-switch"), these results, particularly the increase in f and decrease in TE, suggest that almitrine might be useful in treating apnea in preterm infants.

Almitrine↗
PubMed1998

Pharmacological features of an almitrine-raubasine combination. Activity at cerebral levels.

Treatment with the combination of almitrine-raubasine increases both arterial oxygen partial pressure and haemoglobin oxygen saturation, reflecting an actual increase in the oxygen content of arterial blood. Furthermore, at the trans-cerebral carotid artery/internal jugular vein level, the treatment increases cerebral arterio-venous oxygen and glucose differences, suggesting an actual increase both in oxygen and glucose availability and uptake in cerebral tissues. The increased glucose transfer to the brain is supported also by enhancement of the 3H-deoxyglucose uptake induced by drug pre-treatment both in normoxia and hypoxia. Both almitrine and raubasine act at cerebral mitochondrial levels by decreasing the 'loss' of the 'biological' free energy for phosphorylation supported by the age-related drop in the cerebral enzyme activities, such as phosphofructokinase, pyruvate dehydrogenase and citrate synthase. Furthermore, the components interfere with the alterations induced by peroxidative stress acting at the level of cytochrome c, cytochrome c oxidase and succinate dehydrogenase. Treatment with the combination almitrine-raubasine increases the concentration of noradrenaline metabolites, while alteration of the dopaminergic system is less important. The interference with the noradrenergic system is possibly linked to the electroencephalographic changes induced by drug treatment: increasing alpha-rhythm distribution and reactivity, and increases in beta-rhythm amplitude. Pharmacological effects of almitrine-raubasine, obtained in experimental conditions, correlate with clinical therapeutic efficacy, e.g., in the treatment of cognitive disorders associated with ageing and other cerebral and neurosensory impairments. It is difficult to summarise, in a few pages, the large number of papers related to the cerebral pharmacometabolic and pharmacodynamic activities of the almitrine-raubasine combination. Thus, this review presents in sequential steps some of the interrelated research in humans and laboratory animals which describes in a critical way preclinical to clinical results.

Almitrine↗
PubMed1989

Enhancement of hypoxic pulmonary vasoconstriction by low dose almitrine bismesylate in normal humans.

The effect of almitrine bismesylate on hypoxic pulmonary vasoconstriction (HPV) remains controversial. We therefore investigated in a double-blind, placebo-controlled, randomized design the effects of low dose of almitrine bismesylate (4 micrograms/kg/min given intravenously) on blood gases, pulmonary hemodynamics, and ventilation-perfusion (VA/Q) distributions in normal subjects breathing a hypoxic mixture (FIO2, 0.125), room air (FIO2, 0.21), and oxygen (FIO2, 1.0) in a random sequence. In the placebo group (7 subjects), no change was recorded. In the almitrine group (10 subjects), arterial PO2 improved during hypoxia (from 42 +/- 2 to 47 +/- 1 mm Hg, p less than 0.05, mean +/- SEM) and normoxia (from 99 +/- 3 to 104 +/- 2, p less than 0.05). Pulmonary arterial mean pressure and pulmonary vascular resistance index increased with almitrine during hypoxia, respectively, from 20 +/- 1 to 23 +/- 1 mm Hg (p less than 0.01) and from 207 +/- 22 to 283 +/- 35 dyne.s.cm-5.m2 (p less than 0.01), and during normoxia, respectively, from 12 +/- 1 to 14 +/- 1 mm Hg (p less than 0.05) and from 90 +/- 11 to 137 +/- 13 dyne.s.cm-5.m2 (p less than 0.05). The VA/Q distribution improved during hypoxia, with a shift of the blood flow distribution to better oxygenated lung units with higher VA/Q ratios. We conclude that in normal humans low dose of almitrine improves gas exchange by an enhancement of HPV.

Adult↗
PubMed1986

Ventilatory effects of almitrine bismesylate in congenital central hypoventilation syndrome.

Patients with congenital central hypoventilation syndrome (CCHS) lack hypercapnic and hypoxic stimulation of ventilation but have demonstrated carotid body function in response to hyperoxia and to pharmacological stimulation with doxapram. This study investigated the ventilatory effects of almitrine bismesylate, a carotid body stimulant, in 12 patients with CCHS. Measurements of minute ventilation, tidal volume (VT), respiratory rate (RR) and transcutaneous PO2 (TCPO2) were taken before and after administration of 4.5 mg/kg and 6 mg/kg of almitrine. Twenty-four hour pharmacokinetic studies were performed in 7 patients who received 4.5 mg/kg and in 6 patients who received 6 mg/kg almitrine. There was no significant improvement in ventilatory and gas exchange parameters at either dose of almitrine despite appropriate peak serum concentration of the drug at the time of the studies. These results suggest that almitrine is not a useful ventilatory stimulant in children with CCHS.

Almitrine↗
PubMed1987

Respiratory stimulants and sleep periodic breathing at high altitude. Almitrine versus acetazolamide.

We studied the effects of almitrine, acetazolamide, and placebo on the hypoxic ventilatory response (HVR), sleep periodic breathing, and arterial oxygen saturation (SaO2) in 4 healthy climbers. In a laboratory on Denali (Mt. McKinley) at 4,400 m (PB = 440 mm Hg), we used a double-blind, randomized, three-way crossover design. The HVR was measured during the waking state. Periodic breathing and SAO2% were measured during 3-h sleep studies. Almitrine and acetazolamide both increased SaO2% during sleep, although almitrine increased periodic breathing, whereas acetazolamide decreased periodic breathing. The HVR (delta VE/delta SaO2%) was doubled with almitrine (p less than 0.05), but unchanged with acetazolamide. The HVR was positively related to periodic breathing (p less than 0.05). We conclude that periodic breathing during sleep at high altitude is related to the hypoxic ventilatory response, and that acetazolamide is a superior agent to almitrine for ameliorating periodic breathing.

Acetazolamide↗
PubMed1999

Effects of the respiratory stimulant almitrine on breathing and FOS expression in the brain of fetal and newborn sheep.

Almitrine is a piperazine derivative known to stimulate breathing in the adult but cause apnea in fetal sheep. In fetal sheep (127-133 d gestation; term = 147 d) we confirmed this finding, but found that almitrine (4 mg/kg, i.v. or intra-arterial) had a biphasic effect, briefly stimulating and then suppressing breathing movements for at least 3 h. In 2- to 3-d-old (n = 4) and 7- to 14-d-old (n = 4) lambs almitrine increased both tidal volume and breath frequency, increased arterial partial pressure of oxygen and pH, and decreased partial pressure of carbon dioxide. The changes of tidal volume, partial pressure of oxygen and partial pressure of carbon dioxide were less in the 2- to 3-d-old compared with the 7- to 14-d-old lambs. The distribution of the nuclear phosphoprotein FOS, a marker of neuronal activation was examined in fetal and newborn brains. FOS protein was increased in cardiorespiratory areas of the medulla and pons, in the periaqueductal region of the midbrain, and in the supraoptic and paraventricular regions of the hypothalamus. In the pons, FOS protein was increased in the medial parabrachial and subcoeruleus nuclei in the fetuses but not in the 2- to 3- or 7- to 14-d-old lambs. These observations are similar to those reported for hypoxia, and consistent with the hypothesis that both almitrine and hypoxia inhibit fetal breathing movements by an action on a select group of pontine neurons. Whether these neurons respond directly to these stimuli or receive input from the other centers is yet to be elucidated. The mechanisms that change the almitrine (and hypoxia) response from inhibition to excitation at birth have not been identified, but may be important in preventing apnea in the newborn.

Almitrine↗
PubMed1987

Almitrine in acute respiratory failure. Effects on pulmonary gas exchange and circulation.

The effects of almitrine administration on pulmonary gas exchange and pulmonary and systemic hemodynamics were assessed in eight patients with severe acute respiratory failure (ARF) secondary to sepsis or shock. A control group of five patients not receiving the drug were submitted to the same protocol. All the patients were sedated, paralyzed, and mechanically ventilated. Measurements were made before (BASELINE), during (ALM 15), at the end of (ALM 30), and at 30 minute intervals after (POSTALM 30, 60, 90, 120) the intravenous (IV) infusion of 0.5 mg/kg body weight of almitrine in 30 minutes. Almitrine produced an increase in PaO2 from 86 +/- 14 (BASELINE) to 129 +/- 69 (ALM 15) and 129 +/- 86 mm Hg (ALM 30). The PaO2 quickly declined after stopping the infusion. The P(A-a)O2 and QVA/QT decreased with almitrine administration. The Ppa and QT increased transiently at ALM 30. We conclude that IV almitrine improves gas exchange and may be useful in the management of ARF.

Aged↗
PubMed1990

Hormonal and renal responses to arterial chemoreceptor stimulation by almitrine in healthy and normotensive men.

Healthy and normotensive men (n = 11) were hospitalized and kept under controlled fluid and sodium intake (120 mequ/d) for 5 days. Their systemic arterial blood pressures as well as heart and breathing rates were measured, and venous blood and urine samples were collected at intervals of 1-4 h. Diuresis was induced by scheduled drinking of tea (150 ml/h). Electrolytes, osmolality, and creatinine were determined in both plasma and urine samples. Aldosterone, cortisol, and vasopressin concentrations were measured only in the plasma. On the 2nd and 3rd day of the experiments the participants received orally either a placebo-pill or 100 mg almitrine bismesylate (Vectarion). Each subject was tested in a placebo- and an almitrine experiment. The subjects responded to the almitrine treatment with a suppression of the plasma aldosterone content, a transient rise of glomerular filtration rate, a natriuresis and an increase of renal concentrating ability. In the placebo-experiments, only the transient rise of filtration rate was significant. The data indicate that almitrine, by stimulating the peripheral arterial chemoreceptors, suppresses plasma aldosterone and inhibits renal proximal sodium reabsorption by so far unknown mechanisms. They also suggest that oral and intravenous almitrine administrations, respectively, might differently affect renal hemodynamics and excretory function.

Adult↗
PubMed1985

Pharmacodynamic and pharmacokinetic interactions of almitrine bismesylate.

Repeated administration of almitrine bismesylate, 50 mg b.i.d., to six healthy volunteers for 14 days did not alter any of the kinetic parameters of antipyrine, a test compound which measures the hydroxylating capacity of hepatic drug metabolising enzymes. Similarly, almitrine has no effect on the absorption, distribution or elimination of either erythromycin or digoxin, thus, it is unlikely that drug-kinetic interactions are likely to be important in clinical practice. Arterial oxygen tension (PaO2) is significantly increased (p less than 0.05) in 34 chronic bronchitic patients administrated almitrine bismesylate, 50 mg b.i.d. for 3 months. This improvement in hypoxia (9%) is negatively related to the initial PaO2 (p less than 0.01) and positively related to almitrine plasma concentrations (p less than 0.05). Thus, for each 100 ng X ml-1 increase in drug levels, there is an approximate 2 mmHg increase in PaO2, but there is a suggestion that levels greater than 800 ng X ml-1 may reduce or inhibit activity. The results suggest that the hypoxic state of the individual may modulate the activity of almitrine and influence the drug levels, but further work is required to substantiate these preliminary findings.

Almitrine↗
PubMed1985

[Sleep and nocturnal desaturation of patients with chronic obstructive bronchopneumopathies. Effects of almitrine bismesylate administered orally].

In order to verify the effect of almitrine bismesylate on episodes of nocturnal oxygen desaturation, 10 patients suffering from chronic obstructive pulmonary disease had polygraphic EEG night sleep recordings with simultaneous measurement of O2 saturation. The subjects presented during nocturnal sleep a quantity of desaturation of at least 2,400 sec. X p. cent (this quantity being represented by the surface of the SaO2 curve under the desaturation level defined as the waking SaO2 less 4 p. cent) and had been included in a matched experimental protocol, double blind, almitrine bismesylate versus placebo. After administration of either placebo or almitrine bismesylate for 14 days (100 mg per day in two doses) a control night sleep recording was performed. The effect of treatment was assessed using an analysis of variance for 2 or 3 factors, completed by a Student t test in case of significant interaction between the factors. It appears that almitrine bismesylate produces: a non significant decrease in total sleep, slow wave sleep and REM sleep time; a significantly earlier awakening (p less than 0.05); a significant reduction of the total duration of desaturation episodes (p less than 0.05) without any correlation with the variations of total sleep time; a non significant decrease in the quantity of desaturation; a significant increase in PaO2 (p less than 0.001) and in SaO2 (p less than 0.01) measured two hours after the awakening. However there was no evidence of any significant change in mean SaO2 and lowest SaO2 during the night. Finally the variability of the effect of almitrine bismesylate during day or night time remains unexplained.

Administration, Oral↗
PubMed1987

[Psychometric evaluation of the effects of an almitrine-raubasine combination in the intellectual deterioration of aged subjects. A double-blind controlled trial versus placebo].

The clinical and psychometric evaluation of a drug to be used against the intellectual deterioration associated with cerebral aging is of obvious interest when carried out on ambulatory subjects, since the symptoms likely to be reduced are found in elderly people usually living at home. Thirty-six patients (18 male, 18 female; mean age 65.5 +/- 1.7 years) were selected and allocated at random to two treatment groups. They received during 2 months 80 drops per day in two doses of either an almitrine-raubasine combination or a placebo. Patients definitely entered the trial when Hachinski's score for ischaemia was equal or inferior to 7. They were evaluated at zero, 1 and 2 months by means of 3 performance tests (Toulouse-Pieron test, Tapping test, numbers memorization test) and 2 mood tests (Hamilton's scale, Zung's questionnaire). All mean scores of recognition tests were statistically improved in the almitrine-raubasine group after 2 months of treatment. Compared with the placebo group, the improvement in the almitrine-raubasine group was significant at 1 month for 3 medium scores (symbols omitted, taping, numbers in normal order) and for all scores at 2 months. The psycho-behavioural symptoms evaluated by the two mood scores were significantly improved in the almitrine-raubasine group (P less than 0.001) and in comparison to the placebo group after 1 and 2 months (P less than 0.001). These results concerning intellectual performance and mood demonstrate that the almitrine-raubasine combination is useful in the treatment of intellectual deterioration in elderly people living at home.

Aged↗
PubMed1988

A one year double blind follow-up of blood gas tensions and haemodynamics in almitrine bismesylate therapy.

Almitrine bismesylate, a chemoreceptor agonist, improves blood gases in chronic obstructive lung disease (COLD). Some authors have observed an increase in pulmonary artery pressure (Ppa) after single doses of almitrine bismesylate (A). This led to the present one year double blind placebo (P) controlled study to assess haemodynamic effects of long-term oral treatment in COLD (1.5 mg/kg/day for one year), together with clinical benefit and blood gas improvement. Twenty moderately severe patients entered the study, fifteen of whom completed it (eight in group (A), seven in group (P]. Blood gas values, minute ventilation (VE), mean pulmonary artery pressure (Ppa) and cardiac output (Qc) were periodically measured. Ppa and Qc remained unchanged in both groups throughout the study. We observed relevant clinical improvement without side effects and no significant increase in VE in group (A). Arterial oxygen tension (PaO2) showed a 1.2 kPa (9 mmHg) mean increase in group (A) and remained unchanged in group (P). These data and those from the literature seem to indicate that almitrine induces a vascular effect, especially after a single dose. However, as long as PaO2 improves simultaneously no long-term haemodynamic consequence is apparent. The discrepancy between immediate and long-term vascular effects of almitrine might be explained by the improvement in gas exchange which could reduce and/or counter-balance the vasoactive response. In conclusion, after one year of therapy almitrine bismesylate results in considerable clinical and blood gas improvements without significant haemodynamic change.

Aged↗
PubMedDate not supplied

Almitrine has no effect on gas exchange after bilateral carotid body resection in severe chronic airflow obstruction.

Using a double-blind cross-over design, a single dose of 100 mg almitrine bismesylate and placebo were administered orally to eight patients with chronic airflow obstruction having undergone bilateral carotid body resection (BCBR) up to two years earlier to alleviate their extreme dyspnoea. In an open study, two other patients have been given almitrine before and three weeks after BCBR. In all patients, arterial blood gases, ventilation and breathing patterns, neuromuscular drive and hypoxic responsiveness have been studied before and three hours after drug administration. Almitrine failed to improve gas exchange in the patients with BCBR, nor did it affect ventilation, ventilatory or hypoxic drive. In the patients studied before and after BCBR, almitrine only improved gas exchange significantly before BCBR. It is concluded that in man almitrine acts solely as a peripheral chemoreceptor agonist and that the well-documented improvement in V/Q relationship is mediated through carotid body stimulation.

Adult↗
PubMed1979

[Effect of almitrine on arterial gases in patients with chronic respiratory insufficiency. Comparison with doxapram. Preliminary results].

We compared the effects of almitrine and doxapram on the arterial blood gases and ventilation of patients with chronic respiratory insufficiency and chronic hypercapnia and hypoxemia. Sixteen long-term in-patients were randomly allocated to one of the following treatment groups: the first group (8 patients) received IV almitrine 0.5 mg/kg and the second group (8 patients) IV doxapram 1 mg/kg by IV perfusion during 30 min. All gave their informed consent. Arterial blood gases and ventilation were measured 10 min and 5 min before treatment, at the 5th, 15th and 25th min of perfusion time, and 5, 10 and 15 min after infusion. There was a marked increase in paO2 in almitrine-treated patients, which was maximum at the 25th min of infusion (+ 14.6 mm Hg, p < 0.001), but only a slight improvement was observed in the doxapram group (+ 3.3 mm Hg, p < 0.05). After almitrine the maximum mean paCO2 decrease was at the 10th min after perfusion (-6.9 mm Hg, p < 0.001); after doxapram the maximum decrease, although highly significant, was much less (-2.8 mm Hg, p < 0.01). Thus, at the presently used and well-tolerated doses, almitrine is much more efficient than doxapram in improving gas exchange in patients with chronic hypoxemia and hypercapnia. However, complementary studies using higher dosage of doxapram are warranted.

Aged↗
PubMed1984

[The almitrine dimesylate molecule. Various structure-activity relationship aspects].

The improvement in PaO2 induced by almitrine bismesylate is due to better adjustment between alveolar ventilation and lung perfusion (VA/Q ratio). Experimental studies and clinical pharmacology suggest that this improvement involves changes in both alveolar ventilation and pulmonary circulation. By synthesizing and testing compounds with different structures in a series of trisubstituted triazines, it has been possible to determine qualitative structure-activity relationships and to select almitrine bismesylate is due to better adjustment between the greatest, most rapid and longest lasting increase in PaO2. Almitrine bismesylate is a molecule with three components: a di-allylamino-triazine group, a piperazine ring and a bis-parafluoro-benzhydryl fraction. The di-allylamino-triazine group may be regarded as responsible for the effects on blood gases and ventilation. The presence of two allyl-amino substituents is an absolute prerequisite, and the triazine ring can possibly be replaced by a very similar pyrimidine ring. The piperazine ring is mainly responsible for dissociation between the effects on blood gases and on ventilation as well as for the general kinetics of the biological action of the drug. Molecules of this series which have a pyrrolidine ring or an azetidine ring instead of a piperazine ring do increase PaO2 but much more slowly than almitrine bismesilate. Finally, the bis-parafluoro-benzhydryl group modulates the intensity and duration of the effects on blood gases. Other constituents, such as the cinnamylamino, alpha-cyclohexyl-parafluorobenzyl, beta-naphthyl methyl or 5-fluoro-benzofluranyl-methyl groups also exert favourable biological activities comparable to those of the bis-parafluorobenzhydryl group characteristic of almitrine bismesylate.

Almitrine↗
PubMed1984

[Influence of almitrine dimesylate on gas exchange. Preliminary results in patients with chronic obstructive bronchopneumopathies under artificial ventilation].

From a study conducted in 1981 in patients with chronic obstructive pulmonary disease breathing spontaneously, it was concluded that almitrine ensured a more even distribution of ventilation-perfusion ratios in the lung. Another study has recently been undertaken to suppress the effects of stimulated ventilation observed and to measure more accurately the pulmonary vascular effect of this new drug. This was a randomized double-blind drug versus placebo trial using the same doses of almitrine (1.5 mg/kg orally) in patients of the same type under stable artificial respiration controlled by repeated measurements of ventilation during the weaning period at the end of an episode of acute respiratory failure. The preliminary results obtained in one-half of the patients (4 under almitrine, 4 under placebo) are reported. There was little difference in haemodynamic values between the two groups. Improvement in PaO2 was maximum 90 min after almitrine was administered and varied from 0.7 to 1.4 kPa; there was no modification in the control group. In the absence of any change in ventilation and respiratory rate, perfusion was reduced in lung areas with low ventilation-perfusion ratio. These partial results seem to confirm that almitrine exerts a moderate, though real, effect on pulmonary vessels.

Almitrine↗
PubMed1983

Pattern of breathing and gas exchange following oral almitrine bismesylate in patients with chronic obstructive pulmonary disease.

Almitrine bismesylate (100 mg orally) significantly raised PaO2 and lowered PaCO2 in six patients with chronic obstructive pulmonary disease, compared to placebo, when they were breathing air or 28% oxygen. The estimated ideal alveolar arterial PO2 difference (AaDO2) was less after almitrine bismesylate compared to placebo, when patients were breathing either air or 28% oxygen. After almitrine bismesylate overall ventilation breathing air increased by 10% but this did not reach statistical significance. During 28% oxygen breathing, almitrine bismesylate hardly altered overall ventilation but the inspiratory duty cycle (TI/TTOT) decreased and mean inspiratory flow rate (VT/TI) increased compared to placebo. These changes were significant on a paired T test (P less than 0.05). The improvement in AaDO2 correlated with the rise in VT/TI (r = 0.67, P = 0.02) and thus we suggest that changes in both volume and pattern of breathing might explain the improved gas exchange in the lung after almitrine bismesylate .

Administration, Oral↗