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Respiration Physiology Nov 1988Almitrine bismesylate (Alm) has been shown to increase arterial oxygen tension in patients with chronic obstructive pulmonary disease. This effect is though to be...
Almitrine bismesylate (Alm) has been shown to increase arterial oxygen tension in patients with chronic obstructive pulmonary disease. This effect is though to be attributable to the enhancement of hypoxic pulmonary vasoconstriction (HPV). We evaluated the effect of various doses of Alm on HPV in terms of blood flow diversion associated with anoxic challenge to the left lower lobe (LLL) in dogs with the LLL and the rest of the lung separately ventilated. The stimulus-response curve shifted to the right with increasing rate of Alm infusion, suggesting that Alm enhances the reactivity of the pulmonary vessels to hypoxia. Low doses of Alm enhanced HPV, while higher doses attenuated it. This suggests that the degree of vasoconstriction in hypoxic and non-hypoxic regions depends on the dose of Alm. The same effects of Alm were also observed in peripheral chemoreceptor denervated dogs. It is supposed that the vasoconstriction induced by Alm may be attributable to a direct effect on pulmonary vessels rather than to a nervous reflex effect.
Topics: Almitrine; Animals; Blood Flow Velocity; Central Nervous System Stimulants; Chemoreceptor Cells; Denervation; Dogs; Dose-Response Relationship, Drug; Doxapram; Hypoxia; Male; Piperazines; Pulmonary Artery; Pulmonary Circulation; Ventilation-Perfusion Ratio
PubMed: 2906450
DOI: 10.1016/0034-5687(88)90100-4 -
Effects of almitrine bismesylate on the ionic currents of chemoreceptor cells from the carotid body.Molecular Pharmacology Feb 1998Almitrine 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...
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.
Topics: Almitrine; Animals; Calcium; Calcium Channels; Carotid Body; Cells, Cultured; Chemoreceptor Cells; Electric Conductivity; Ion Channel Gating; Membrane Potentials; Oxygen; Patch-Clamp Techniques; Potassium Channels; Rabbits; Rats
PubMed: 9463492
DOI: 10.1124/mol.53.2.330 -
Clinical Neuropharmacology 1990Cerebral ischemia occurs frequently and is disabling. In addition to preventing and correcting risks factors, drugs prevent cell death induced by ischemia-hypoxia.... (Review)
Review
Cerebral ischemia occurs frequently and is disabling. In addition to preventing and correcting risks factors, drugs prevent cell death induced by ischemia-hypoxia. Precise knowledge of the pathophysiology of cerebral ischemia is the prerequisite for drug development, and the main proofs of efficiency are histopathological and clinical (i.e., the results of controlled studies). Different animal models are considered valid for global, focal, or multifocal ischemia. These models have enabled the identification of deleterious phenomena that could be corrected or neutralized by drugs: hypoxia, lactic acidosis, release of neurotransmitters, influx of calcium, activation of phospholipase A2, release of excitatory amino acids, excess of free radicals, and neuronal cell metabolic paralysis (decrease of oxygen and glucose consumption). The chronology of these events clearly described herein will prompt the choice of the best drug, based on the delay between the ischemic event and the decision to treat. The main pharmacological effects required are the following: antagonism of hypoperfusion, oxygenation improvement, blockade of calcium influx and neurotransmitters action, reduction of acidosis and potassium efflux, blockade of arachidonic cascade and free radicals production, and antiedematous effect. The analysis of almitrine-raubasine (Duxil) pharmacological properties will be used as an example of these potentially anti-ischemic drugs. Almitrine-raubasine pharmacological studies indicate that this drug has several beneficial effects on cerebral ischemic processes. These studies have dealt with effects of hypobaric hypoxia on deoxyglucose uptake in the rat, protective effects on permanent or temporary cerebral ischemia-induced neurobehavioral problems in the gerbil, and preservation of the glycogen content and of the swelling in astrocytes after bilateral occlusion of the carotid arteries in the rabbit.
Topics: Almitrine; Animals; Brain Ischemia; Disease Models, Animal; Drug Combinations; Humans; Secologanin Tryptamine Alkaloids; Yohimbine
PubMed: 2093421
DOI: 10.1097/00002826-199013003-00002 -
British Journal of Pharmacology Jul 19921. Almitrine increases ventilation by stimulating the carotid body (CB) arterial chemoreceptors but neither its intraglomic target nor its mechanism of action have been...
1. Almitrine increases ventilation by stimulating the carotid body (CB) arterial chemoreceptors but neither its intraglomic target nor its mechanism of action have been elucidated. 2. We have tested the hypothesis that chemoreceptor cells are targets for almitrine by studying its effects on the release of 3H-catecholamines in an in vitro rabbit CB preparation. 3. It was found that almitrine (0.3 and 1.5 x 10(-6) M; i.e. 0.2 and 1 mg ml-1) increases the resting release of 3H-catecholamines from CBs (previously loaded with [3H]-tyrosine) incubated in a balanced 95% O2/5% CO2-equilibrated solution. 4. Almitrine at a concentration of 3 x 10(-6) M (2 mg l-1) also augmented the release of 3H-catecholamines elicited by incubating the CBs in a hypoxic solution (equilibrated with 7% O2/5% CO2 in N2), by high external K+ (35 mM) and by veratridine (2 x 10(-5) M), but did not modify release induced by dinitrophenol (7.5 x 10(-5) M). 5. At the same concentration (3 x 10(-6) M), almitrine increased the rate of dopamine synthesis and was ineffective in modifying the cyclic AMP levels in either normoxic or hypoxic CBs. 6. It is concluded that chemoreceptor cells are the intraglomic targets for almitrine. The mechanisms of action of almitrine on chemoreceptor cells are discussed.
Topics: Almitrine; Animals; Carotid Body; Catecholamines; In Vitro Techniques; Malates; Rabbits; Tritium
PubMed: 1504753
DOI: 10.1111/j.1476-5381.1992.tb14397.x -
Clinical Neuropharmacology 1990Two-hundred four patients between 70 and 85 years of age were included in a double-blind randomized controlled multicenter study (almitrine-raubasine/placebo). Inclusion... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Two-hundred four patients between 70 and 85 years of age were included in a double-blind randomized controlled multicenter study (almitrine-raubasine/placebo). Inclusion criteria were a complaint of cognitive disorders and an objective cognitive impairment evaluated by Folstein et al. "Mini-Mental State" (MMS) and by Sandoz Clinical Assessment for Geriatrics (SCAG). Patients were treated for 6 months and evaluations were performed at the beginning of the trial (T0), then 3 (T3) and 6 (T6) months later. Evaluations included a visual analogic self-rating scale and the following psychometric tests: Trail Making A (TMA), Shopping List Task, Word Fluency, Crossing Out Letters, Logical Memory, Digit Span, and Visual Retention. Anxiety and Depression Scales were also used to assess the effects of almitrine-raubasine on affective status. Statistical analysis involving the whole sample did not show any significant difference between the almitrine-raubasine and placebo groups concerning changes in assessment criteria from T0 to T6. However, these results may have been due to the wide heterogeneity of baseline performances in psychometric tests. To prevent this possible bias, further statistical analysis was performed for each psychometric test after patients had been divided into three classes according to baseline score levels. Considering scores on TMA and Digit Span for patients with scores in the intermediate class on TMA, almitrine-raubasine induced a significantly higher improvement in performance from T0 to T6 than that induced by placebo. On the other hand, no side effects were noted with almitrine-raubasine when compared with placebo. These data suggest that almitrine-raubasine enhances concentrated attention in patients with mild to moderate impairment of this function.
Topics: Aged; Aged, 80 and over; Almitrine; Anxiety; Cognition Disorders; Depression; Double-Blind Method; Drug Combinations; Female; Humans; Male; Memory; Psychological Tests; Secologanin Tryptamine Alkaloids; Yohimbine
PubMed: 2093414
DOI: 10.1097/00002826-199013003-00011 -
The European Respiratory Journal Jun 1991To test whether the effect of almitrine on hypoxic pulmonary vasoconstriction was dose-dependent, two series of experiments were performed on isolated rat lungs perfused...
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.
Topics: Almitrine; Animals; Dose-Response Relationship, Drug; Hypoxia; Lung; Male; Pulmonary Artery; Rats; Rats, Inbred Strains; Vasoconstriction
PubMed: 1889495
DOI: No ID Found -
The American Journal of Physiology Aug 1992The 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...
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).
Topics: Almitrine; Animals; Cyclooxygenase Inhibitors; Drug Interactions; Hypoxia; In Vitro Techniques; Male; Pressure; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Inbred Strains; Sodium Cyanide; Vasoconstriction
PubMed: 1510135
DOI: 10.1152/ajpheart.1992.263.2.H383 -
Nihon Naika Gakkai Zasshi. the Journal... Sep 1990
Topics: Acute Disease; Almitrine; Animals; Chronic Disease; Humans; Hyperbaric Oxygenation; Oxygen Inhalation Therapy; Respiratory Insufficiency; Tissue Plasminogen Activator
PubMed: 2124249
DOI: 10.2169/naika.79.1134 -
European Journal of Respiratory... 1983We have carried out sequential studies of respiration and sleep state, from two weeks to two years of age in a girl with congenital central hypoventilation. When awake...
We have carried out sequential studies of respiration and sleep state, from two weeks to two years of age in a girl with congenital central hypoventilation. When awake her minute ventilation (VE) and blood gases are normal, and when asleep she shows hypoventilation, with progressive hypoxia, hypercarbia and respiratory acidosis, most marked in NREM sleep. There has been no consistent change in VE (expressed as ml/kg/min) with age, awake or asleep, and she remains ventilator dependent when asleep. Growth and development are normal. We report a trial of almitrine bismesylate at the age of 21 months. A dose of 1.5 mg/kg/day orally for eight days produced minimal changes in VE, but when given 2.6 mg/kg/day for a further seven days there was a significant increase in VE in both NREM (27% increase) and in REM sleep (30% increase). These changes were accompanied by substantial improvements in blood gases, with PaCO2 less than 50 mmHg and PaO2 greater than 60 mmHg throughout a four hour study period asleep, off the ventilator, in air. After stopping almitrine bismesylate VE and blood gas values returned to pretreatment values. Almitrine bismesylate may be of value as an alternative to artificial ventilation in this condition.
Topics: Almitrine; Carbon Dioxide; Female; Humans; Hypoventilation; Infant, Newborn; Piperazines; Respiration
PubMed: 6426994
DOI: No ID Found -
Thorax Jan 1990The effect of oral treatment with the thiazine derivative almitrine bismesylate was studied in 28 patients with chronic obstructive pulmonary disease and arterial... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
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.
Topics: Almitrine; Carbon Dioxide; Double-Blind Method; Female; Half-Life; Humans; Male; Middle Aged; Oxygen; Oxygen Inhalation Therapy; Pulmonary Heart Disease; Randomized Controlled Trials as Topic
PubMed: 2108510
DOI: 10.1136/thx.45.1.16